Journal articles: 'Lymphocyte precursors, chronic inflammation, autoimmune diseases'

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Martin Calderon, L., and J. Pope. "AB0721 From Undifferentiated Connective Tissue Disease to Identifiable Disease: Precursors of Systemic Sclerosis and Systemic Lupus Erythematosus." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1487.3–1488. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4241.

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BackgroundThe pathogenesis of systemic lupus erythematosus and systemic sclerosis is characterized by derangements of the innate and adaptive immune systems, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. Diagnosis is rooted in meeting established criteria. However, in pre-clinical states criteria is not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, presents a prognostic opportunity, and could enable timely treatment leading to limiting disease progression.ObjectivesWe aim to describe the role of the innate and adaptive immune system in the pre-clinical states of UCTD-risk-SSc and prescleroderma, the underlying immune dysregulation in these pre-clinical states, and the evolution of antibodies from nonspecific antinuclear antibodies to specific prior to SLE development.MethodsOur search strategy was developed alongside an experienced information specialist. We searched the databases EMBASE and MEDLINE with restrictions for the English language. Reference lists of all primary studies and review articles were searched for additional references. Studies reported in full-text and abstract formats were included.ResultsMultiple cytokines are observed to increase along a disease spectrum from UCTD-risk-SSc to classified SSc and include sICAM-1, CCL2, CXCL8, ang-2, CXCL16, e-selectin, and IL-13. The mechanism of action of these cytokines includes transmigration of lymphocytes endothelium, innate immune cell activation and signal propagation, and extracellular matrix deposition. The progressive nature of cytokine increase through a spectrum from pre-clinical to clinical emphasizes disease evolution and enables the discernment of patients who may warrant early intervention. Furthermore, there are disease markers which are observed to be predictive of established SSc and include sIL-2Rα, PIIINP, CXCL4, CXCL10, and CXCL11. Pre-clinical SLE is characterized by an evolving IFN signature and progressive SLE-specific antibody formation prior to disease classification.ConclusionThe coordinated dysregulation of the innate and adaptive immune systems, and inflammatory signalling pathways leads to the pathogenesis of connective tissue disease. Our improved understanding of these underlying aberrations in pre-clinical stages of disease will serve to better identify patients at increased risk.References[1]Valentini G, Pope JE. Undifferentiated connective tissue disease at risk for systemic sclerosis: Which patients might be labeled prescleroderma? Autoimmunity reviews. 2020 Nov;19(11):102659.[2]Lambers WM, Westra J, Bootsma H, de Leeuw K. From incomplete to complete systemic lupus erythematosus; A review of the predictive serological immune markers. Seminars in arthritis and rheumatism. 2021;51(1):43–8.Disclosure of InterestsNone declared

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Sesti-Costa, Renata, Carolina Lanaro, Dulcinéia Martins de Albuquerque, Sara T. Olalla Saad, and Fernando Ferreira Costa. "Sickle Cell Disease Patients Have Altered Number and Function of Dendritic Cells." Blood 134, Supplement_1 (November 13, 2019): 3569. http://dx.doi.org/10.1182/blood-2019-129854.

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Dendritic cells (DCs) are the sentinels of the immune system able to recognize pathogen- and damage-associated molecular patterns (PAMPs and DAMPs), promoting a bridge between the innate and adaptive immune systems. They form a heterogeneous group of cells with different development, phenotype and functions, and they are mainly classified in conventional DCs 1 (cDC1) and 2 (cDC2), plasmacytoid DCs (pDC) and inflammatory DCs. Changes in the development of DCs, in the ratio of the subsets or in the maturation and activation can impair immunity or tolerance, inducing susceptibility to infections, as well as the development of inflammatory and autoimmune diseases. Sickle cell disease (SCD), one of the most common hemoglobinophaties throughout the world, can be considered as a chronic inflammatory disease, with systemic release of TNF-α, IL-6, IL-1β and IL-8. Despite presenting more inflammation, SCD patients have dysfunction of lymphocytes T and B responses, and are more susceptible to infections. Although DCs are the main responsible for the activation and polarization of lymphocytes function and are able to produce the pro-inflammatory cytokines present in the serum of SCD patients, very little attention has been giving to these cells so far. In the present study, we characterized the subpopulations of circulating DCs in SCD patients. Our data of flow cytometry show that SCD patients (SS) have higher percentage (AA: 0.6±0.09, n=20; SS: 1.25±0.2 n=22; p<0.05) and total number/μl (AA: 10.92±1.9, n=17; SS: 27.9±5.2, n=22; p=0.01) of circulating DCs than healthy individuals (AA) as shown by gating on linage- (CD19/CD56/CD3/CD14) and HLA-DR+ cells. The development of these cells from the bone marrow is likely to be, at least in part, responsible for this raise, since the percentage (AA: 1.7±0.45, n=17; SS: 10.85±1.53, n=11; p=0.0001) and total number/μl (AA: 0.25±0.05, n=12; SS 1.52±0.31, n=16; p=0.0004) of the DCs precursors are increased in the blood of the patients. The ratio of the different subpopulations of DCs is also altered, with a decrease in the percentage of circulating cDC1 (linage-HLA-DR+CD141high) (AA: 2.6±0.2, n=16; SS: 2.0±0.3, n=18; p=0.02), whereas no change was seen on cDC2 (linage-HLA-DR+CD1c+) and pDCs (linage-HLA-DR+CD123+) (AA: n=18; SS: n=22). Isolated circulating monocytes from patients are able to differentiate in vitro in DCs with the expression of the characteristic markers CD1c and CD209, however, unlike healthy individuals, a great percentage of these cells also express CD14 (AA: 5.5±2.2, n=16; SS: 17.6±6.1, n=14; p=0.02), indicating the presence of inflammatory DCs. These cells are more mature and activated in steady state as shown by CD83 (p=0.007), CD86 (p=0.0001) and HLA-DR (p<0.0001) expression (n=14 pairs of CD14- and CD14+ DCs). Since SCD patients have higher number of circulating monocytes as shown by previous studies, it is possible that part of the raise in circulating DCs comes from the differentiation of inflammatory monocytes in vivo. Monocyte-derived DCs (mo-DCs) from patients are able to induce more proliferation of CD4+ and CD8+ T lymphocytes than mo-DCs from healthy individuals (AA: n=4; SS: n=4), and CD14+ DCs induce higher proliferation of T lymphocytes than CD14- DCs from the same patient (n=2 pairs of CD14- and CD14+ DCs). We have also seen that SCD patients have reduced percentage of regulatory T cells, as shown by Foxp3+ in the gate of CD3+CD4+ cells (AA: 4.0±0.26, n=17; SS: 3.1±0.3, n=17; p=0.01), and increased IL-17-producing CD4+ (AA: 1.1±0.08, n=18; SS: 1.7±0.18, n=17; p=0.05) and CD8+ (AA: 0.24±0.02; SS: 0.68±0.1, n=17; p=0.0001) T lymphocytes in the blood. Whether DCs are responsible for this skewing of T lymphocyte phenotype in SCD is still to be determined. Our data so far show that there are differences in circulating DC populations in SCD patients and they could explain the changes observed on T cell responses and the susceptibility to infections. The present data add new knowledge about the chronic inflammation in SCD, which is one of the major events in the pathophysiology of the disease. Disclosures No relevant conflicts of interest to declare.

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Weinberg, J. Brice, David J. DiLillo, Yohei Iwata, Takashi Matushita, Karen M. Matta, Guglielmo M. Venturi, Giandomenico Russo, et al. "Chronic Lymphocytic Leukemia Shares a Common Cellular Origin with Regulatory B10 Cells." Blood 118, no. 21 (November 18, 2011): 286. http://dx.doi.org/10.1182/blood.v118.21.286.286.

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Abstract Abstract 286 Background: The cell of origin of CLL is unknown. Researchers have proposed various B cell subsets as the normal counterparts based on surface marker similarities or Ig gene utilization comparisons of normal and CLL cells. Regulatory B lymphocytes (“B10” cells), with the capacity to produce IL-10, negatively regulate T cell, B cell, and mononuclear phagocyte function. CLL patients are immunosuppressed with abnormalities in both humoral and cellular immunity. B10 cells have a phenotype similar to CLL cells (CD24hiCD27+CD5+CD19+). B10 cells are increased in autoimmune mice and in humans with autoimmune diseases—situations in which these cells negatively regulate immune-mediated inflammation. Since CLL cells and B10 cells may share common phenotypes and immunosuppressive mechanisms, we sought to determine if mouse and human CLL cells share common cellular origins and regulatory properties. Methods: Mouse spleen, lymph node, and bone marrow cell, and human blood B lymphocyte and CLL cell preparation and culture; IL-10, TNF, IGHV determinations; and flow cytometry were done as we have reported before (Blood 109:1559, 2007; Blood 117:530–541, 2010; Immunity 28:639–650, 2008). After culture for 5 hours with LPS and PMA+ionomycin+brefeldin A (PIB), or CpG+PIB, we assessed for intracellular IL-10 by flow cytometry. We term these IL-10 producing cells “B10” cells. Alternately, cells were cultured 48 hours with CD40 ligand+LPS or CD40L+CpG, and then PIB was added during the last 5 hours, after which cells were assessed for intracellular IL-10. We term these IL-10 positive cells “B10+B10pro” cells. Results: We examined CLL cells from 54 CLL patients. Most had low-risk disease: 90% were either Rai stage 0 or stage 1, 89% were CD38 negative, 46% were Zap70 negative, and 70% had a mutated IGHV. Twenty percent had normal cytogenetics, 48% del13q, 20% trisomy 12, 4% del17p, 4% del11q, and 4% with complex abnormalites. Patients with CLL as compared to healthy controls had higher numbers of B10pro cells compared to those of normal controls (7.7±0.9% and 3.2±0.3%, respectively; p<0.0001). CLL cells had a CD24hiCD27+ memory B cell phenotype similar to normal human B10 cells, and CLL cells secreted IL-10 when treated in vitro with CpG or CD40L/CpG, as do normal human B10 cells. CLL cell TCL-1 protein levels (immunoblot) correlated directly with CLL B10pro percentages (p=0.001) and absolute numbers (p=0.01). CLL patients' plasma IL-10 levels were 1.5 fold higher than those of age-matched healthy controls (p=0.008), and these levels correlated directly with the absolute numbers of CLL cells that were competent to produce IL-10 after 48 hours stimulation with CD40L/CpG. To validate the precursor/product relationship between B10 cells and CLL, we studied the TCL-1 transgenic mouse model of CLL. TCL-1 transgenic mice had an age-dependent expansion of splenic CD5+B220int cells, and these leukemic cells were IL-10-competent. Likewise, aged TCL-1 mice had increased numbers of B10 cells in the bone marrow, lymph nodes, and peritoneal cavity. The TCL-1 CLL cells were similar in phenotype (IgM+CD11BhiCD23lowCD43hiCD19+) to mouse regulatory B10 cells (CD1dhiIgMhiIgDlowCD19hiCD23lowCD24hiCD43±) that we have previously reported. TCL-1 CLL cells produced IL-10 in vitro and in vivo, and depressed mouse macrophage TNF production. This TCL-1 CLL cell-mediated inhibition of mouse TNF production was blocked by anti-IL-10 antibody. Plasma IL-10 increased with age and with development of overt leukemia in TCL-1 mice. Summary: We demonstrate for the first time that human CLL cells and CLL-like cells from TCL-1 mice share a common origin with regulatory B10 and B10pro cells. Both CLL cells and B10 cells can produce the immuno-inhibitory cytokine IL-10 in vitro and in vivo, and they can suppress mononuclear phagocyte activation in vitro through IL-10-dependent pathways. The immunophenotype of CLL cells matches that of human B10, and B10pro cells. It is likely that IL-10 competent CLL cells derive directly from either regulatory B10pro or B10 cells. B10 cell-derived IL-10 may contribute to the immunosuppression noted in mice and humans with CLL. Future studies may lead to new and better treatments that take advantage of links between B10 cells, IL-10, and CLL. Disclosures: Lanasa: GlaxoSmithKline: Consultancy, Speakers Bureau. Tedder:Angelica: Consultancy, Share holder; Takeda Therapeutics: Consultancy.

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Gray, Kathryn J., and Julie E. Gibbs. "Adaptive immunity, chronic inflammation and the clock." Seminars in Immunopathology 44, no. 2 (March 2022): 209–24. http://dx.doi.org/10.1007/s00281-022-00919-7.

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Abstract The adaptive arm of the immune system facilitates recognition of specific foreign pathogens and, via the action of T and B lymphocytes, induces a fine-tuned response to target the pathogen and develop immunological memory. The functionality of the adaptive immune system exhibits daily 24-h variation both in homeostatic processes (such as lymphocyte trafficking and development of T lymphocyte subsets) and in responses to challenge. Here, we discuss how the circadian clock exerts influence over the function of the adaptive immune system, considering the roles of cell intrinsic clockwork machinery and cell extrinsic rhythmic signals. Inappropriate or misguided actions of the adaptive immune system can lead to development of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and multiple sclerosis. Growing evidence indicates that disturbance of the circadian clock has negative impact on development and progression of these chronic inflammatory diseases and we examine current understanding of clock-immune interactions in the setting of these inflammatory conditions. A greater appreciation of circadian control of adaptive immunity will facilitate further understanding of mechanisms driving daily variation in disease states and drive improvements in the diagnosis and treatment of chronic inflammatory diseases.

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Conti, Pio, Luisa Stellin, Alesssandro Caraffa, Carla E. Gallenga, Rhiannon Ross, Spyros K. Kritas, Ilias Frydas, Ali Younes, Paolo Di Emidio, and Gianpaolo Ronconi. "Advances in Mast Cell Activation by IL-1 and IL-33 in Sjögren’s Syndrome: Promising Inhibitory Effect of IL-37." International Journal of Molecular Sciences 21, no. 12 (June 16, 2020): 4297. http://dx.doi.org/10.3390/ijms21124297.

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Sjögren’s syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4+ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role.

