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1
Bird, Lucy. "NKT cells linked to immune tolerance breakdown." Nature Reviews Immunology 8, no. 7 (July 2008): 493. http://dx.doi.org/10.1038/nri2370.
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Hampe, Christiane S., and Hiroshi Mitoma. "A Breakdown of Immune Tolerance in the Cerebellum." Brain Sciences 12, no. 3 (February 28, 2022): 328. http://dx.doi.org/10.3390/brainsci12030328.
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Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum.
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Emmanuel K, Mugisha. "Adaptive Immunity and Autoimmune Disease: Mechanisms, Pathogenesis, and Therapeutic Approaches." NEWPORT INTERNATIONAL JOURNAL OF BIOLOGICAL AND APPLIED SCIENCES 5, no. 3 (December 1, 2024): 44–48. https://doi.org/10.59298/nijbas/2024/5.3.444811.
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Autoimmune diseases arise when the adaptive immune system mistakenly targets self-antigens, leading to chronic inflammation and tissue damage. This review explores the mechanisms by which adaptive immunity, particularly T and B lymphocyte responses, contributes to the development and persistence of autoimmune diseases. It examines the underlying factors that influence autoreactivity, including genetic susceptibility, environmental triggers, and breakdowns in immune tolerance. Additionally, we discuss the role of T cells, B cells, and autoantibodies in various autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis. Insights into the molecular and cellular pathways driving autoimmunity have informed current therapeutic strategies, including immune modulation and targeted biologics. This review highlights the challenges of restoring tolerance in autoimmune disease management and outlines future directions for research and therapeutic development. Keywords: Adaptive immunity, autoimmunity, T cells, B cells, immune tolerance, autoimmune diseases
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Kamyshny, Alex, Denis Putilin, and Vita Kamyshna. "BREAKDOWN IN PERIPHERAL IMMUNE TOLERANCE IN EXPERIMENTAL DIABETES MELLITUS." Journal of Molecular Pathophysiology 5, no. 3 (2016): 31. http://dx.doi.org/10.5455/jmp.20160609022446.
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Cheng, Mickie, and Lawrence Nelson. "Mechanisms and Models of Immune Tolerance Breakdown in the Ovary." Seminars in Reproductive Medicine 29, no. 04 (July 2011): 308–16. http://dx.doi.org/10.1055/s-0031-1280916.
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Bukhari, Shoiab, Aaron F. Mertz, and Shruti Naik. "Eavesdropping on the conversation between immune cells and the skin epithelium." International Immunology 31, no. 7 (February 5, 2019): 415–22. http://dx.doi.org/10.1093/intimm/dxy088.
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Abstract The skin epithelium covers our body and serves as a vital interface with the external environment. Here, we review the context-specific interactions between immune cells and the epithelium that underlie barrier fitness and function. We highlight the mechanisms by which these two systems engage each other and how immune–epithelial interactions are tuned by microbial and inflammatory stimuli. Epithelial homeostasis relies on a delicate balance of immune surveillance and tolerance, breakdown of which results in disease. In addition to their canonical immune functions, resident and recruited immune cells also supply the epithelium with instructive signals to promote repair. Decoding the dialogue between immunity and the epithelium therefore has great potential for boosting barrier function or mitigating inflammatory epithelial diseases.
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Peter, Elise, Isabelle Treilleux, Valentin Wucher, Emma Jougla, Alberto Vogrig, Daniel Pissaloux, Sandrine Paindavoine, et al. "Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo–Associated Paraneoplastic Cerebellar Degeneration." Neurology - Neuroimmunology Neuroinflammation 9, no. 5 (July 12, 2022): e200015. http://dx.doi.org/10.1212/nxi.0000000000200015.
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Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis.MethodsUsing clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs.ResultsYo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G–plasma cells.DiscussionThese data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.
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Jones, DEJ, JM Palmer, AJ Robe, MH Bone, AD Burt, SJ Yeaman, JA Kirby, and MF Bassendine. "A Novel Mechanism of Immune Tolerance Breakdown and Autoimmune Disease Induction." Clinical Science 100, s44 (February 1, 2001): 13P. http://dx.doi.org/10.1042/cs100013pb.
