Academic literature on the topic 'Lymphocyte precursors, chronic inflammation, autoimmune diseases'

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

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.

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.

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.

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.

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.

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.

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.

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.

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.