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Tomczyńska, Małgorzata, and Joanna Saluk-Bijak. "The mutual cooperation of blood platelets and lymphocytes in the development of autoimmune thyroid diseases." Acta Biochimica Polonica 65, no. 1 (May 27, 2018): 17–24. http://dx.doi.org/10.18388/abp.2017_2321.

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Autoimmune thyroid diseases include several distinct clinical entities and mainly concern Graves` disease and Hashimoto's thyroiditis. An incompetent immune response directed against the body’s own tissues and the production of antibodies against specific cell antigens, accompanied by chronic inflammation occur in autoimmune thyroid diseases. The autoimmune process is induced by difficult to identify genetic and environmental factors, and generates the development of concomitant diseases of other systems. The inflammatory mediators, high level of thyroid hormones, lymphocyte activation and other immune cells play an important role in the chronic course of these diseases. Autoimmune thyroid diseases are caused by disruptions of T-cells and other cells functions. The autoantibodies react with target antigens in different kinds of cells, including blood platelets. The autoimmune processes can cause the increased activity different kinds of cells including blood platelets and lymphocytes. The activity of blood platelets and lymphocytes is reciprocally regulated. It is suggested that blood platelets can influence lymphocyte function by direct contact through the receptors and via soluble mediators. The platelet–immune cell interactions represent a hallmark of immunity, as they can potently enhance immune cell functions.

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Wongkar, Martini, Handoko Lowis, Sarah M. Warouw, Julius Lolombulan, and Stefanus Gunawan. "Blood count to determine chronic inflammation severity in obese adolescents." Paediatrica Indonesiana 60, no. 1 (January 28, 2020): 6–12. http://dx.doi.org/10.14238/pi60.1.2020.6-12.

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Background Obesity is a growing public health problem of rapidly increasing prevalence in developing countries. Chronic low-grade inflammation plays a key role in the pathophysiology of obesity. Blood count values and ratios have been used as markers of inflammatory diseases. These parameters may be useful to determine the severity of chronic inflammation in obese children. Objective To determine if red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), platelet distribution width (PDW), and platelet-to-lymphocyte ratio (PLR) can be useful for determining the severity of chronic inflammation in obese children. Methods This observational, analytic study was conducted in obese adolescents aged 14-18 years at senior high schools in Manado, North Sulawesi, from July to September 2018. Students with congenital anomalies, autoimmune diseases, history of asthma, or malignancy were excluded. Pearson’s correlation was used to analyze for potential relationships between obesity and red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), platelet distribution width (PDW), and platelet-to-lymphocyte ratio (PLR). Results There was a negative relationship between obesity and MPV, but it was not statistically significant (r=-0.006; P=0.485). There were positive, but not significant relationships between obesity and RDW (r=0.139; P=0.192), NLR (r=0.155; P=0.166), PDW (r=0.02; P=0.45), and PLR (r=0.146; P=0.181). Conclusion The RDW, NLR, MPV, PDW, and PLR values are not significantly associated with severity of obesity in adolescents.

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Hwang, Il-Young, Chung Park, Kathleen Harrison, and John H. Kehrl. "TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones." Journal of Experimental Medicine 206, no. 12 (November 16, 2009): 2641–57. http://dx.doi.org/10.1084/jem.20091982.

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B lymphocyte–intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of preexisting germinal centers even when transferred with antigen-specific B cells. The TLR4-activated cells persist much better than nonstimulated cells, expanding both within the memory and plasma cell compartments. TLR-mediated activation of B cells may help to feed and stabilize the spontaneous and ectopic germinal centers that are so commonly found in autoimmune individuals and that accompany chronic inflammation.

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Contaldo, Maria, Mariarosaria Boccellino, Giuseppa Zannini, Antonio Romano, Antonella Sciarra, Alessandra Sacco, Giuliana Settembre, et al. "Sex Hormones and Inflammation Role in Oral Cancer Progression: A Molecular and Biological Point of View." Journal of Oncology 2020 (June 27, 2020): 1–14. http://dx.doi.org/10.1155/2020/9587971.

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Oral cancers have been proven to arise from precursors lesions and to be related to risk behaviour such as alcohol consumption and smoke. However, the present paper focuses on the role of chronic inflammation, related to chronical oral infections and/or altered immune responses occurring during dysimmune and autoimmune diseases, in the oral cancerogenesis. Particularly, oral candidiasis and periodontal diseases introduce a vicious circle of nonhealing and perpetuation of the inflammatory processes, thus leading toward cancer occurrence via local and systemic inflammatory modulators and via genetic and epigenetic factors.

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Petryk, Nataliia, and Oleksandr Shevchenko. "CORRELATION BETWEEN THE LYMPHOCYTE-MONOCYTE RATIO AND CYTOKINES IN CHRONIC INFLAMMATION IN RATS TREATED WITH ALLOGENEIC MESENCHYMAL STEM CELLS." Inter Collegas 7, no. 3 (October 24, 2020): 109–17. http://dx.doi.org/10.35339/ic.7.3.109-117.

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The chronic inflammatory process is a pathological condition characterized by an ongoing active inflammatory response and tissue destruction. Many studies show that chronic inflammation can play a severe role in various age-related diseases, including diabetes, cardiovascular, and autoimmune diseases. One of the important but poorly studied factors affecting the regulation of chronic inflammation is the regulatory activity of MSCs. In this regard, the study of mesenchymal stem cells preventing chronic inflammation in the experiment is an important area of modern pathology. On the one hand, increased cytokines, such as α-TNF, IL 6, and CRP, are reliable tools in diagnostic different inflammatory processes, especially chronic inflammation. On the other hand, nowadays, we need a more straightforward and not so expensive criterion for this purpose, for instance, a common total blood count and LMR. For the first time, we investigated how trustworthy can be LMR and how possible to use it in chronic inflammation in rats to achieve prognostic goals. This study investigated the correlation between α-TNF, IL-6, and CRP with LMR in rats' plasma in groups with chronic carrageenan inflammation and chronic inflammation with local injection of MSCs into the affected area. The study involved 132 adult male rats (180-220g), which were divided into groups. The inflammation model was chronic aseptic myositis caused by an intramuscular injection of 10mg λ-carrageenan (Sigma-Aldrich GmbH). Our experimental groups of rats were treated with MSCs (the injection into the inflamed site) in the amount of 1-2 million cells once. Blood sampling was performed from 6 hours to 28 days. We calculated our results using Statistica (data analysis software) version 13. For comparison, we used one-way ANOVA, Turkey's post hoc test, where p <0.05 was considered statistically significant. In our experiment, the correlation between levels of α-TNF, IL-6, and CRP with lymphocyte-monocyte ratio in rats was described for the first time, demonstrating the suppression of chronic inflammation through MSCs.

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Petryk, Nataliia, and Oleksandr Shevchenko. "CORRELATION BETWEEN THE LYMPHOCYTE-MONOCYTE RATIO AND CYTOKINES IN CHRONIC INFLAMMATION IN RATS TREATED WITH ALLOGENEIC MESENCHYMAL STEM CELLS." Inter Collegas 7, no. 3 (October 24, 2020): 109–17. http://dx.doi.org/10.35339/ic.7.3.109-117.

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The chronic inflammatory process is a pathological condition characterized by an ongoing active inflammatory response and tissue destruction. Many studies show that chronic inflammation can play a severe role in various age-related diseases, including diabetes, cardiovascular, and autoimmune diseases. One of the important but poorly studied factors affecting the regulation of chronic inflammation is the regulatory activity of MSCs. In this regard, the study of mesenchymal stem cells preventing chronic inflammation in the experiment is an important area of modern pathology. On the one hand, increased cytokines, such as α-TNF, IL 6, and CRP, are reliable tools in diagnostic different inflammatory processes, especially chronic inflammation. On the other hand, nowadays, we need a more straightforward and not so expensive criterion for this purpose, for instance, a common total blood count and LMR. For the first time, we investigated how trustworthy can be LMR and how possible to use it in chronic inflammation in rats to achieve prognostic goals. This study investigated the correlation between α-TNF, IL-6, and CRP with LMR in rats' plasma in groups with chronic carrageenan inflammation and chronic inflammation with local injection of MSCs into the affected area. The study involved 132 adult male rats (180-220g), which were divided into groups. The inflammation model was chronic aseptic myositis caused by an intramuscular injection of 10mg λ-carrageenan (Sigma-Aldrich GmbH). Our experimental groups of rats were treated with MSCs (the injection into the inflamed site) in the amount of 1-2 million cells once. Blood sampling was performed from 6 hours to 28 days. We calculated our results using Statistica (data analysis software) version 13. For comparison, we used one-way ANOVA, Turkey's post hoc test, where p <0.05 was considered statistically significant. In our experiment, the correlation between levels of α-TNF, IL-6, and CRP with lymphocyte-monocyte ratio in rats was described for the first time, demonstrating the suppression of chronic inflammation through MSCs.

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Tobón, Gabriel J., Jorge H. Izquierdo, and Carlos A. Cañas. "B Lymphocytes: Development, Tolerance, and Their Role in Autoimmunity—Focus on Systemic Lupus Erythematosus." Autoimmune Diseases 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/827254.

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B lymphocytes are the effectors of humoral immunity, providing defense against pathogens through different functions including antibody production. B cells constitute approximately 15% of peripheral blood leukocytes and arise from hemopoietic stem cells in the bone marrow. It is here that their antigen receptors (surface immunoglobulin) are assembled. In the context of autoimmune diseases defined by B and/or T cell autoreactive that upon activation lead to chronic tissue inflammation and often irreversible structural and functional damage, B lymphocytes play an essential role by not only producing autoantibodies but also functioning as antigen-presenting cells (APC) and as a source of cytokines. In this paper, we describe B lymphocyte functions in autoimmunity and autoimmune diseases with a special focus on their abnormalities in systemic lupus erythematosus.

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Moysidou, Eleni, Georgios Lioulios, Aliki Xochelli, Vasiliki Nikolaidou, Michalis Christodoulou, Zoi Mitsoglou, Stamatia Stai, Asimina Fylaktou, Aikaterini Papagianni, and Maria Stangou. "Different Types of Chronic Inflammation Engender Distinctive Immunosenescent Profiles in Affected Patients." International Journal of Molecular Sciences 23, no. 23 (November 24, 2022): 14688. http://dx.doi.org/10.3390/ijms232314688.

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Immunosenescence encompasses a spectrum of lymphocyte phenotypic alterations. The aim of the study was to evaluate immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosous (SLE), a systemic autoimmune disease, and End-Stage Kidney Disease (ESKD), a chronic inflammatory disorder. Certain lymphocyte surface molecules, including CD31, CD45RA, CCR7, CD28, CD57, for T, and IgD, CD27 for B lymphocytes, were analyzed by flow cytometry in 30 SLE and 53 ESKD patients on hemodialysis (HD), and results were compared to 31 healthy controls (HC) of similar age, gender, and nationality. Significant Lymphopenia was evident in both SLE and ESKD-HD patients, compared to HC, affecting B cells 75.4 (14.4–520.8), 97 (32–341), and 214 (84–576) cells/μL, respectively, p < 0.0001, and CD4 cells 651.2 (71.1–1478.2), 713 (234–1509), and 986 (344–1591) cells/μL, respectively, p < 0.0001. The allocation of B cell subpopulations was remarkably different between SLE and ESKD-HD patients. SLE showed a clear shift to senescence (CD19IgD-CD27−) cells, compared to ESKD-HD and HC, 11.75 (10)% vs. 8 (6) vs. 8.1 (10), respectively. Regarding T lymphocytes, Central Memory CD8 cells predominated in both SLE and ESKD-HD patients compared to HC, 53 (50)%, 52 (63), and 24 (64)%, respectively, while ESKD-HD but not SLE patients also had increased expression of CD4CD28− and CD8CD28− cells. In conclusion, both diseases are followed by significant lymphopenia; however, the senescent phenomenon affects the B lymphocyte compartment in SLE patients and T lymphocytes in ESKD-HD patients.

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Kazama, Itsuro. "Roles of Lymphocyte Kv1.3-Channels in the Pathogenesis of Renal Diseases and Novel Therapeutic Implications of Targeting the Channels." Mediators of Inflammation 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/436572.

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Delayed rectifier K+-channels (Kv1.3) are predominantly expressed in T lymphocytes. Based on patch-clamp studies, the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models,in vivostudies then revealed the clinically relevant relationship between the channel expression and the pathogenesis of autoimmune diseases. In renal diseases, in which “chronic inflammation” or “the overstimulation of cellular immunity” is responsible for the pathogenesis, the overexpression of Kv1.3-channels in lymphocytes promotes their cellular proliferation and thus contributes to the progression of tubulointerstitial fibrosis. We recently demonstrated that benidipine, a potent dihydropyridine calcium channel blocker, which also strongly and persistently inhibits the lymphocyte Kv1.3-channel currents, suppressed the proliferation of kidney lymphocytes and actually ameliorated the progression of renal fibrosis. Based on the recentin vitroevidence that revealed the pharmacological properties of the channels, the most recent studies have revealed novel therapeutic implications of targeting the lymphocyte Kv1.3-channels for the treatment of renal diseases.

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Hasiakos, S., Y. Gwack, M. Kang, and I. Nishimura. "Calcium Signaling in T Cells and Chronic Inflammatory Disorders of the Oral Cavity." Journal of Dental Research 100, no. 7 (February 4, 2021): 693–99. http://dx.doi.org/10.1177/0022034521990652.