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Liao, Xiaofeng, Alec M. Reihl, and Xin M. Luo. "Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells." Journal of Immunology Research 2016 (2016): 1–15. http://dx.doi.org/10.1155/2016/6269157.
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Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensivein vitroandin vivostudies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.
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P. Singh, Ram, David S. Bischoff, Satendra S Singh, and Bevra H. Hahn. "Peptide-based immunotherapy in lupus: Where are we now?" Rheumatology and Immunology Research 4, no. 3 (September 1, 2023): 139–49. http://dx.doi.org/10.2478/rir-2023-0020.
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Abstract In autoimmune rheumatic diseases, immune hyperactivity and chronic inflammation associate with immune dysregulation and the breakdown of immune self-tolerance. A continued, unresolved imbalance between effector and regulatory immune responses further exacerbates inflammation that ultimately causes tissue and organ damage. Many treatment modalities have been developed to restore the immune tolerance and immmunoregulatory balance in autoimmune rheumatic diseases, including the use of peptide-based therapeutics or the use of nanoparticles-based nanotechnology. This review summarizes the state-of-the-art therapeutic use of peptide-based therapies in autoimmune rheumatic diseases, with a specific focus on lupus.
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Liong, Stella, Felicia Liong, Mitra Mohsenipour, Elisa L. Hill-Yardin, Mark A. Miles, and Stavros Selemidis. "Early-Life Respiratory Syncytial Virus (RSV) Infection Triggers Immunological Changes in Gut-Associated Lymphoid Tissues in a Sex-Dependent Manner in Adulthood." Cells 13, no. 20 (October 18, 2024): 1728. http://dx.doi.org/10.3390/cells13201728.
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Severe respiratory syncytial virus (RSV) infection during early life has been linked to gut dysbiosis, which correlates with increased disease severity and a higher risk of developing asthma later in life. However, the impact of such early-life RSV infections on intestinal immunity in adulthood remains unclear. Herein, we show that RSV infection in 3-week-old mice induced persistent differential natural killer (NK) and T cell profiles within the lungs and gastrointestinal (GI) lymphoid tissues (GALT) in adulthood. Notably, male mice exhibited more pronounced RSV-induced changes in immune cell populations in both the lungs and GALT, while female mice displayed greater resilience. Importantly, early-life RSV infection was associated with the chronic downregulation of CD69-expressing T lymphocytes, particularly T regulatory cells in Peyer’s patches, which could have a significant impact on T cell functionality and immune tolerance. We propose that RSV infection in early life is a trigger for the breakdown in immune tolerance at mucosal surfaces, with potential implications for airways allergic disease, food allergies, and other GI inflammatory diseases.
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Inaoki, Makoto, Shinichi Sato, Bennett C. Weintraub, Christopher C. Goodnow, and Thomas F. Tedder. "CD19-Regulated Signaling Thresholds Control Peripheral Tolerance and Autoantibody Production in B Lymphocytes." Journal of Experimental Medicine 186, no. 11 (December 1, 1997): 1923–31. http://dx.doi.org/10.1084/jem.186.11.1923.
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The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.
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Singh, Ram P., David S. Bischoff, and Bevra H. Hahn. "CD8+ T regulatory cells in lupus." Rheumatology and Immunology Research 2, no. 3 (September 1, 2021): 147–56. http://dx.doi.org/10.2478/rir-2021-0021.
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Abstract T regulatory cells (Tregs) have a key role in the maintenance of immune homeostasis and the regulation of immune tolerance by preventing the inflammation and suppressing the autoimmune responses. Numerical and functional deficits of these cells have been reported in systemic lupus erythematosus (SLE) patients and mouse models of SLE, where their imbalance and dysregulated activities have been reported to significantly influence the disease pathogenesis, progression and outcomes. Most studies in SLE have focused on CD4+ Tregs and it has become clear that a critical role in the control of immune tolerance after the breakdown of self-tolerance is provided by CD8+ Tregs. Here we review the role, cellular and molecular phenotypes, and mechanisms of action of CD8+ Tregs in SLE, including ways to induce these cells for immunotherapeutic modulation in SLE.