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Acute immune responses to microbial insults in the oral cavity often progress to chronic inflammatory diseases such as periodontitis and apical periodontitis. Chronic oral inflammation causes destruction of the periodontium, potentially leading to loss of the dentition. Previous investigations have demonstrated that the composition of oral immune cells, rather than the overall extent of cellular infiltration, determines the pathological development of chronic inflammation. The role of T lymphocyte populations, including Th1, Th2, Th17, and Treg cells, has been extensively described. Studies now propose pathogenic Th17 cells as a distinct subset, uniquely classifiable from traditional Th17 populations. In situ differentiation of pathogenic Th17 cells has been verified as a source of destructive inflammation, which critically drives pathogenesis in chronic inflammatory diseases such as diabetes, rheumatoid arthritis, and inflammatory bowel disease. Pathogenic Th17 cells resemble a Th1 penotype and produce not only interleukin 17 (IL-17) but also γ-interferon (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The proinflammatory cytokine-specific mechanisms known to induce IL-17 expression in Th17 cells are well characterized; however, differentiation mechanisms that lead to pathogenic Th17 cells are less understood. Recently, Ca2+ signaling through Ca2+ release-activated Ca2+ channels (CRAC) in T cells has been uncovered as a major signaling axis involved in the regulation of T-cell-mediated chronic inflammation. In particular, pathogenic Th17 cell–mediated immunological diseases appear to be effectively targeted via such Ca2+ signaling pathways. Pathogenic plasticity of Th17 cells has been extensively illustrated in autoimmune and chronic inflammatory diseases. Although their specific causal relationship to oral infection-induced chronic inflammatory diseases is not fully established, pathogenic Th17 cells may be involved in the underlining mechanism. This review highlights the current understanding of T-cell phenotype regulation, calcium signaling pathways in this event, and the potential role of pathogenic Th17 cells in chronic inflammatory disorders of the oral cavity.

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Velozo, Leosvaldo S. M., Thiago Martino, Mariana V. Vigliano, Fabiana A. Pinto, Girlaine P. Silva, Maria da Graça A. Justo, Kátia C. C. Sabino, and Marsen G. P. Coelho. "Pterodon polygalaeflorusEssential Oil Modulates Acute Inflammation and B and T Lymphocyte Activation." American Journal of Chinese Medicine 41, no. 03 (January 2013): 545–63. http://dx.doi.org/10.1142/s0192415x13500390.

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The increased life expectancy of the population has led to increasing incidences of cancer, chronic inflammatory and autoimmune diseases. Thus the continuous search for new drugs is necessary because ineffectiveness and adverse effects have been described for standard drugs. Essential oils are important sources of bioactive metabolites and several clinical trials have been developed using them. The Pterodon genus has been used in traditional medicine to treat rheumatic disorders, thus this work investigated the properties of essential oil from Pterodon polygalaeflorus fruits (EsOPpg) on acute inflammation and lymphocyte activation. The essential oil was obtained by hydrodistillation and its components were identified by GC/MS. The anti-inflammatory response was assessed using the air pouch model. Antinociceptive potential was evaluated using the writhing model. Lymphocyte phenotyping, cell cycle and apoptosis were analyzed by flow cytometry. EsOPpg promoted a reduction in leukocyte counts and protein concentration in the exudate, and reduced vasodilatation and inflammatory cell infiltrate in air pouch tissue. No antinociceptive effect was demonstrated for the doses tested. EsOPpg inhibited lymphocyte proliferation, arresting the cell cycle in G1phase, and induced apoptosis in these cells. EsOPpg downregulated both the total number of CD8+T cells and the activated subpopulation (CD8+CD69+), while promoting upregulation of the total number of CD19+and CD19+CD69+B cells. In conclusion, Pterodon polygalaeflorus essential oil diminished the acute inflammatory response and inhibited lymphocyte proliferation, reducing neutrophil recruitment into the cavity and air pouch tissue and promoting distinct modulations of the activation level of each lymphocyte subpopulation.

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Domerecka, Weronika, Anna Kowalska-Kępczyńska, Iwona Homa-Mlak, Agata Michalak, Radosław Mlak, Marcin Mazurek, Halina Cichoż-Lach, and Teresa Małecka-Massalska. "The Usefulness of Extended Inflammation Parameters and Systemic Inflammatory Response Markers in the Diagnostics of Autoimmune Hepatitis." Cells 11, no. 16 (August 17, 2022): 2554. http://dx.doi.org/10.3390/cells11162554.

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(1) Introduction: Autoimmune hepatitis (AIH) is a chronic disease. A persistent autoimmune reaction in the liver is significantly related to the systemic inflammatory response. Extended Inflammation Parameters (EIP) can be used to assess the activation of immune cells such as activated neutrophils (NEUT-RI and NEUT-GI) and activated lymphocytes (RE-LYMP and AS-LYMP) in the phase of active inflammation. The role of the systemic inflammatory response markers should also be emphasised, especially: NLR, PLR, and RLR, which have recently been widely studied as markers in autoimmune skin diseases or liver diseases. (2) Materials and Methods: The study included 30 patients with AIH and 30 healthy volunteers. The parameters of the EIP group (RE-LYMP, AS-LYMP, NEUT-RI, NEUT-GI), calculated haematological indices Red Blood Cell Distribution Width-to-Platelet Ratio (RPR), Mean Platelet Volume-to-Platelet Ratio (MPR), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Red Blood Cell Distribution Width-to-Lymphocyte Ratio (RLR), and selected blood morphological and biochemical indices were analysed. The aim of the study was to assess the usefulness of the EIP and systemic inflammatory response markers in the diagnostics of AIH. (3) Results: Compared to the controls, the patients with AIH showed significantly higher EIP values: NEUT-RI (48.05 vs. 43.30), NEUT-GI (152.65 vs. 147.40), RE-LYMP (0.07 vs. 0.03), and the inflammatory response markers: MPR (0.05 vs. 0.04), RPR (0.07 vs. 0.05), and NLR (2.81 vs. 1.42. Among the examined markers, EIP has significant diagnostic potential: NEUT-RI (AUC = 0.86), NEUT-GI (AUC = 0.80), and RE-LYMP (AUC = 0.78), and so do calculated haematological indices, i.e., MPR (AUC = 0.75), PLR (AUC = 1.00), and RLR (AUC = 1.00) Moreover, the importance of NEUT-GI (AUC = 0.89), MPR (AUC = 0.93), PLR (AUC = 0.86), RPR (AUC = 0.91), and FIB-4 (AUC = 0.83) in the detection of liver fibrosis in the course of AIH has also been proven. (4) Conclusions: EIP and systemic inflammatory response markers may turn out to be useful in detecting AIH and in looking for features of already developed liver cirrhosis in its course.

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Mititelu, Radu Răzvan, Rodica Pădureanu, Manuela Băcănoiu, Vlad Pădureanu, Anca Oana Docea, Daniela Calina, Andreea Lili Barbulescu, and Ana Maria Buga. "Inflammatory and Oxidative Stress Markers—Mirror Tools in Rheumatoid Arthritis." Biomedicines 8, no. 5 (May 15, 2020): 125. http://dx.doi.org/10.3390/biomedicines8050125.

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Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease, associated with significant morbidity, mainly due to progressive damage and consequent disability. Oxidative stress is an important part of RA pathophysiology, as in autoimmune disease the interaction between immune response and endogenous/exogenous antigens subsequently induce the production of reactive oxygen species. The oxidative stress process seems to be positively strongly correlated with inflammation and accelerated joint destruction. We were asking ourselves if the oxidative stress biomarkers are the mirror tools of disease activity, outcome, and inflammation level in a group of RA patients under standard or biological therapy compared to healthy age-matched controls. In order to do this, the oxidative stress damage biomarkers (lipids peroxide and protein carbonyl level), antioxidant defense capacity, and pro-inflammatory status of plasma were quantified. In this study, we took into account the complete picture of RA diseases and assessed, for the first time, the inflammatory level in correlation with the oxidative stress level and antioxidant capacity of RA patients. Our results revealed that protein oxidation through carbonylation is significantly increased in RA groups compared to controls, and both protein carbonyl Pcarb and thiobarbituric acid reactive substance (TBARS) are reliable markers of ROS damage. Therefore, it is unanimous that neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PltLR) correlated with Pcarb, and TBARS can provide a view of the complex phenomenon represented by proteins/lipids damage, key contributors to disease outcome, and an increased awareness should be attributed to these biomarkers.

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Gokce, Aksanur, Tulay Omma, Mustafa Çelikc, and Işılay Taşkaldıran. "An overview of the hematological picture with antithyroid therapy in Graves' disease." Acta Facultatis Medicae Naissensis 39, no. 4 (2022): 467–75. http://dx.doi.org/10.5937/afmnai39-36192.

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Aim: Graves' disease is an autoimmune thyroid disease that is the most common cause of hyperthyroidism. Peripheral blood cell parameters such as neutrophils, lymphocytes, and platelets play a role in inflammation control. Several studies have proven that neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio are indicators of chronic subclinical inflammation in various diseases. In our study, we aimed to review the peripheral blood picture by evaluating these parameters before and after antithyroid treatment in patients with Graves' disease. Patients and methods: A total of 120 patients (93 female, 27 male) between the ages of 18-65 were included. Demographic data, hemogram and biochemical data of the patients were recorded retrospectively at the time of diagnosis and after euthyroidism was achieved with medical treatment. Results: During the treatment, there was an increase in hemoglobin, lymphocytes, neutrophils and red cell distribution width, while a decrease in monocytes was observed. There was no significant difference between white blood cell, platelet and mean platelet volume. In addition, while there was no statistically significant difference between neutrophil-lymphocyte ratio (p = 0.8) and thrombocyt-lymphocyte ratio (p = 0.078) after euthyroid state, a statistically significant difference was found in favor of a decrease in monocyte-lymphocyte ratio (p = 0.006). Conclusion: Changes in hematopoiesis are relatively common in patients with newly diagnosed Graves' disease, and initiation of antithyroid therapy leads to improvement in these parameters. Although neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio are accepted as new, non-invasive markers in clinical evaluation, in our study only a significant decrease in monocyte-lymphocyte ratio levels was observed after euthyroidism was achieved with antithyroid treatment.

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Darrigues, Julie, Joost P. M. van Meerwijk, and Paola Romagnoli. "Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review." Gerontology 64, no. 1 (July 14, 2017): 28–35. http://dx.doi.org/10.1159/000478044.

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The generation and function of immuno-suppressive regulatory T lymphocytes (Treg), which can differentiate in the thymus (tTreg) or in the periphery (pTreg), are regulated in an age-dependent manner. tTreg are produced at high levels in the first weeks of age, when they expand and colonize secondary lymphoid organs and peripheral tissues to protect the organism from autoimmune diseases and to promote tissue repair. Once this population of Treg is operational in the periphery, at puberty, thymic output of Treg declines, but self-reactive tTreg generated early on in life are maintained over time and play a major role in preserving homeostasis of the immune system. Extra-thymic pTreg differentiation declines later on in life. pTreg generated throughout life mainly protect the organism from chronic inflammation and the semi-allogeneic fetus from rejection. In this review, age-dependent modulation of the production and function of these two populations of Treg is described.

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Striz, Ilja. "Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations." Clinical Science 131, no. 17 (August 10, 2017): 2241–56. http://dx.doi.org/10.1042/cs20170098.

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Interleukin 1 (IL-1) family is a group of cytokines with multiple local and systemic effects, which regulates both innate and adaptive immune responses. Generally, most IL-1 family cytokines express prevailing pro-inflammatory activities (IL-1α, IL-1β, IL-18, IL-33, IL-36 α, β, γ), whereas others are anti-inflammatory (IL-1Ra (IL-1 receptor antagonist), IL-36Ra, IL-38, IL-37). In addition to their immunomodulatory roles, some of them are also involved in the physiological modulation of homeostatic processes and directly affect mRNA transcription. IL-1 family cytokines bind to specific receptors composed of a ligand-binding chain and an accessory chain. The pro-inflammatory effects of IL-1 family cytokines are regulated on the level of transcription, enzymatic processing of precursors, release of soluble antagonists, and expression of decoy receptors. Members of the IL-1 family regulate the recruitment and activation of effector cells involved in innate and adaptive immunity, but they are also involved in the pathogenesis of chronic disorders, including inflammatory bowel disease, rheumatoid arthritis, and various autoimmune and autoinflammatory diseases. There are only limited data regarding the role of IL-1 cytokines in transplantation. In recent years, targeted therapeutics affecting IL-1 have been used in multiple clinical studies. In addition to the recombinant IL-1Ra, anakinra (highly effective in autoinflammatory diseases and tested for other chronic diseases), the monoclonal antibodies canakinumab, gevokizumab, and rilonacept (a long-acting IL-1 receptor fusion protein) provide further options to block IL-1 activity. Furthermore, new inhibitors of IL-18 (GSK 1070806, ABT-325, rIL-18BP (IL-18 binding protein)) and IL-33 (CNTO-7160) are presently under clinical studies and other molecules are being developed to target IL-1 family cytokines.

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Chung, Chi-Li, Kam-Wing Leung, Wan-Jung Lu, Ting-Lin Yen, Chia-Fu He, Joen-Rong Sheu, Kuan-Hung Lin, and Li-Ming Lien. "Hinokitiol Negatively Regulates Immune Responses through Cell Cycle Arrest in Concanavalin A-Activated Lymphocytes." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/595824.

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Autoimmune diseases are a group of chronic inflammatory diseases that arise from inappropriate inflammatory responses. Hinokitiol, isolated from the wood ofChamaecyparis taiwanensis, engages in multiple biological activities. Although hinokitiol has been reported to inhibit inflammation, its immunological regulation in lymphocytes remains incomplete. Thus, we determined the effects of hinokitiol on concanavalin A- (ConA-) stimulated T lymphocytes from the spleens of mice. In the present study, the MTT assay revealed that hinokitiol (1–5 μM) alone did not affect cell viability of lymphocytes, but at the concentration of 5μM it could reduce ConA-stimulated T lymphocyte proliferation. Moreover, propidium iodide (PI) staining revealed that hinokitiol arrested cell cycle of T lymphocytes at the G0/G1 phase. Hinokitiol also reduced interferon gamma (IFN-γ) secretion from ConA-activated T lymphocytes, as detected by an ELISA assay. In addition, hinokitiol also downregulated cyclin D3, E2F1, and Cdk4 expression and upregulated p21 expression. These results revealed that hinokitiol may regulate immune responses. In conclusion, we for the first time demonstrated that hinokitiol upregulates p21 expression and attenuates IFN-γsecretion in ConA-stimulated T lymphocytes, thereby arresting cell cycle at the G0/G1 phase. In addition, our findings also indicated that hinokitiol may provide benefits to treating patients with autoimmune diseases.