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Ortega-Hernandez, Oscar-Danilo, Nancy-Agmon Levin, Arie Altman, and Yehuda Shoenfeld. "Infectious Agents in the Pathogenesis of Primary Biliary Cirrhosis." Disease Markers 29, no. 6 (2010): 277–86. http://dx.doi.org/10.1155/2010/923928.
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Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria,Escherichia Coli, andNosphingobium aromaticivoransare the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.
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Gholijani, Nasser, Gholamreza Daryabor, and Fatemeh Rezaei Kahmini. "T cell-Intrinsic Peripheral Tolerance: A Checkpoint Target to Treat Autoimmunity." Journal of Cellular Immunology 6, no. 2 (2024): 87–97. http://dx.doi.org/10.33696/immunology.6.194.
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Recent advances highlight the importance of intrinsic peripheral tolerance in the maintenance of a steady state. Peripheral tolerance is tightly regulated and any alteration in its biological process contributes to the breakdown of immune tolerance and induction of autoimmunity. Recent evidence related to T cell tolerance mechanisms inspired researchers to treat autoimmunity via modulation of tolerant checkpoints that are involved in intrinsic T-cell tolerance such as ignorance, anergy, exhaustion, and senescence. So, understanding the underlying mechanisms might present an opportunity for therapeutic intervention. Here, we primarily highlight the importance of T cell-intrinsic peripheral tolerance mechanisms and their contribution to the development of autoimmune disorders, and then briefly discuss potential strategies to normalize T cell hemostasis in autoimmunity.
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Khan, Asif Iqbal, and Yi Xin. "The Role of Dietary Peptides and the Gut Bacteria in Maintaining Intestinal and Homeostatic Balance." Microbiological & Immunological Communications 2, no. 1 (June 30, 2023): 41–63. http://dx.doi.org/10.55627/mic.002.01.0191.
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The gut bacteria and the host have a mutually beneficial relationship. This complex interdependence plays a critical role in resource collection via prebiotic carbohydrate breakdown in the intestinal tract, the supply of important nutrients, vitamin synthesis, metabolic operations and maintenance, as well as sheltering against colonization of pathogens, and opportunistic fungal infections. This leads to ‘gut microbiota homeostasis’ or ‘gut microbial equilibrium’, i.e., a stable and healthy gastrointestinal tract microbial community. In this review, we discuss the gut micro biome’s role in the development of the immune system, including oral tolerance and immunity. The therapeutic approach must begin with the interaction of functional foods and enterocytes. Furthermore, we discuss current knowledge and the promising application of functional foods that may stimulate the immune system to perform a further pro- or anti-inflammatory activity in the gastrointestinal system. When evaluating the immune system function of nutraceuticals, designs that modulate the membrane must be used whenever possible. Moreover, nutraceutical products’ claim to be immunity boosters should have valid and accurate data to back it up. While assessing the stimulation of blood cell immunity through functional foods is more useful, it does not accurately reflect physical reality, and an investigation into the colonic immune response is a better way to understand it.
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Yang, Shu-Han, Cai-yue Gao, Liang Li, Christopher Chang, Patrick S. C. Leung, M. Eric Gershwin, and Zhe-Xiong Lian. "The molecular basis of immune regulation in autoimmunity." Clinical Science 132, no. 1 (January 5, 2018): 43–67. http://dx.doi.org/10.1042/cs20171154.