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Liao, Yi-Chu, and Chi-Chang K. Shieh. "NOX2-deficient neutrophils facilitate joint inflammation in serum-induced arthritis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 219.5. http://dx.doi.org/10.4049/jimmunol.204.supp.219.5.

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Abstract Immune-mediated inflammatory arthritis, including rheumatoid arthritis (RA), is a family of chronic inflammatory diseases of joints. NADPH oxidases 2 (NOX2) complex in phagocytes generates high concentrations of ROS to kill the engulfed microbes. Inherited mutations in the subunits of NOX2 result in chronic granulomatous disease (CGD). Subjects with defective NOX2 are susceptible to recurrent infections and a variety of autoimmune conditions. According to our previous studies, NOX2-deficient mice developed more severe immune-mediated arthritis, but depletion of neutrophils suppressed the development of serum-induced arthritis in these mice. Based on the hypothesis that NOX2-deficient neutrophils play a pro-inflammatory role in immune-mediated arthritis, we investigated the activity of neutrophil from joints to facilitate inflammation. We found that there are more neutrophils accumulations in NOX2-deficient joints, compared to WT joints. Both NOX2-deficient /WT neutrophils affected the anti-CD3 and anti-CD28 induced T lymphocyte proliferation, however, NOX2-deficient neutrophils were less suppressive. Moreover, NETs formation and high level of citrullinated histone H3 were detected in joints of NOX2-deficient mice at day 3 of arthritis induction. Furthermore, neutrophils from RA joints were found to suppress the T cell proliferation. Finally, carbonylated protein and total GSH level were lower in synovial fluid of RA patients when compared with those in osteoarthritis joints. Our results implicate that neutrophils may be an important cellular factor that lead to more severe arthritis in the NOX2-deficient subjects.

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Cetin, Yasin, Nafiye Fulya Ilhan, Deniz Sen, and Sevim Karakas Celik. "The investigation of BTLA single-nucleotide polymorphisms in patients with Behcet disease in Elazıg province." Turkish Journal of Biochemistry 45, no. 3 (February 11, 2020): 323–27. http://dx.doi.org/10.1515/tjb-2019-0221.

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AbstractObjectiveBehcet Disease (BD) is a systemic chronic autoinflammatory disorder that significantly increases mortality and morbidity. Although B- and T-lymphocyte attenuator (BTLA) is important in regulating lymphocyte activation during inflammation and infection, it is unclear whether any polymorphism in the gene encoding the BTLA is associated with autoimmune diseases and cancer. The goal of the study was to research the relationship between the alleles, genotypes and haplotypes frequencies of chosen BTLA gene polymorphisms (rs184489 and rs9288952) and the risk of Behcet disease.Materials and methodsThe population of this study consisted of 108 patients with BD and 108 healthy controls. Genotyping for the rs184489 and rs9288952 polymorphisms were performed using PCR-RFLP method.ResultsIn terms of genotype and allele frequencies between the patient and control groups, there were no statistically significant differences (p > 0.05). However, there was a statistically significant difference in haplotype analysis between the two groups (p = 0.001). Moreover, carrying the T allele for the rs1844089 polymorphism and C allele for the rs9288952 polymorphism increase the risk of disease.ConclusionOur findings propose that CT haplotype might have a potential function in the susceptibility to BD.

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Berglová, Irena, Jan Krejsek, Martina Koláčková, and Radovan Slezák. "B Cell Toll-like Receptors with Respect to the Pathogenesis of Sjögren’s Syndrome." Acta Medica (Hradec Kralove, Czech Republic) 54, no. 2 (2011): 51–57. http://dx.doi.org/10.14712/18059694.2016.18.

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Sjőgren’s syndrome (SS) is a chronic autoimmune immunopathological disease of unknown aetiology. It is characterized by focal lymphocyte infiltration and inflammation in exocrinne glands, involving especially salivary and lacrimal glands. Hypofunction of the glands leads to the decreased glandular secretion together with impaired production of saliva and tears, resulting in dryness of the mouth and eyes (xerostomia and xerophthalmia, respectively). Some of the studies have suggested that Toll-like receptors and B cells play a pivotal role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and SS etc. Stimulation of B cells via the TLRs pathway leads to several important changes including increase in antibody production, differentiation to plasma cells, cytokine production and up-regulation of molecules essential for antigen presentation to (autoreactive) T cells. Experimental data support the idea that co-engagement of BCR and TLR might be sufficient for B cell activation and lead to the failure of tolerance. In human naive B cells, most TLRs are expressed at very low or undetectable level, but expression of TLR 7 and 9 is rapidly induced by B cell receptor triggering. This review will focus on the possible role of B cells and TLRs signaling in the pathogenesis of SS.

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Derakhshani, Afshin, Zahra Asadzadeh, Hossein Safarpour, Patrizia Leone, Mahdi Abdoli Shadbad, Ali Heydari, Behzad Baradaran, and Vito Racanelli. "Regulation of CTLA-4 and PD-L1 Expression in Relapsing-Remitting Multiple Sclerosis Patients after Treatment with Fingolimod, IFNβ-1α, Glatiramer Acetate, and Dimethyl Fumarate Drugs." Journal of Personalized Medicine 11, no. 8 (July 27, 2021): 721. http://dx.doi.org/10.3390/jpm11080721.

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Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity.

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Blomberg, Bonnie, Alain Diaz, Maria Romero, and Daniela Frasca. "Old mice and elderly humans make increased autoimmune antibodies, inflammation and SASP from aged-increased B cells (ABCs in mice and DN in humans) which are hypermetabolic." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 108.05. http://dx.doi.org/10.4049/jimmunol.208.supp.108.05.

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Abstract Immune mechanisms of human and murine diseases of aging include generation of chronic inflammation and autoimmunity. We and others have associated aging in mice and humans with increased chronic inflammation, reduced vaccine response and an increase in a B lymphocyte subset referred to as Age-associated B cells (ABCs) in mice and DN (double negative) in humans. Immune cell function is dependent on metabolic pathways and to date understudied. A. In this work we sorted splenic ABCs (CD19+AA4.1-CD21-CD23−) from young (3–4 months) and old (18–22 months) C57BL/6 mice showing an increased percentage in old and increased RNA expression of SASP (senescence-associated secretory phenotype) pro-inflammatory cytokines (TNFa, IL-6), proinflammatory micro-RNAs (miRs 155 and 16) and cell cycle regulators p16INK4 and p21Waf1 in old ABCs. We also show here old B cells produce more autoimmune IgG antibodies (to MDA, malondialdehyde and ADA, adipocyte-derived antigens), ABCs more than FO (follicular), and ABCs from old more than those from young. Total B cells and ABCs from old mice also have a higher metabolic profile compared with those of young mice. B. The frequency of DN cells is increased in human elderly as well as those younger with obesity. Plasma of obese had more autoantibodies to dsDNA, MDA, and ADA and the DN B cells showed higher levels of IA (Immune activation) markers and transcription factors, e.g. tbx21 (TBET) associated with autoimmunity. We have recently found that elderly human B cells are, like murine, hypermetabolic and are discovering possible mechanisms, such as fatty acids. Supported by grants from NIH (AG32576, AG059719, and AG023717)

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Li, Yajuan, Mei Yan, Yong Du, Soyoun Min, Chandra Mohan, and Quanzhen Li. "The anti-oxidative role of glutathione s-transferase mu 2 in anti-GBM induced glomerulonephritis by inhibiting inflammation and oxidative stress (P5121)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 137.2. http://dx.doi.org/10.4049/jimmunol.190.supp.137.2.

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Abstract Oxidative stress is a common manifestation in chronic inflammation and closely associated with autoimmune diseases. Impaired balance between oxidative stress and antioxidant systems exhibits an important impact on pathogenesis of immune-mediated nephritis. Using anti-GBM induced nephritis mouse model, we have identified a group of redox related genes dysregulated in mouse kidney upon anti-GBM antibody challenge. In this study, we investigated the anti-oxidative effect of glutathione s-transferase mu 2 (Gstm2) on immune-mediated nephritis. Human GSTM2 gene was transduced into mesenchymal stem cell (MSC) and hGSTM2-MSCs were injected to anti-GBM antibody challenged 129/svj mice. Mouse blood urea nitrogen (BUN) and proteinuria were measured to evaluate renal function change and renal histopathological changes were appraised. We found the Gstm2 could alleviate the renal inflammatory damage by suppressing expression of inflammatory chemokines, CCL2, IL1β and IL6 to reduce macrophage and T lymphocyte infiltration. Gstm2 improved renal function by reducing BUN and proteinuria. Moreover, hGSTM2-MSCs significantly reduced the apoptosis of tubular cell by regulating the expression of anti-apoptotic genes (BCL2 and CD40LG) and hGSTM2-MSCs resisted oxidative stress by increasing the expression of catalase and glutathione peroxidase 1. In summary, Gstm2 exhibits protective effect on immune-mediated nephritis by inhibiting inflammatory damage and oxidative stress during inflammatory process.

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Savasan, Sureyya, Batool Al-Qanber, Steven Buck, Erin Wakeling, and Manisha Gadgeel. "Clonal T-Large Granular Lymphocyte Proliferations in Childhood: Friend or Foe?" Blood 132, Supplement 1 (November 29, 2018): 3719. http://dx.doi.org/10.1182/blood-2018-99-119124.

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Abstract Background: The pathophysiology of clonal T-large granular lymphocyte (T-LGL) proliferations is not well understood; the distinction between reactive and malignant entities is not very clear given the fact that acquired STAT3 mutations can be seen with clonal T-LGL proliferations in non-malignant Felty syndrome and with frequent use of immunosuppression for the treatment of T-LGL leukemia. Historically, determination of clonality has been often seen as an indicator of T-LGL leukemia. We reviewed our experience on clonal T-LGL proliferations in children. Material and Methods: T-LGLs were identified by CD3 and dim CD5 staining on flow cytometric analysis and observation of lymphocytes with large granular cytoplasm appearance in peripheral blood. Cases with peripheral blood lymphocyte T-LGL population greater than 10% were reviewed in patients whom had flow cytometry studies performed for different indications. Among them, ones with available T cell receptor (TCR) gene rearrangement studies were selected and 16 cases with clonal TCR rearrangement patterns were included in this study. Fifty-seven peripheral blood flow cytometric tests using 15 surface markers were analyzed in those 16 cases. Patients have been followed for up to 7 years. Results: Sixteen cases of clonal T-LGL proliferation associated with different diseases were included in this analysis. Three patients had chronic graft versus host disease, 2 Evans syndrome, and one case each with the following conditions: common variable immunodeficiency disorder, severe combined immunodeficiency who developed CMV infection following umbilical cord blood transplantation (UCBT) and later acute EBV infection, co-existing Langerhans cell histiocytosis and primary hemophagocytic lymphohistiocytosis, autoimmune hemolytic anemia, chronic idiopathic thrombocytopenic thrombocytopenia, Hodgkin lymphoma, X-linked lymphoproliferative disorder, Rosai Dorfman disease (RDD), acute EBV infection, acute parvovirus B19 infection and paroxysmal nocturnal hemoglobinuria with history of treated severe aplastic anemia. Pathophysiological processes involved in these cases included various combinations of inherited immune deficiency in 4, acquired immune deficiency in 5, lymphoproliferation in 6, alloimmune reaction in 3, autoimmune reaction in 5, infection in 4, inflammation in 3 and malignancy in 1. One patient had three different clonal populations at different times due to maternal engraftment, CMV infection following UCBT and during an acute EBV infection after immune suppression withdrawal, respectively. The patient with RDD developed clonal T-LGL expansion when his disease flared. In some cases, clonal T-LGL proliferations disappeared with the resolution of the underlying pathological process. However, the T-LGL clone persisted and was frequently associated with relative increase over time, if the disease process continued to be active and/or progressed, even despite use of therapeutic approaches often including immunosuppression. Four clonal T-LGL proliferations in 2 patients have resolved, remaining 10 were persistent and have not been reevaluated in 4 cases. None of the cases showed a purely monoclonal pattern. The size of the clonal T-LGL population was variable with a median value of 18.6%, as high as 58.7% of the lymphocyte population. T-LGL population has positively correlated with CD3, CD8, CD57 (p<0.001) and inversely with CD19 (p=0.001) expression. There was also an overall positive correlation between the percent of T-LGL cells and absolute T-LGL count (p<0.001). Discussion: Clonal T-LGL proliferations in childhood is a reactive process reflecting the activity of the underlying disease process, including immunodeficiency, autoimmunity, alloimmunity, infection, inflammation, lymphoproliferation and malignancy. Use of immunosuppression has been associated with relative increase in the clone size despite decrease in peripheral blood absolute lymphocyte count along with relative reduction in T and B lymphocyte compartments in patients with active disease. Presence of clonal T-LGL proliferations in a polyclonal background is not an indicator of malignant process. It is very possible that such proliferations are an effort of the immune system to control the most prominently involved immunogenic stressors. Disclosures No relevant conflicts of interest to declare.

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Hsieh, Y. T., C. Hubeau, V. Massa, W. LI, S. Frei, B. Capraro, A. Umana, et al. "OP0316 EMERGING BEST-IN-CLASS IL-2 VARIANT HIGHLIGHTS TREG-DIRECTED THERAPY FOR AUTOIMMUNE DISEASE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 195.1–195. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1999.