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Autoimmune diseases can be triggered and modulated by various molecular and cellular characteristics. The mechanisms of autoimmunity and the pathogenesis of autoimmune diseases have been investigated for several decades. It is well accepted that autoimmunity is caused by dysregulated/dysfunctional immune susceptible genes and environmental factors. There are multiple physiological mechanisms that regulate and control self-reactivity, but which can also lead to tolerance breakdown when in defect. The majority of autoreactive T or B cells are eliminated during the development of central tolerance by negative selection. Regulatory cells such as Tregs (regulatory T) and MSCs (mesenchymal stem cells), and molecules such as CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and IL (interleukin) 10 (IL-10), help to eliminate autoreactive cells that escaped to the periphery in order to prevent development of autoimmunity. Knowledge of the molecular basis of immune regulation is needed to further our understanding of the underlying mechanisms of loss of tolerance in autoimmune diseases and pave the way for the development of more effective, specific, and safer therapeutic interventions.
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Yu, Jin, Susanne Heck, Vivek Patel, Jared Levan, Yu Yu, James B. Bussel, and Karina Yazdanbakhsh. "Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura." Blood 112, no. 4 (August 15, 2008): 1325–28. http://dx.doi.org/10.1182/blood-2008-01-135335.
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Abstract Immune thrombocytopenic purpura (ITP) is characterized by the presence of antiplatelet autoantibodies as a result of loss of tolerance. CD4+CD25+ regulatory T cells (Tregs) are important for maintenance of peripheral tolerance. Decreased levels of peripheral Tregs in patients with ITP have been reported. To test whether inefficient production or reduced immunosuppressive activity of Tregs contributes to loss of tolerance in patients with chronic ITP, we investigated the frequency and function of their circulating CD4+CD25hi Tregs. We found a com-parable frequency of circulating CD4+CD25hiFoxp3+ Tregs in patients and controls (n = 16, P > .05). However, sorted CD4+CD25hi cells from patients with chronic ITP (n = 13) had a 2-fold reduction of in vitro immunosuppressive activity compared with controls (n = 10, P < .05). The impaired suppression was specific to Tregs as shown by cross-mixing experiments with T cells from controls. These data suggest that functional defects in Tregs contribute to breakdown of self-tolerance in patients with chronic ITP.
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Matsuzaka, Yasunari, and Ryu Yashiro. "Immune Modulation Using Extracellular Vesicles Encapsulated with MicroRNAs as Novel Drug Delivery Systems." International Journal of Molecular Sciences 23, no. 10 (May 18, 2022): 5658. http://dx.doi.org/10.3390/ijms23105658.
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Self-tolerance involves protection from self-reactive B and T cells via negative selection during differentiation, programmed cell death, and inhibition of regulatory T cells. The breakdown of immune tolerance triggers various autoimmune diseases, owing to a lack of distinction between self-antigens and non-self-antigens. Exosomes are non-particles that are approximately 50–130 nm in diameter. Extracellular vesicles can be used for in vivo cell-free transmission to enable intracellular delivery of proteins and nucleic acids, including microRNAs (miRNAs). miRNAs encapsulated in exosomes can regulate the molecular pathways involved in the immune response through post-transcriptional regulation. Herein, we sought to summarize and review the molecular mechanisms whereby exosomal miRNAs modulate the expression of genes involved in the immune response.
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Zouali, Moncef. "B Cells at the Cross-Roads of Autoimmune Diseases and Auto-Inflammatory Syndromes." Cells 11, no. 24 (December 12, 2022): 4025. http://dx.doi.org/10.3390/cells11244025.
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Whereas autoimmune diseases are mediated primarily by T and B cells, auto-inflammatory syndromes (AIFS) involve natural killer cells, macrophages, mast cells, dendritic cells, different granulocyte subsets and complement components. In contrast to autoimmune diseases, the immune response of patients with AIFS is not associated with a breakdown of immune tolerance to self-antigens. Focusing on B lymphocyte subsets, this article offers a fresh perspective on the multiple cross-talks between both branches of innate and adaptive immunity in mounting coordinated signals that lead to AIFS. By virtue of their potential to play a role in adaptive immunity and to exert innate-like functions, B cells can be involved in both promoting inflammation and mitigating auto-inflammation in disorders that include mevalonate kinase deficiency syndrome, Kawasaki syndrome, inflammatory bone disorders, Schnitzler syndrome, Neuro-Behçet’s disease, and neuromyelitis optica spectrum disorder. Since there is a significant overlap between the pathogenic trajectories that culminate in autoimmune diseases, or AIFS, a more detailed understanding of their respective roles in the development of inflammation could lead to designing novel therapeutic avenues.