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Background:Impairment or deficiency of regulatory T cells (Treg) is associated with chronic inflammation and autoimmune diseases. Interleukin 2 (IL-2) is a cytokine indispensable for Treg expansion and immunosuppressive function. However, expansion of cytotoxic effector T (Teff) and NK cells and the associated vascular leakage side effect limit the use of IL-2 in autoimmune diseases [1].Objectives:Cugene developed a long-acting IL-2 variant with high Treg specificity and low toxicity to restore immune homeostasis and self-tolerance, and potentially cure autoimmune and inflammatory diseases.Methods:IL-2 variants were generated based on the quaternary structure of IL-2 and IL-2Rαβγ (alpha, beta, gamma) complex. Biological activity was determined by examining differential signaling activity in induction of STAT5 phosphorylation in defined lymphocyte populations of human PBMC using flow cytometry. Binding activity was evaluated by ELISA. Pharmacokinetics, pharmacodynamics, safety and tolerability were assessed in mice and cynomolgus monkeys. Treg suppressive function was determinedin vivo/ex vivo,and anti-inflammatory and anti-antibody production efficacy were determined in delayed-type hypersensitivity (DTH) and T-cell-dependent antibody response (TDAR) models.Results:Structure-based rational design and activity-guided fine-tuning generated an optimized IL-2 variant, CUG252. It demonstrated a strong and near wild-type IL-2 ability to stimulate STAT5 phosphorylation in IL-2Rαβγ dominant Treg cells but abolished activities in IL-2Rβγ dominant effector CD4, CD8 and NK cells. This was a result of biased binding activity to IL-2Rα while dramatically attenuated binding to IL-2Rβγ complex. In mice and monkeys, administration of CUG252 resulted in dose-dependent increases in Treg proliferation and expansion by more than 10- and 30-fold, respectively, with largely abolished activities in CD4+ T conventional, cytotoxic CD8+ Teff and NK cells. The ratio of Treg/Teff cells achieved was as high as 0.4 in mice and 1.2 in monkeys. Both CD4+ and CD8+ Tregs were expanded with preferential increases in memory over naïve subsets. A substantial increase in Treg-suppressive capacity over T effector cells was corroborated by enhanced expression of functional and inhibitory markers, including CD25, Foxp3, PD-1, CTLA-4, Tim3 and ICOS. In DTH and TDAR models, CUG252 strongly inhibited antigen-driven inflammation, B cell maturation, and antibody production. The sustained PK/PD profile supports monthly dosing or better in humans. CUG252 was well-tolerated and no changes in body weight, body temperature, clinical pathology or signs of vascular leakage were observed. Moreover, CUG252 demonstrated superior manufacturability.Conclusion:CUG252 demonstrates an emerging best-in-class profile among IL-2 variants. It displayed exquisite Treg-selectivity while retaining potency comparable to wild-type IL-2. It showed strong anti-inflammatory and anti-antibody production efficacy with significantly improved therapeutic index and manufacturability. Its favorable drug-like property and robust preclinical efficacy warrant further evaluation in patients with a variety of inflammation and autoimmune diseases.References:[1]Tahvildari M. et al. Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases. J Immunol. 2019; 203: 2749-2755Disclosure of Interests:Yao-te Hsieh Employee of: Cugene INC., CEDRIC HUBEAU Employee of: Cugene INC., Virginia MASSA Employee of: Cugene INC., WEN Li Employee of: Cugene INC., SANDRA FREI Employee of: Cugene INC., BEN CAPRARO Employee of: Cugene INC., ANDREA UMANA Employee of: Cugene INC., ANDREW AHERRERA Employee of: Cugene INC., YUESHENG LI Employee of: Cugene INC., JING XU Employee of: Cugene INC., LINGYUN RUI Employee of: Cugene INC.

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Skupnevsky, S. V., E. G. Pukhaeva, A. K. Badtiev, F. K. Rurua, F. E. Batagova, and Z. G. Farnieva. "Metabolic changes of lymphocytes in a rat model of autoimmunity." Medical Immunology (Russia) 24, no. 2 (April 20, 2022): 247–56. http://dx.doi.org/10.15789/1563-0625-mco-2408.

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Autoimmune diseases are highly prevalent in humans, being characterized by early onset and high risks of disability, thus determining the relevance of the present work and its aim, i.e., studying metabolic characteristics of lymphocytes upon the adjuvant-induced autoimmune disorder in rats. Modeling of the autoimmune process was performed in Wistar rats by subcutaneous administration of a Freund’s complete adjuvant, i.e., water-oil emulsion with heat-killed M. tuberculosis. Hematology testing (complete blood counts), biochemical markers (hydroperoxides, malondialdehyde (MDA), catalase), and cytobiochemical changes in lymphocytes (lactate dehydrogenase, succinate dehydrogenase; LDH, SDH) were followed in dynamics. X-ray examination was performed at the end of the experiment. At the initial stage of autoimmune arthritis (2 weeks), leukocytosis was registered (26.12±2.30 × 109 /L, i.e., 65% over the controls, p < 0.01), thrombocytosis (675±30 × 109 /L, compared with 536±27 × 109 /L in controls, p < 0.01), and oxidative stress were also observed (hydroperoxides increased by 7%, and MDA, by 32%, p < 0.001); energy levels of the lymphocytes increased due to activation of LDH by 6.5%, and SDH, by 49% against the controls. At chronic stage of the disorder (7 weeks), the systemic inflammation was milder (total WBC counts of 19.6±1.40 × 109 /L, compared with 13.68±0.86 × 109 /L in controls, p < 0.01, associated with shift to the right in differential conuts), along with persisting oxidative stress (MDA exceeds the control levels by 37%; decrease in catalase activity), and lower LDH activity in lymphocytes (by 43%, p < 0.01) associated by their decrease in size (the correlation quotient between the lymphocyte radius and LDH activity is rxy = 0.87). Profound molecular changes were observed in the cell energy supply: the respiratory quotient for control animals (LDH/SDH ratio) varied within 4.6-5.0. Meanwhile, in autoimmune animals, metabolic contribution of glycolysis showed a significant decrease (the quotient of 3.2 by the 2nd week, and 2.4 by the 7th week). On the radiograph by 7th week, the experimental animals show uneven joint space narrowing, cyst-like formations and subchondral sclerosis of the bone heads. Autoimmune rheumatoid arthritis in rats is characterized by metabolic disorders of lymphocytes manifesting as general energy deficiency, and imbalance between glycolysis and oxidative phosphorylation pathways. These findings allow of deeper insight into pathogenesis and suggesting further search for molecular targeted therapy and prevention of the disease.

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Yang, Fan, Yan Yan, Zeyu Xiong, Irene H. Chen, Hong Wang, and Xiao-Feng Yang. "Novel Model of Stimulation-Responsive Splicing for Generation of Immunogenic Isoforms of Tumor Antigens and Autoantigens." Blood 108, no. 11 (November 16, 2006): 5188. http://dx.doi.org/10.1182/blood.v108.11.5188.5188.

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Abstract Alternative splicing is a process that removes introns and alters exons to generate multiple isoforms from a single pre-mRNA transcript. Alternative splicing is the major mechanism by which a small number of human genes (6 × 104) can encode the larger complexity of the human proteome (1 × 106 proteins). Previously we demonstrated that alternative splicing of apoptosis-regulatory protein transcripts regulates immune responses by modulating lymphocyte survival (Immunity, 1997; Mol. Immunol. 2002; J Exp Med, 2002; Oncogene 2005; Biochem J, 2005). To examine the hypothesis that alternative splicing plays a role in selection of nonmutated self-protein isoforms for tumor antigens and autoantigens, recently, we showed that alternative splicing is a major mechanism in regulation of the immunogenicity of tumor antigen CML66 (J. Immunol. 2004). In addition, we found that alternative splicing occurs in 100% of the autoantigen transcripts. This is significantly higher than the approximately 42% rate of alternative splicing observed in the 10,000 randomly selected human gene transcripts (p<0.001) [J. Allergy Clin. Immunol., 2004 (cover article)]. Here, we report that essential alternative splicing factor ASF/SF2 expression in samples from patients with chronic inflammation is lower than that of the healthy controls (p<0.05). In addition, TNF-a significantly downregulates ASF/SF2 expression (7 folds) in cultured cells in comparison to the expression variations of b-actin control. These findings demonstrate that ASF/SF2, presumably affecting splicing of self-antigen transcripts, is downregulated in autoimmune inflammatory disease potentially via a TNF-a-mediated pathway. Collectively, we propose for the first time a novel model of “stimulation-responsive splicing”, which emphasizes that stimulation-responsive splicing plays a critical role in selection of nonmutated self-protein isoforms to become tumor antigens and autoantigens (Clin. Immunol. Invited Review, in press, 2006). The new model for the definition of immunogenic isoforms of tumor antigens and autoantigens is significant in facilitating the development of: immunogenic antigen isoform microarrays for disease diagnosis and prognosis; autoantigen-tolerizing therapy and splicing-redirection therapy for autoimmune diseases; and immunogenic antigen isoforms-based immunotherapy for tumors.

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Demchenko, E. N., E. D. Gavrilova, E. V. Goiman, N. N. Volskiy, and V. A. Kozlov. "Dynamics of cell-free DNA levels in the in vivo LPS-induced inflammation model." Russian Journal of Immunology 25, no. 4 (October 7, 2022): 423–30. http://dx.doi.org/10.46235/1028-7221-1179-doc.

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An increased concentration of extracellular cell free DNA (cfDNA) is a distinctive characteristic of pathologies that mainly occur in acute inflammation (myocardial infarction, sepsis, stroke, trauma). The increase of cfDNA in chronic inflammatory processes, oncological, autoimmune diseases is less significant and is mainly due to aberrant cell death processes. One of such diseases is systemic lupus erythematosus (SLE). It has recently been shown that, in addition to increased cfDNA concentration, the degree of inflammation can reflect the N/L index (neutrophil to lymphocyte ratio), being a simple and informative marker of disease activity in patients with SLE. The aim of the study was to study the dynamics of the level of cfDNA and the N/L index in the model of LPS-induced inflammatory response as observed in intact mice, and their relation to the phenotypic heterogeneity of model SLE. We used female hybrid mice (C57Bl/6xDBA/2) F1 and female DBA/2 mice at the age of 6-8 weeks. LPS of E. coli strain 111: B4 (Sigma) was injected intraperitoneally once at doses of 10 ng, 1 g and 100 g per mouse in PBS. The control group was injected with the appropriate volume of buffer. The TNF-binding domain of the variola virus CRMB protein was used as an inhibitor of TNF, which was administered 30 min before the introduction of LPS. The dynamics of the response to LPS was assessed after 4, 8, 11, 24 hours by the N/L index and the level of cfDNA; at the zero point, the parameters were determined before the introduction of LPS. A day after a single injection of LPS at a dose of 1 g/mouse, a SLE model was induced on the same hybrid mice (double intravenous administration with an interval of 6 days of spleen cells of the DBA/2 line, 60-70 106 cells each). Three months later, with proteinuria of 3 mg/ mL or more, mice were assigned to the SLEnephritis+ group, with a protein of less than 3 mg/mL, to the SLEnephritis- group. Statistical processing of the results was carried out by nonparametric statistics using the MannWhitney test. Differences were considered statistically significant at p 0.05. It was found that the change in the N/L index, as well as the change in the level of cfDNA, depends on the dose of LPS administered. It was shown that the level of cfDNA reaches its maximum after 8 and 11 hours after the introduction of LPS is reliably reduced when using the inhibitor TNF. A retrospective analysis indicates that there is a definite relationship between the response of intact mice to LPS before induction of cGVHD, and their subsequent division into variants of SLEnephritis + and SLEnephritis - in the course of disease development.

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Al-Awadhi, Adel M., Mohammad Z. Haider, Jalaja Sukumaran, Eman AH Hasan, and Youssef A. Bartella. "The Protein Tyrosine Phosphatase Non-receptor Type N22 (PTPN22) Gene Functional Polymorphism (1858T) is not Associated with Rheumatoid Arthritis in Kuwaiti Patients." Open Rheumatology Journal 15, no. 1 (July 12, 2021): 45–50. http://dx.doi.org/10.2174/1874312902115010045.

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Background: Rheumatoid Arthritis (RA) is a chronic disorder characterized by an inflammation of synovial tissue in joints resulting in pain, deformities and affects the quality of life. The gene for protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes a lymphoid specific phosphatase (LYP), which serves as a negative regulator of T lymphocyte activation and is associated with a number of autoimmune/chronic diseases in various ethnic groups. Objective: This study was undertaken to investigate an association between PTPN22 gene functional polymorphism (C1858T; rs2476601) and rheumatoid arthritis (RA) in Kuwaiti Arabs. The frequency of this candidate locus was compared between Kuwaiti RA patients and the controls and with that reported from other populations. Methods: The study was carried out in 191 Kuwaiti RA patients and 214 healthy controls. The diagnosis of RA was carried out according to the guidelines of the American College of Rheumatology (ACR). The genotypes of PTPN22 gene (C1858T) polymorphism were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by DNA sequence analysis in RA patients and controls. Results: The TT genotype of PTPN22 gene functional polymorphism C1858T was found in 2/191 (1%) in RA patients compared to 2/214 (1%) in the controls (P = 1.0). In contrast, heterozygous CT genotype was detected in 3/191 (1.57%) RA patients compared to 32/214 (14.9%) in the controls. The CC genotype was detected in 186/191 (97.38%), RA patients while it was detected in 180/214 (84.1%) of the controls. The two RA patients who carried the homozygous variant (TT) genotype were both positive for rheumatoid factor (RF) and did not have any extra-articular manifestations. Amongst the Kuwaiti RA patients, 27% had a family history of RA. No correlation was found between the activity/severity of the disease and PTPN22 gene polymorphism genotypes. Conclusion: This study did not find an association between the PTPN22 gene functional polymorphism (C1858T) and clinical manifestation and activity/severity of RA in Kuwaiti Arabs. This is in sharp contrast to previous reports from Caucasian and some other populations in which a positive association of PTPN22 gene (C1858T) polymorphism with genetic susceptibility to RA has been reported.

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Wang, Y. Y., R. Su, B. C. Li, Q. L. Guo, H. Xue, X. Li, and C. Wang. "AB0269 THE CHARACTERISTICS OF PERIPHERAL LYMPHOCYTE SUBSETS AND CYTOKINES LEVEL IN RHEUMATOID ARTHRITIS WITH CORONARY ARTERY DISEASE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1433.1–1433. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2754.

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Background:Rheumatoid arthritis (RA) is a systemic autoimmune disease. It is characterized by highly disabling polyarthritis, but extra-articular features are also common and portend a poor prognosis. Compared with the general population, the incidence and mortality of cardiovascular disease in RA are significantly increased. Chronic autoimmune inflammation is the common pathogenesis of RA and coronary heart disease(CAD). We’ve proved that lymphocyte subsets imbalance and high cytokines expression play an important role in the occurrence and development of RA diseases. However, the level of lymphocyte subsets and cytokines of RA patients with CAD are rarely reported[1-2].Objectives:To explore the clinical characteristic of lymphocyte subsets and cytokines of RA patients with CAD,and make comparisons with simple RA patients and healthy controls.Methods:The study included 96 patients with a diagnosis of RA according to the 1987 revised criteria of the ACR, including 54 RA patients with CAD and 42 RA patients without CAD and other cardiovascular disease, 40 healthy controls are also concluded. The absolute numbers of lymphocyte subsets and T subsets in peripheral blood were measured by Flow Cytometer (FCM). Serum levels of IL-2, IL-4, IL-6, IL-10, IL-17, INF-γ, and TNF-α were measured by flow microsphere capture chip technique (CBA) for 19 RA patients with CAD and 38 simple RA patients among 96 patients.We also collected relevant clinical information and made DAS28 score, and all patients are in the middle-high disease activity group (DAS28>3.2).Results:(1) There was no difference in DAS28 scores between the two groups(p=0.572). (2)Compared with RA patients without CAD, the absolute number of total T cell(P=0.035), total B cell (P=0.006), CD4+T cell(P=0.012), Th1 cell(P=0.037), Th17 cell(P=0.033) and CD4+CD25+FOXP3+ Treg(P=0.003) was lower than RA patients with CAD, the number of NK cell(P=0.685), CD8+T cell(P=0.322) and Th2 cell(P=0.770) had no obvious difference between them. (3)Compared with the healthy control, the absolute number of total T cell(P=0.014), total B cell (P=0.006), CD8+T cell(P=0.000) in RA with CAD was evidently lower, but there was no siginificant difference in absolute number of CD4+T cell(P=0.582), Th1 cell(P=0.052), Th2 cell(P=0.595), Th17 cell(P=0.148) and Treg(P=0.176) (Figure 1).(4) In RA patients with CAD,the level of cytokines IL-2(P=0.042), IL-4(P=0.043) and IL-17(P=0.012) was lower, while other cytokines had no difference (Table 1).Figure 1.The absolute number of lymphcytes of RA patients with CAD(n=54),RA patients without CAD (n=42) and healthy control (n=40). (*P<0.05,**P<0.01, ***P<0.001).Table 1.The expression level of cytokines of RA patients with CAD(n=19) and RA patients without CAD (n=38).Cytokines (pg/ml)RA and CAD group(A) (n = 19)RA group(B) (n = 38)PvalueA vs. BIL-25.50(1.96, 12.82)6.82(4.45, 14.44)0.042IL-44.93(1.67, 9.41)6.28(4.49, 11.88)0.043IL-623.69(10.93, 73.08)36.67(15.40, 72.50)0.636IL-107.76(4.54, 10.50)7.62(5.69, 19.91)0.223IL-1710.81(4.04, 20.25)20.68(13.88, 45.58)0.012IFN-γ6.10(3.27, 13.84)7.13(5.79, 15.83)0.115TNF-α10.49(2.50, 29.04)14.96(10.03, 30.39)0.097Conclusion:Our research shows that there is lymphocyte imbalance and immune disorder existing in RA patients with CAD. Both the number of lymphocyte subsets and cytokine levels decreased in these patients than pure RA patients. It suggests that this group may be in lower immune state, which providing guidance for further clinical treatment of RA patients with CAD.References:[1]Winchester R, Giles JT, Nativ S, et al. Association of Elevations of Specific T Cell and Monocyte Subpopulations in Rheumatoid Arthritis With Subclinical Coronary Artery Atherosclerosis. [J]. Arthritis Rheumatol, 2016,68(1): 92-102.[2]England BR, Thiele GM, Anderson DR, et al. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. [J]. BMJ, 2018 04 23;361.Disclosure of Interests:None declared

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Liphaus, Bernadete L., Maria H. B. Kiss, Solange Carrasco, and Claudia Goldenstein-Schainberg. "Increased Fas and Bcl-2 Expression on Peripheral Blood T and B Lymphocytes from Juvenile-Onset Systemic Lupus Erythematosus, but not from Juvenile Rheumatoid Arthritis and Juvenile Dermatomyositis." Clinical and Developmental Immunology 13, no. 2-4 (2006): 283–87. http://dx.doi.org/10.1080/17402520600877786.

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Defective regulation of apoptosis may play a role in the development of autoimmune diseases. Fas and Bcl-2 proteins are involved in the control of apoptosis. The aims of this study were to determine the expression of Fas antigen and Bcl-2 protein on peripheral blood T and B lymphocytes from patients with juvenile-onset systemic lupus erythematosus (JSLE), juvenile rheumatoid arthritis (JRA) and juvenile dermatomyositis (JDM). Thirty-eight patients with JSLE, 19 patients with JRA, 10 patients with JDM and 25 healthy controls entered the study. Freshly isolated peripheral blood mononuclear cells (PBMC) were stained for lymphocyte markers CD3, CD4, CD8, CD19 and for Fas and Bcl-2 molecules. Expressions were measured by three-color flow cytometry. Statistical analysis was performed using Kruskal–Wallis test. Percentages of freshly isolated T lymphocytes positively stained for Fas protein from JSLE patients were significantly increased compared to healthy controls, patients with JRA and patients with JDM. Percentages of B lymphocytes positive for Fas from JSLE patients were higher than healthy controls and JRA patients. In addition, Fas expression on T cells from patients with JRA was increased compared to JDM patients. Otherwise, Fas expression on T and B cells from JRA and JDM patients were similar to healthy controls. MFI of Bcl-2 positive T lymphocytes from JSLE patients were significantly increased compared to healthy controls and JRA patients. MFI of Bcl-2 protein on B lymphocytes from JSLE patients was similar to healthy controls and patients with JRA and JDM. Bcl-2 expression did not differ between JRA and JDM patients and healthy controls. In conclusion, increased expression of Fas and Bcl-2 proteins observed in circulating T and B lymphocytes from patients with JSLE, but not from patients with JRA and JDM, suggests that abnormalities of apoptosis may be related to the pathogenesis of JSLE and probably are not a result of chronic inflammation.

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Epling-Burnette, P. K., Xianhong Chen, Junmin Zhou, Fanqi Bai, Sokol Lubomir, Edna Ku, Jeffrey S. Painter, et al. "Aberrant NK Receptor Signaling Associated with Large Granular Lymphoycte Leukemia and Primary Pulmonary Hypertension." Blood 110, no. 11 (November 16, 2007): 4704. http://dx.doi.org/10.1182/blood.v110.11.4704.4704.

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Abstract INTRODUCTION: Large granular lymphocyte (LGL) leukemia is associated with increased numbers of circulating NK or T-LGL cells with only 5% of these cases related to NK-cell expansion. NK-LGL leukemia is primarily characterized by chronic anemia in association with low to normal numbers of erythroid precursors in the bone marrow and chronic neutropenia. Here, we explore the mechanism of pathogenesis in the first case report of a patient with NK-LGL leukemia in association with primary pulmonary hypertension (PPH). This patient displayed a diffuse pulmonary infiltrate with sustained elevated mean pulmonary artery pressure at rest confirmed by right-sided cardiac catheterization meeting the clinical diagnostic criteria for PPH. Association between T-LGL leukemia and PPH has been reported previously suggesting a causitive link between LGL expansion and PPH pathogenesis. METHODS: Cytotoxicity of a normal pulmonary endothelial cell line (CRL-2598) was determined by 5-hr 51-Cr-release assays using NK-cells from this NK-LGL patient compared to healthy controls. Specific NK receptors were blocked by antibodies added to the effector cells for 30 min prior to the cytotoxicity assay. Production of TNFα was assessed by intracellular cytokine staining with detection by flow cytometry. To block NK receptor signals, dominant negative adaptor proteins, DAP10 and DAP12, were constructed and expressed in recombinant vaccinia viruses. These viruses were engineered to carry a single Y-A mutation at Y102 or a double mutation at both Y9 and Y102 within the YxxM activating ITAM motif of the adaptor protein. Perforin granule mobilization was determined by immunofluorescence microscopy. RESULTS: Sixty-eight % of peripheral blood and bone marrow mononuclear cells from this patient were phenotypically NK-LGLs with skewed reactivity to the anti-CD158a antibody (KIR2DS1/2DS2), which was shown by mRNA analysis to consist primarily of activating KIR2DS1. We examined the susceptibility of CRL-2598 cells to NK lysis and found that patient-derived NK-cells produced greater lysis without prior activation than healthy controls. Furthermore, NK-cells from this patient produced more TNF-α in response to paraformaldehyde-fixed CRL-2598 cells and displayed perforin granule mobilization to the contact site between effector and target cells. Addition of blocking antibodies against the activating receptors NKG2D and KIR2DS1/KIR2DL1 (anti-CD158a) produced a blockade in this process showing that these receptors were responsible for lysis. When DAP10 and DAP12 adaptor signaling steps were blocked, killing and perforin granule redistribution toward the contact site of the conjugated targets was suppressed. CONCLUSION: This study shows that the presence of activating NK-receptors and DAP10/DAP12 adaptors contibuted to lysis of normal endothelial cells in this patient. DAP10 and DAP12 are key initiators for both NK− and T−cell function suggesting that targeted disruption of these signaling events may prove beneficial for autoimmune inflammatory diseases such as PPH and LGL leukemia.

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Niu, H. Q., and L. Hao. "AB0237 CHANGES AND CLINICAL SIGNIFICANCES OF PERIPHERAL REGULATORY T CELLS IN RHEUMATOID ARTHRITIS PATIENTS WITH CARDIOVASCULAR DISEASE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1246.2–1246. http://dx.doi.org/10.1136/annrheumdis-2022-eular.316.

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BackgroundRheumatoid arthritis (RA) is an independent risk factor for cardiovascular diseases (CVD), driven by the underlying chronic systemic inflammation [1]. The imbalance of CD4+ T lymphocyte subsets, especially between T helper (Th) 17 cells and regulatory T (Treg) cells, can mediate autoimmune inflammatory process, promoting the overproduction of cytokines and abnormal antibodies [2,3]. However, the levels of peripheral Th17 and Treg cells in RA patients with CVD are still unknown.ObjectivesTo explore the expression of circulating Th17 and Treg cells in RA patients with CVD and analyze its clinical significance.MethodsA total of 192 patients with RA and 86 healthy controls (HCs) were enrolled from January 2019 to January 2021. The peripheral blood CD4+T lymphocyte subsets of all participants were assessed by flow cytometry. Patients were divided into RA-CVD group (n=72) and RA only group (n=120), and the clinical data were recorded. The statistical differences between two groups were analyzed by independent-samples t test, χ2 test or Mann-Whitney U test, and risk factors of CVD were analyzed using Logistic regression.Results① The median age and the percentage of male patients in the RA-CVD group were significantly higher than those in the RA only group. ② The absolute numbers of peripheral Treg cells in the patients with RA only and RA-CVD were all significantly lower than those in HCs [24.94（19.32, 34.12）cells/μl vs. 33.13（24.96, 45.83）cells/μl，Z=-4.135，P＜0.01; 19.13（13.76, 27.34）cells/μl vs. 33.13（24.96, 45.83）cells/μl，Z=-5.354，P＜0.01]. While the numbers of peripheral Th17 cells in two groups of patients were not significantly different with those in HCs. The ratios of Th17/Treg cells in two group patients were higher than those of HCs, but only the difference between RA-CVD patients and HCs were significant [0.40（0.23，0.63）vs. 0.18（0.13，0.29）, Z=-4.696，P＜0.01]. ③ Compared to the RA only patients, the absolute counts of Treg cells in RA-CVD patients were significantly lower [Z=-3.047，P＜0.01], the numbers of Th17 cells were significantly higher [7.48（3.72, 13.63）cells/μl vs. 5.59（3.49，8.91）cells/μl，Z=-1.989，P＜0.05], and the ratio of Th17/Treg cells was significantly higher [0.40（0.23，0.63）vs. 0.23（0.14，0.35），Z=-4.289，P＜0.01]. ④ Logistic regression analysis showed that the level of circulating Treg cells (OR=0.936, 95%CI: 0.906-0.968) was a protective factor, while Th17 cells (OR=1.068, 95%CI: 1.020-1.119), elder age (OR=1.039, 95%CI: 1.004-1.076) and hypertension (OR=2.712, 95%CI: 1.254-5.865) were independent risk factors of RA patients complicated with CVD.ConclusionIt is suggested that the immune imbalance caused by the deficiency of Treg cells may be involved in the occurrence and development of RA complicated with CVD, and to restore Treg numbers and function may be a promising preventive strategies.References[1]Hansildaar R, Vedder D, Baniaamam M, et al. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol, 2021, 3(1): e58-e70.[2]Wu R, Li N, Zhao X, et al. Low-dose Interleukin-2: Biology and therapeutic prospects in rheumatoid arthritis. Autoimmun Rev, 2020, 19(10): 102645.[3]Niu HQ, Yuan C, Yan C, et al. Decreased numbers and sex-based differences of circulating regulatory T cells in patients with seropositive undifferentiated arthritis. Ther Adv Chronic Dis, 2021, 12: 2040622320986721.Disclosure of InterestsNone declared

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Lin, Ann E., Sonia Reyes, Xiaoyu An, Sonia Reyes, Wenqing Yang, Derron Yu, Duan Dan, and Henry Li. "Experimental Modeling of Acute- and Chronic-GvHD By Xenotransplanting Human Donor PBMCs or Cord Blood CD34+ Cells (HSC) into NSG Mice." Blood 132, Supplement 1 (November 29, 2018): 5684. http://dx.doi.org/10.1182/blood-2018-99-115462.