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Uggenti, Carolina, Alice Lepelley, and Yanick J. Crow. "Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies." Annual Review of Immunology 37, no. 1 (April 26, 2019): 247–67. http://dx.doi.org/10.1146/annurev-immunol-042718-041257.
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Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self–nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid–driven inflammation.
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Ridgway, W. M., M. Fassò, A. Lanctot, C. Garvey, and C. G. Fathman. "Breaking self-tolerance in nonobese diabetic mice." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1657–62. http://dx.doi.org/10.1084/jem.183.4.1657.
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Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.
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Sato, Shinsuke, Tasuku Kawano, Erina Ike, Kento Takahashi, Junji Sakurai, Tomomitsu Miyasaka, Yasuo Miyauchi, Fumiaki Ishizawa, Motoaki Takayanagi, and Tomoko Takahashi. "IL-1β Derived Th17 Immune Responses Are a Critical Factor for Neutrophilic-Eosinophilic Airway Inflammation on Psychological Stress-Induced Immune Tolerance Breakdown in Mice." International Archives of Allergy and Immunology 184, no. 8 (2023): 797–807. http://dx.doi.org/10.1159/000529108.
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<b><i>Introduction:</i></b> Asthma is an inflammatory reaction mediated by type 2 helper T (Th2) cells and is known to increase eosinophil levels. Our previous study showed that stress-related asthma can cause neutrophilic and eosinophilic airway inflammation by suppressing immune tolerance. However, the mechanism of stress-induced neutrophilic and eosinophilic airway inflammation remains unclear. Therefore, to elucidate the cause of neutrophilic and eosinophilic inflammation, we investigated the immune response during the induction of airway inflammation. In addition, we focused on the relationship between immune response modulation immediately after stress exposure and the development of airway inflammation. <b><i>Methods:</i></b> Asthmatic mice were induced by three phases using female BALB/c mice. During the first phase, the mice were made to inhale ovalbumin (OVA) to induce immune tolerance before sensitization. Some mice were exposed to restraint stress during the induction of immune tolerance. In the second phase, the mice were sensitized with OVA/alum intraperitoneal injections. In the final phase, onset of asthma was induced through OVA exposure. Asthma development was evaluated based on airway inflammation and T-cell differentiation. Microarray and qPCR analyses were used to enumerate candidate factors to investigate the starting point of immunological modification immediately after stress exposure. Furthermore, we focused on interleukin-1β (IL-1β), which initiates these immune modifications, and performed experiments using its receptor blocker interleukin-1 receptor antagonist (IL-1RA). <b><i>Results:</i></b> Stress exposure during immune tolerance induction increased eosinophil and neutrophil airway infiltration. This inflammation was associated with decreased T regulatory cell levels and increased Th2 and Th17 levels in bronchial lymph node cells. Microarray and qPCR analyses showed that the initiation of Th17 differentiation might be triggered by stress exposure during tolerance induction. IL-1RA administration during stress exposure suppressed neutrophilic and eosinophilic airway inflammation via Th17 reduction and Treg increase. <b><i>Conclusions:</i></b> Our results show that psychological stress causes both eosinophilic and neutrophilic inflammatory responses due to the breakdown of immune tolerance. Furthermore, stress-induced inflammation can be abolished using IL-1RA.
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Yudiati, Ervia, Rustadi Rustadi, Fanny Iriany Ginzel, Jelita Rahma Hidayati, Mila Safitri Rizfa, Nuril Azhar, Muhammad Salauddin Ramadhan Djarod, Eny Heriyati, and Rabia Alghazeer. "Oral Administration of Alginate Oligosaccharide from Padina sp. Enhances Tolerance of Oxygen Exposure Stress in Zebrafish (Danio rerio)." ILMU KELAUTAN: Indonesian Journal of Marine Sciences 25, no. 1 (February 21, 2020): 7–14. http://dx.doi.org/10.14710/ik.ijms.25.1.7-14.