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Abstract Graft vs. host diseases (GvHD) is a life-threatening complication accounting for 15-30% of deaths following allergenic hematopoietic stem cell transplantation (allo-HSCT) for treatment of malignant diseases. There are two types of GvHD: acute (aGvHD) and chronic (cGvHD), which have different parthenogenesis and phenotype. aGvHD typically involves skin, gastrointestinal and hepatic inflammation, and occurs within 100 days of transplantation; and cGvHD involves multiple organs and occurs beyond 100 days. The former is largely due to the rapid activation of donor T cells (Th1, CD8+ biased), causing tissue damage (via cell killing) and often leading to mortality; in contrast, the latter (Th2, CD4+ biased) typically display autoimmune-like syndrome, involving both T- and B-cell, as well as auto antibody production and systemic fibrosis. The current understanding of the parthenogenesis, as well as developing treatment strategy, is largely based on experimental animal models, many aspects of which remain to be investigated. At present, the most commonly used GvHD models are allo-transplantation between mice, the result of which many may not all adequately translate into clinic for the donor species difference. Xeno-transplantation of human donor into mice could potential represents a better alternative GvHD model in some respects. Methods. Human peripheral blood mononuclear cells (PBMC) derived from the consent normal donor were transplanted into NSG (other NSG-like strains) and B2M-NSG (MHC class I, b-2 micro-globulin, deficiency) mice for modeling aGvHD, while cord blood derived HSCs (hCD34+) (Jackson Lab, huNSG) were transplanted for modeling cGvHD. Following transplantation, the disease progress will be monitored twice weekly, including clinical observations (e.g. animal postures, activity, fur texture, and skin integrity), body weight changes, gross pathology and histo-pathology upon termination, along with human-immunological phenotype of peripheral blood, spleen, lung, and liver by flow (e.g. lymphocyte populations), multiplex, complete blood count, histo-pathology and immunohistochemistry at different time-points. Results. NSG mice engrafted with human PBMC, or purified T-cells, from normal donors rapidly developed typical symptoms of aGvHD, onset 2~3 weeks post transplantation, including severe body loss, reduced activity, hunched posture, loss of fur in combination with severe ruffling and overall poor grooming. Mortality is observed typically from 4th or 5th weeks post transplantation. In correlation, we have observed significant engraftment of human CD45+ human leukocytes (0.5~1.5% on Day 6, 10~30% on Day 16, 30~50% on Day 26 post transplantation, with variations depending on donors, route of transplantation, IP vs. IV, etc), including dominant CD3+ human T-cells of single positive of either CD4+ or CD8+ T-cells. This correlated kinetics between clinical symptoms and degree of engraftment of human leukocytes, particularly T-lymphocytes, suggests xenografting human T-cells are responsible for the observed aGvHD. Further comprehensive analysis on the pathology and immunophenotypes of relevant organs are ongoing. In parallel to NSG, we assessed aGvHD in the absence of mouse MHC-I using the PBMC engrafted B2M mice. Additionally, NSG-mice were engrafted with CD34+ cells derived from cord blood with cGvHD high- risk and low-risk HLA haplotypes. We observed cGvHD development between 18 weeks to 39 weeks post-engraftment, in contrast to the short duration seen aGvHD; symptoms include severe weight loss, impaired movement, severe ruffling, facial/full body alopecia, and scaly skin. Interestingly, in correlation of this, human engraftment of CD45+, particularly T-cells including CD4+, CD8+ and their CD30+ subsets, are kinetically increased in blood and spleen with similar timeline, suggesting their roles in the observed cGvHD. Conclusions. The xenograft murine model using adult human PBMC and cord blood derived CD34+ HSCs could be alternative experimental systems to model human aGvHD and cGvHD for investigating disease mechanisms and evaluating treatment strategy. Disclosures No relevant conflicts of interest to declare.

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Novella-Navarro, M., J. L. Cabrera-Alarcón, J. L. Rosales, J. J. González Martin, P. García de la Peña, and O. Carrion. "AB0437 RISK FACTORS ASESSMENT FOR SUBCLINICAL ARTHEROSCLEROSIS IN PRIMARY SJÖGREN´S SYNDROME." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1517.2–1518. http://dx.doi.org/10.1136/annrheumdis-2020-eular.989.

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Background:Some autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are considered to be independent risk factors for vascular morbidity and mortality. These pathologies present accelerated atherosclerosis, partly because of a chronic sustained inflammation, greater prevalence of cardiovascular risk factors (CVRFs) and pharmacological therapy. However, regarding primary Sjögren’s syndrome (pSS), available data are heterogeneous and proceed from small case series. For this reason, the aim of this study was to provide further information on the identification of atherosclerosis in pSS and its possible association with clinical and analytical parameters of the disease.Objectives:To assess presence of subclinical atherosclerosis by means of carotid ultrasound in patients with pSS and to analyze clinical, analytical and CVRF along with their potential association with the presence of subclinical cardiovascular affectation.Methods:This is a cross-sectional study of 38 patients with pSS (all patients met ACR/EULAR1classification criteria for pSS) and 38 age and sex matched controls. Demographic variables and classical CVRFs were collected (Hypertension, Diabetes mellitus, dyslipemia, Body Mass Index and smoking habit) and the presence of subclinical atherosclerosis was assessed by carotid ultrasound with carotid intima-media thickness (CIMT) measurement and determination of the presence of atheromatous plaques2, both in pSS patients and controls. Disease features were also collected in pSS patients (disease duration, disease activity measured by ESSDAI, glandular vs extraglandular involvement, serological features and treatments received).Statistical analysis: To evaluate differences between patients and controls, T-test or Wilcoxon test with continuity correction, were used for quantitative features and Fisher test for categorical variables. In order to test the presence of pSS as an independent risk factor for subclinical atherosclerosis, from other features as classic CVRFs or analytical data, first we adjusted logistic binomial regression in a bivariate analysis, to select possible predictors to be included in a multivariate analysis. Statistical significance was p<0.05, and OR CI 95% vas calculated.R-Statistics v- 3.6Table 1.Comparison of clinical data of two case groups and healthy control group M (p25, p75)GroupsCase group ACase group BHealthy control groupH valueP valueHistory of thrombus (case)4a8a-13.7090.001History of adverse pregnancy (case)3a19a-34.596<0.001ESR20.00(12.25,111.00)a35.00(14.25,95.00)a9.00(6.00,13.00)34.381<0.001CRP15.00(4.03,37.83)ab7.33(1.76,21.13)ab2.10(1.28,2.31)35.263<0.001PLT228.00(189.50,573.25)ab197.00(66.00,260.50)ab258.50(228.25,272.25)33.482<0.001Note:aComparison with healthy control groupP< 0.05;bComparison with case groupP<0.05.Table 2.Comparison of lymphocyte subsets in peripheral blood of two case groups and healthy control group M (p25, p75)Results:All of the 76 patients included were women, with a mean age of 53.7 ± 11.7 years. For both groups, no differences between prevalence of classical CVRFs were found. Subclinical atherosclerosis presence was higher in patients with pSS than in controls [OR= 4.17, 95%CI (1.27- 16.54), p<0.001], as well as CIMT values (0.79± 0.43 mm vs. 0.66 ± 0.27 mm; p=0.02). An association of subclinical atherosclerosis with erythrocyte sedimentation rate [OR=1.18, 95%CI (1.05-1.37), p<0.05] and Rheumatoid Factor [OR=1.28, 95%CI (1.63-2.26), p<0.05].Conclusion:This cohort showed a greater prevalence of subclinical atherosclerosis in patients with pSS, indicating this disease as an independent risk factor for presence of early vascular damage.References:[1]Vitali C et al. Classification Criteria for Sjögren Syndrome: a revised version of the European criteria proposed by the American-European Consensous Group. Ann Rheum Dis. 2002; 61: 554-8[2]Touboul PJ et al. Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis. 2012; 34: 290-6Disclosure of Interests:Marta Novella-Navarro: None declared, José Luis Cabrera-Alarcón: None declared, José Luis Rosales Grant/research support from: I have received financial support from Novartis, UCB, Pfizer, Abvie to meeting and symposia, Jorge Juan González Martin Grant/research support from: I have received finacial grants from Novartis, Lilly, Pfizer, Abvie for meetings and symposia assistance, Paloma García de la Peña Grant/research support from: I have received finacial grants from Novartis, Lilly, Pfizer, Abvie for meetings and symposia assistance, Ofelia Carrion: None declared

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Aly, Mai, Hassan Awada, Douaa Sayed, Esam ElBeih, Raafat Abdel El Fattah, Refat Fathy Abdel-Aal Naseer, Reem Alagooz, et al. "Predicting the Outcome in Egyptian Patients with Severe Aplastic Anemia Following Allogeneic Hematopoietic Stem Cell Transplantation Using Matched Sibling Donors." Blood 134, Supplement_1 (November 13, 2019): 5652. http://dx.doi.org/10.1182/blood-2019-132183.

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Patients presented with pancytopenia in the presence of bone marrow (BM) hypoplasia, aplastic anemia (AA), may get cured by specific medical care, if patients are under 40 years, mainly in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) which is the treatment of choice for severe AA (SAA) in young age. In Egypt, SAA may get allo-HSCT only with availability of matched sibling (MSD). Success rate of allo HSCT-MSD is still suboptimal although it is a life challenging and expensive procedure with an outcome difficult to predict. Reports suggest that measurement of serum ferritin may help in predicting favorable MSD-alloHSCT outcome. Evidences showed that total infused CD34 cells and/ or measurements of hematogones (HGs) levels at the time of engraftment by flow cytometry may better predict the outcome of MSD-alloHSCT. HGs, normal B lymphocyte precursors, levels may be affected by the status of BM and humoral immunity. Elevated HGs have been noticed in healthy children, called reactive HGs. Regenerative HGs exist in non-malignant disorders such as autoimmune diseases, congenital cytopenia, acquired immunodeficiency and neoplastic disorders such as lymphoma. In addition they have been found in response to regeneration of humoral immunity post chemotherapy and post allo-HSCT. We aimed to examine predictive value of HGs in comparison to pre-transplant ferritin and/ or infused CD34⁺ counts for a favorable outcome of SAA patients treated with allo-HSCT from MSD. This is a prospective cross-sectional study, following institutional approval. In total 21 patients with SAA were consented and enrolled. All patients were treated with MSD allo-HSCT, between December 2013 and January 2016. Patients > 40years age, clinically unfit, with abnormal cytogenetic, diagnosed with inherited BM failure or paroxysmal nocturnal hemoglobinuria (PNH) were excluded. HGs were measured in BM samples at engraftment using flow cytometry where cells were stained with an anti-CD34, anti-CD38, anti- CD10, anti-CD19, and lineage (Lin) mixture (anti-CD3, -CD4, -CD8 -CD20, -CD14, and -CD56). Early HGs referred to both CD38ˉCD10⁺ CD19ˉCD34⁺ and CD38-CD10⁺CD19ˉCD34ˉ. Late HGs referred to CD38⁺CD10⁺CD19⁺CD34ˉ, and CD38⁺CD10ˉCD19⁺CD34ˉ cellss. The mean ± SD of early HG was 0.8 ± 1.6 and median with range was 0.05 (0-7.8) while mean ± SD of late HG was 0.6 ± 0.5 (p=0.4) and median with range 0.4 (0-1.4). Total HG mean ± SD was 0.7±1.2 and median with range 0.2 (0 - 7.8).Interestingly the mean ± SD of HG levels were higher in survivors vs non-survivors (2.3 ± 3.4 vs. 0.2 ± 0.2; P=0.01). Infused CD34 count (10^6) were in survivors vs non-survivors (6.7 ± 3 vs 7.8 ± 4) while pre-transplant serum ferritin levels (pm/mL) were in survivors vs non-survivors (1493 ± 1025 vs 1213 ± 371) without showing significant differences. Using ROC curve analysis, it showed the following for engraftment HGs%, best cut-off value was 0.37%, with AUC of 0.88, likelihood ratio (LR) of 3.85, it was the most sensitive 76.9% (95% CI; 35.4-84.8) and specific 80% (95% CI; 28.4 - 99.5) predicting favorable MSD-alloHSCT outcome. Infused CD34⁺ count showed best cut-off level of 6.8 x 10⁶ cells/kg, 0.63 for AUC, 3.13 for LR; 62% sensitivity (95% CI; 46.2-95) and 80% specificity (95% CI; 28.4-99.5). Pre-transplant serum ferritin showed best cut-off level of 1337, 0.59 for AUC; 1.6 LR; 64% for sensitivity (95%CI; 35.14 - 87.24) and only 60% specific (95% CI, 14.66 - 94.73). Moreover, patients with high HG (>0.37%; 57% vs. <0.37%;43%) had significantly high white cell count (WBCs); (median; 5 x 10⁹ /L, range; 2-9 vs 3.5,1.3-5; 95% CI; -3.5 to -0.1; p=0.03), absolute neutrophil count (ANC); (0.7 ± 0.4 vs 2 ± 0.8; p=0.0004), platelet; (26 ± vs 89 ± 46; p=0.001), at engraftment time in addition to superior OS (P=0.005). There was no difference in incidence of acute and chronic GVHD, infections or transfusion frequency rate among survivors with HGs below or above 0.37%. Noticeably donor age of transplanted patients with high HGs tended to be younger. Neither pre-transplant ferritin level nor infused CD 34⁺ count showed any impact on the OS (P=0.9 and 0.1 respectively). In sum HGs% FCM assay may be a highly sensitive and specific biomarker predicting HSCT outcome in SAA patients.. Estimating HGs% at engraftment time seem to be a promising predictor for the outcome of MSD-alloHSCT in SAA patients. SAA patients with HGs 0.37% or higher had better OS. Disclosures No relevant conflicts of interest to declare.

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Li, Chris M., and Zhibin Chen. "Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation." Frontiers in Cell and Developmental Biology 9 (June 21, 2021). http://dx.doi.org/10.3389/fcell.2021.664305.

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Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

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Martin Calderon, Leonardo, and Janet E. Pope. "Precursors to Systemic Sclerosis and Systemic Lupus Erythematosus: From Undifferentiated Connective Tissue Disease to the Development of Identifiable Connective Tissue Diseases." Frontiers in Immunology 13 (May 5, 2022). http://dx.doi.org/10.3389/fimmu.2022.869172.

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The pathogenesis of connective tissue diseases (CTDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), is characterized by derangements of the innate and adaptive immune system, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. The diagnosis of these diseases is based on meeting established criteria with symptoms, signs and autoantibodies. However, there are pre-clinical states where criteria are not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, represents an opportunity for early identification and potentially enables timely treatment with the goal of limiting disease progression and improved prognosis. This scoping review describes the role of the innate and adaptive immune responses in the pre-clinical states of undifferentiated CTD at risk for SSc and prescleroderma, the evolution of antibodies from nonspecific to specific antinuclear antibodies prior to SLE development, and the signaling pathways and inflammatory markers of fibroblast, endothelial, and T cell activation underlying immune dysregulation in these pre-clinical states.

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Strauss, Laura, Valentina Guarneri, Alessandra Gennari, and Antonio Sica. "Implications of metabolism-driven myeloid dysfunctions in cancer therapy." Cellular & Molecular Immunology, October 19, 2020. http://dx.doi.org/10.1038/s41423-020-00556-w.

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Abstract Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.

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Dean, David, and Herve Sroussi. "Oral Chronic Graft-Versus-Host Disease." Frontiers in Oral Health 3 (May 20, 2022). http://dx.doi.org/10.3389/froh.2022.903154.

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Chronic oral graft-versus-host disease (cGVHD) is a complex, frequent, and highly impactful complication of allogeneic hematopoietic cell transplantation (alloHCT). It represents the leading cause of morbidity and mortality in long-term alloHCT survivors. cGVHD can affect almost any visceral organ system and commonly affects the skin, eyes and mouth, manifesting with signs and symptoms similar to other known immune-mediated and autoimmune diseases. Oral manifestations of GVHD include inflammation, thinning, and ulceration of oral mucosal tissues (similar to lichen planus), lymphocyte-mediated salivary gland dysfunction (similar to Sjögren/Sicca Syndrome), and decreased oral opening (trismus) secondary to sclerosis of oral and perioral tissues (analogous to limitation in scleroderma). Potential sequelae include severe mucosal pain, compromised nutrition, weight loss, limitation in opening, and sometimes irreversible fibrosis of the salivary glands. While some cases can be managed with topical therapies, management may also require long-term targeted immunosuppressive and/or corticosteroid therapy with associated risk of local and systemic infection, hyperglycemia, kidney dysfunction, osteopenia/osteoporosis, and possibly secondary malignancies. The aim of this mini-review is to provide an up-to-date review of literature related to the diagnosis and management of oral cGVHD to aid dental and medical clinicians in optimizing oral cGVHD therapy while minimizing potential adverse effects.

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Avril Goveas, Christina, Jayaprakash C S, and Sumanth D. "Diagnostic Utility of Platelet - Lymphocyte Ratio in Adults with Sepsis: A Case - Control Study." RGUHS Journal of Allied Health Sciences 1, no. 1 (2021). http://dx.doi.org/10.26463/rjahs.1_1_4.

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Background The platelet-lymphocyte ratio PLR a novel inflammatory marker may act as an indicator of inflammation and also the severity of the sepsis in patients. Objective We investigated the diagnostic utility of PLR in sepsis in adults by calculating the PLR in culturepositive and negative groups as no studies have been conducted in this regard.Materials and Methods Retrospectively adult patients gt18 years clinically diagnosed with sepsis and who had undergone blood culture analysis were included. The patients with a negative culture were considered as the control group. Patients with malignancy autoimmune diseases chronic inflammatory diseases congenital heart disease and concomitant illnesses like malaria dengue or any other viral fever which could alter the PLR and those who were on antiplatelet drugs or had undergone antibiotic therapy previously were excluded. The platelet and absolute lymphocyte counts on the day of admission were used for the calculation of PLR. Each group comprised 76 n76 patients. Statistical analysis was done by using the mean standard deviation and t-test.Results The PLR between the two groups showed a mean difference with a P value of 0.148 which was not statistically significant.Conclusion Although there was a difference in the PLR between the 2 groups it was not statistically significant. Further studies with a bigger sample size and a prospective approach will help in further establishing the diagnostic utility of PLR in sepsis.nbsp

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Broome, Hanna J., and Michael J. Ryan. "Abstract 535: Chronic High Sodium Diet Attenuates The Development Of Renal Injury And Inflammation In Murine Systemic Lupus Erythematosus." Hypertension 64, suppl_1 (September 2014). http://dx.doi.org/10.1161/hyp.64.suppl_1.535.

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Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent renal disease, a consequence of increased and abnormal survival of B and T lymphocytes. Recent evidence suggests that dietary salt may be an important environmental factor that promotes certain autoimmune diseases by stimulating pro-inflammatory T lymphocyte differentiation. Therefore, we hypothesized that a long-term high salt diet would accelerate the progression of renal disease during SLE. In order to test this, an established experimental model of SLE (female NZBWF1 mice) was fed a standard (0.4% NaCl) or high salt (4% NaCl) diet starting at 10 weeks of age. Sodium intake (in meq/day) was measured three times throughout the study and was significantly greater in high salt fed animals at 16 weeks of age (2.9±0.6 vs. 0.5±0.06 , p=0.01), 23 weeks (4.8±0.8 vs. 0.6±0.06, p=0.004) and 29 weeks (5.7±0.6 vs. 0.6±0.05, p=0.0007). Urinary albumin was monitored monthly until 30 weeks then weekly by dipstick assay as a marker of renal injury until 34 weeks of age, at which time catheters were implanted into the carotid arteries for measurement of mean arterial pressure (MAP). Mice were then euthanized and kidneys collected. Renal cortex enriched mRNA was analyzed by qRT-PCR for inflammatory markers, and renal medullary enriched mRNA was analyzed for expression of serum glucocorticoid kinase 1 (SGK1), a salt-sensing kinase. Counter to our hypothesis, 75% (9/12) of animals on a normal diet developed albuminuria (≥ 100 mg/dL), whereas 17% (2/12) of the high salt fed animals developed albuminuria (p=0.0002). MAP was not different between groups (132±4 mmHg 0.4% NaCl vs. 144±8 mmHg 4% NaCl), nor was renal medullary expression of SGK1 mRNA (0.25±0.03 vs. 0.20±0.04). However, renal cortical interleukin-2 (IL-2), a cytokine important for T cell differentiation, expression was significantly lower in high salt fed animals (0.31±0.03 vs. 1.16±0.34, p=0.03). These data suggest that a long-term high salt diet may protect against the renal injury associated with SLE, possibly through alterations in IL-2 mediated T cell differentiation, without a significant effect on MAP. Furthermore, the data advance our overall understanding of how dietary salt may impact different autoimmune disorders.

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Liu, Hanchao, Xinning Zhu, Xiaohui Cao, Ani Chi, Jian Dai, Zhenqing Wang, Chunhua Deng, and Min Zhang. "IL-1β-primed mesenchymal stromal cells exert enhanced therapeutic effects to alleviate Chronic Prostatitis/Chronic Pelvic Pain Syndrome through systemic immunity." Stem Cell Research & Therapy 12, no. 1 (September 25, 2021). http://dx.doi.org/10.1186/s13287-021-02579-0.

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Abstract Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) seriously affects patient health. Despite the elusiveness of innate therapeutic effects, mesenchymal stromal cells (MSCs) hold great promise for inflammation-related diseases. Recent evidence indicates that disease-specific inflammatory cytokines could enhance the therapeutic effects of MSCs. Methods By establishing a CP/CPPS mouse model and pretreating MSCs with the cytokine interleukin-1β (IL-1β), we studied the IL-1β-primed MSC immunoregulatory ability and targeted migration ability in vitro and in CP/CPPS mice. Results IL-1β levels significantly increased in the prostate tissue and serum of experimental autoimmune prostatitis (EAP) mice. Pretreatment with IL-1β enhanced the immunomodulatory potential and targeted migration of MSCs in vitro. Furthermore, intravenous infusion of IL-1β-primed MSCs dampened inflammation in prostate tissues and alleviated hyperalgesia in EAP mice. The infused MSCs inhibited monocyte infiltration and promoted regulatory T lymphocyte formation in prostate tissue, thus remodeling the local environment. Surprisingly, IL-1β-primed MSCs exhibited improved accumulation in the spleen but not in prostate tissue. Accordingly, infused MSCs reshaped systemic immunity by reducing the proportion of Ly6ChighCD11b+ monocytes and boosting the proportion of CD4+Foxp3+ regulatory T lymphocytes in the spleen and lung. Inflammatory chemokine (C–C motif) ligand 2 (CCL2) decreased through the downregulation of the NF-κB and JNK/MAPK pathways by inflammatory resolution via MSCs infusion to alleviate pain. Conclusion In summary, IL-1β-primed MSCs restored systemic immunologic homeostasis to alleviate CP/CPPS by modulating systemic immunity. These findings provide a novel strategy to boost the therapeutic effects of MSC-based therapy for CP/CPPS and reveal the essential role of systematic immunity in the treatment of CP/CPPS with MSC infusion.

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Abu El-Asrar, Ahmed M., Jo Van Damme, Sofie Struyf, and Ghislain Opdenakker. "New Perspectives on the Immunopathogenesis and Treatment of Uveitis Associated With Vogt-Koyanagi-Harada Disease." Frontiers in Medicine 8 (November 12, 2021). http://dx.doi.org/10.3389/fmed.2021.705796.

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Uveitis associated with Vogt-Koyanagi-Harada (VKH) disease is a bilateral, chronic, granulomatous autoimmune disease associated with vitiligo, poliosis, alopecia, and meningeal and auditory manifestations. The disease affects pigmented races with a predisposing genetic background. Evidence has been provided that the clinical manifestations are caused by a T-lymphocyte-mediated autoimmune response directed against antigens associated with melanocytes in the target organs. Alongside of T lymphocytes, autoreactive B cells play a central role in the development and propagation of several autoimmune diseases. The potential role of B lymphocytes in the pathogenesis of granulomatous uveitis associated with VKH disease is exemplified within several studies. The early initial-onset acute uveitic phase typically exhibits granulomatous choroiditis with secondary exudative retinal detachment and optic disc hyperemia and swelling, subsequently involving the anterior segment if not adequately treated. The disease eventually progresses to chronic recurrent granulomatous anterior uveitis with progressive posterior segment depigmentation resulting in “sunset glow fundus” appearance and chorioretinal atrophy if not properly controlled. Chronically evolving disease is more refractory to treatment and, consequently, vision-threatening complications have been recognized to occur in the chronic recurrent phase of the disease. Conventional treatment with early high-dose systemic corticosteroids is not sufficient to prevent chronic evolution. Addition of immunomodulatory therapy with mycophenolate mofetil as first-line therapy combined with systemic corticosteroids in patients with acute initial-onset disease prevents progression to chronic evolution, late complications, vitiligo, and poliosis. Furthermore, patients under such combined therapy were able to discontinue treatment without relapse of inflammation. These findings suggest that there is a therapeutic window of opportunity for highly successful treatment during the early initial-onset acute uveitic phases, likely because the underlying disease process is not fully matured. It is hypothesized that early and aggressive immunosuppressive therapy will prevent remnant epitope generation in the initiation of the autoimmune process, the so-called primary response. B cell depleting therapy with the anti-CD20 monoclonal antibody rituximab is effective in patients with refractory chronic recurrent granulomatous uveitis. The good response after rituximab therapy reinforces the idea of an important role of B cells in the pathogenesis or progression of chronic recurrent uveitis associated with VKH disease.

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Liu, Yong, Zhihui Zhang, Dongran Han, Yiding Zhao, Xiaoning Yan, and Shengnan Cui. "Association between environmental chemicals co-exposure and peripheral blood immune-inflammatory indicators." Frontiers in Public Health 10 (November 22, 2022). http://dx.doi.org/10.3389/fpubh.2022.980987.

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Chronic inflammation is closely related to chronic inflammatory diseases, autoimmune diseases and cancer. Few studies have evaluated the effects of exposure to multiple chemical combinations on immunoinflammatory related indicators and their possible molecular mechanisms. This study explored the effect of exposure to various chemicals on immune-inflammatory biomarkers and its molecular mechanism. Using data from 1,723 participants in the National Health and Nutrition Examination Survey (NHANES, 2011–2012), the aim was to determine the association between chemical mixtures and immunoinflammatory biomarkers [including White blood cell (Wbc), neutrophil (Neu), lymphocytes (Lym), and Neutrophil-to-lymphocyte ratio (NLR)] using linear regression model, weighted quantile sum regression (WQSR) model, and bayesian nuclear machine regression (BKMR) model. Meanwhile, functional enrichment analysis and protein–protein interaction network establishment were performed to explore the molecular mechanism of inflammation induced by high-weight chemicals. In the linear regression model established for each single chemical, the four immunoinflammatory biomarkers were positively correlated with polycyclic aromatic hydrocarbons (PAHs), negatively correlated with perfluoroalkyl substances (PFASs), and positively or negatively correlated with metallic and non-metallic elements. WQSR model showed that cadmium (Cd), perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDE) had the highest weights. In BKMR analysis, the overall effect of chemical mixtures was significantly associated with Lym and showed an increasing trend. The hub genes in high-weight chemicals inflammation-related genes were interleukin-6 (IL6), tumor necrosis factor (TNF), and interleukin-1B (IL1B), etc. They were mainly enriched in inflammatory response, Cytokine-cytokine receptor interaction, Th17 cell differentiation and IL-17 signaling pathway. The above results show that exposure to environmental chemical cocktails primarily promotes an increase in Lym across the immune-inflammatory spectrum. The mechanism leading to the inflammatory response may be related to the activation of IL-6 amplifier by the co-exposure of environmental chemicals.

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Journal articles on the topic 'Lymphocyte precursors, chronic inflammation, autoimmune diseases'

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