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Alginate is rich in bioactive compounds and has been known to act as a stimulator on the innate immune system. The objective of this study is to determine polysaccharide and oligosaccharide alginate yield, that percentage inhibition with a different type of extraction, to evaluate growth performance as well as immune response by oxygen stress tolerance. Thermal heating with oven laboratory at 140oC for 4.5 hr was done to breakdown the polysaccharide into oligosaccharide. The extraction was conducted by maceration, filtration, precipitation, and centrifugation. Factorial design with two factors was implemented to 260 Zebrafish and reared in thirteen aquariums (20 fish per aquarium) for 12 days. Zebrafish was fed at different dose (4.0g; 6.0g; 8.0g.kg-1) and different type of extraction [noEDTA/noKCl; KCl; EDTA and (EDTAandKCl)]. The evaluation of radical scavenging activity was done spectrophotometrically at 515 nm. Results showed that the highest alginate yield either polysaccharide or oligosaccharide was gained from KCL treatments, percentage inhibition (82.61%), growth performance as well as tolerance of stress (P<0.05). The best growth performance was reached in oligosaccharide supplementation at 6.0g.kg-1 treatment. It can be concluded that alginate oliogosaccharide produced by thermal heating enhanced the antioxidant activity, boost the fish’s immune system, proofed by better growth performance and more tolerant to the low oxygen stress.
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Hoyne, Gerard F. "Mechanisms That Regulate Peripheral Immune Responses to Control Organ-Specific Autoimmunity." Clinical and Developmental Immunology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/294968.
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The immune system must balance the need to maintain a diverse repertoire of lymphocytes to be able to fight infection with the need to maintain tolerance to self-proteins. The immune system places strict regulation over the ability of T cells to produce the major T cell growth factor interleukin 2 as this cytokine can influence a variety of immune outcomes. T cells require the delivery of two signals, one through the antigen receptor and a second through the costimulatory receptor CD28. The immune system uses a variety of E3 ubiquitin ligases to target signaling proteins that function downstream of the TCR and CD28 receptors. Mutations in these E3 ligases can lead to a breakdown in immune tolerance and development of autoimmunity. This paper will examine the role of a range of E3 ubiquitin ligases and signaling pathways that influence the development of T-cell effector responses and the development of organ-specific autoimmune diseases such as type 1 diabetes.
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Abraham, R., A. Choudhury, S. K. Basu, V. Bal, and S. Rath. "Disruption of T cell tolerance by directing a self antigen to macrophage-specific scavenger receptors." Journal of Immunology 158, no. 9 (May 1, 1997): 4029–35. http://dx.doi.org/10.4049/jimmunol.158.9.4029.
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Abstract Breakdown of immune self tolerance is speculated to cause autoimmune diseases, but most studies on tolerance use foreign molecules as targets. In this study, we show another approach using delivery of a maleylated self protein to macrophage-specific scavenger receptors. Mice generate Abs against the maleylated form of a ubiquitous self Ag, mouse serum albumin (MSA), although native MSA is nonimmunogenic. This generation of anti-maleyl MSA Abs depends on binding of maleyl MSA to scavenger receptors in vivo, since coinjection of a serologically unrelated scavenger receptor ligand inhibits it, suggesting that the Ab response is T cell dependent. Spleen cells as well as nylon adherence-purified splenic T cells from maleyl MSA-immune mice proliferate in response to both maleyl MSA and MSA; this response is blocked by anti-MHC class II mAbs, and the autoimmune cells can recognize at least five 15-mer peptides from the MSA sequence, establishing that T cell tolerance to MSA has been broken in these mice. Maleyl MSA and MSA are recognized equally well, provided the scavenger receptor-specific delivery of maleyl MSA is blocked during stimulation in vitro, indicating that maleyl MSA-specific non-self peptides are unlikely to play a major role in the observed disruption of T cell tolerance. Thus, delivery of some self molecules to scavenger receptors may lead to disruption of immune tolerance. These results are relevant to mechanisms of immune tolerance and the etiopathogenesis of autoimmunity.
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Uraki, Ryuta, Masaki Imai, Mutsumi Ito, Hiroaki Shime, Mizuyu Odanaka, Moe Okuda, Yoshihiro Kawaoka, and Sayuri Yamazaki. "Foxp3+ CD4+ regulatory T cells control dendritic cells in inducing antigen-specific immunity to emerging SARS-CoV-2 antigens." PLOS Pathogens 17, no. 12 (December 9, 2021): e1010085. http://dx.doi.org/10.1371/journal.ppat.1010085.
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Regulatory T (Treg) cells, which constitute about 5–10% of CD4+T cells expressing Foxp3 transcription factor and CD25(IL-2 receptor α chain), are key regulators in controlling immunological self-tolerance and various immune responses. However, how Treg cells control antigen-specific immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. In this study, we examined the effect of transient breakdown of the immunological tolerance induced by Treg-cell depletion on adaptive immune responses against administered SARS-CoV-2 antigen, spike protein 1 (S1). Notably, without the use of adjuvants, transient Treg-cell depletion in mice induced anti-S1 antibodies that neutralized authentic SARS-CoV-2, follicular helper T cell formation and S1-binding germinal center B cell responses, but prevented the onset of developing autoimmune diseases. To further clarify the mechanisms, we investigated maturation of dendritic cells (DCs), which is essential to initiate antigen-specific immunity. We found that the transient Treg-cell depletion resulted in maturation of both migratory and resident DCs in draining lymph nodes that captured S1-antigen. Moreover, we observed S1-specific CD4+ T cells and CD8+ T cells with interferon-γ production. Thus, captured S1 was successfully presented by DCs, including cross-presentation to CD8+ T cells. These data indicate that transient Treg-cell depletion in the absence of adjuvants induces maturation of antigen-presenting DCs and succeeds in generating antigen-specific humoral and cellular immunity against emerging SARS-CoV-2 antigens. Finally, we showed that SARS-CoV-2 antigen-specific immune responses induced by transient Treg-cell depletion in the absence of adjuvants were compatible with those induced with an effective adjuvant, polyriboinosinic:polyribocytidyl acid (poly IC) and that the combination of transient Treg-cell depletion with poly IC induced potent responses. These findings highlight the capacity for manipulating Treg cells to induce protective adaptive immunity to SARS-CoV-2 with activating antigen-presenting DCs, which may improve the efficacy of ongoing vaccine therapies and help enhance responses to emerging SARS-CoV-2 variants.
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Abdel-Gadir, Azza, Amir H. Massoud, and Talal A. Chatila. "Antigen-specific Treg cells in immunological tolerance: implications for allergic diseases." F1000Research 7 (January 10, 2018): 38. http://dx.doi.org/10.12688/f1000research.12650.1.
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Allergic diseases are chronic inflammatory disorders in which there is failure to mount effective tolerogenic immune responses to inciting allergens. The alarming rise in the prevalence of allergic diseases in recent decades has spurred investigations to elucidate the mechanisms of breakdown in tolerance in these disorders and means of restoring it. Tolerance to allergens is critically dependent on the generation of allergen-specific regulatory T (Treg) cells, which mediate a state of sustained non-responsiveness to the offending allergen. In this review, we summarize recent advances in our understanding of mechanisms governing the generation and function of allergen-specific Treg cells and their subversion in allergic diseases. We will also outline approaches to harness allergen-specific Treg cell responses to restore tolerance in these disorders.
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Chen, Min, Yui-Hsi Wang, Yihong Wang, Hector Sandoval, Yong-Jun Liu, and Jin Wang. "Autoimmunity Caused by Cell Type-Specific Deficiency in Apoptosis." Blood 106, no. 11 (November 16, 2005): 3913. http://dx.doi.org/10.1182/blood.v106.11.3913.3913.
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Abstract Apoptosis in the immune system is essential for maintaining self-tolerance. Defective apoptosis causes systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone does not induce significant autoimmune responses, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. To study whether apoptosis in dendritic cells (DCs) regulates self-tolerance, we generated transgenic mice expressing a potent caspase inhibitor from baculovirus, p35, in dendritic cells (DC-p35). DC-p35 transgenic mice displayed defective apoptosis in DCs, leading to DC accumulation, chronic lymphocyte activation and systemic autoimmune manifestations resembling the phenotypes in Fas-deficient lpr mice. Our results suggest that apoptosis in DCs is critical for limiting lymphocyte activation and preventing autoimmunity.
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Rivas, Magali Noval, Yi T. Koh, Andrew Chen, Annie Nguyen, Young Ho Lee, Greg Lawson, and Talal A. Chatila. "MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice." Journal of Clinical Investigation 122, no. 5 (May 1, 2012): 1933–47. http://dx.doi.org/10.1172/jci40591.
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Pardo-Camacho, Cristina, Ana M. González-Castro, Bruno K. Rodiño-Janeiro, Marc Pigrau, and María Vicario. "Epithelial immunity: priming defensive responses in the intestinal mucosa." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 2 (February 1, 2018): G247—G255. http://dx.doi.org/10.1152/ajpgi.00215.2016.
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As the largest interface between the outside and internal milieu, the intestinal epithelium constitutes the first structural component facing potential luminal threats to homeostasis. This single-cell layer is the epicenter of a tightly regulated communication network between external and internal factors that converge to prime defensive responses aimed at limiting antigen penetration and the maintenance of intestinal barrier function. The defensive role developed by intestinal epithelial cells (IEC) relies largely on the variety of receptors they express at both extracellular (apical and basolateral) and intracellular compartments, and the capacity of IEC to communicate with immune and nervous systems. IEC recognize pathogen-associated molecules by innate receptors that promote the production of mucus, antimicrobial substances, and immune mediators. Epithelial cells are key to oral tolerance maintenance and also participate in adaptive immunity through the expression of immunoglobulin (Ig) receptors and by promoting local Ig class switch recombination. In IEC, different types of antigens can be sensed by multiple immune receptors that share signaling pathways to assure effective responses. Regulated defensive activity maintains intestinal homeostasis, whereas a breakdown in the control of epithelial immunity can increase the intestinal passage of luminal content and microbial invasion, leading to inflammation and tissue damage. In this review, we provide an updated overview of the type of immune receptors present in the human intestinal epithelium and the responses generated to promote effective barrier function and maintain mucosal homeostasis.
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SUTTON, Ian, and John B. WINER. "The immunopathogenesis of paraneoplastic neurological syndromes." Clinical Science 102, no. 5 (April 12, 2002): 475–86. http://dx.doi.org/10.1042/cs1020475.
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Paraneoplastic neurological syndromes are rare non-metastatic complications of cancer that have an immune-mediated aetiology. The central and peripheral nervous systems are considered to be immune-privileged sites, since the presence of the ‘blood-brain/nerve barrier’ means that antigens sequestered within the nervous system do not normally induce an immune response. Aberrant expression of a neuronal antigen by a tumour arising outside this barrier can lead to the breakdown of immune tolerance to the nervous system. However, in many cases the immune mechanisms that result in neurological dysfunction remain poorly defined. Furthermore, aberrant expression of neuronal antigens can be detected in many tumours that are not complicated by non-metastatic neurological syndromes. This review article examines current concepts in the immunopathogenesis of paraneoplastic neurological syndromes.
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Frosali, Simona, Danilo Pagliari, Giovanni Gambassi, Raffaele Landolfi, Franco Pandolfi, and Rossella Cianci. "How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology." Journal of Immunology Research 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/489821.
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The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.
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Chentoufi, Aziz Alami, and Vincent Geenen. "Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes." Clinical and Developmental Immunology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/349368.
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Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting isletβcells, leading to the breakdown of immune homeostasis with an enrichment of isletβcell reactive effector T cells and a deficiency ofβcell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases.
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Xian, Hongxu. "Circulating oxidized mitochondrial DNA drives autoimmunity." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 0012_4129. http://dx.doi.org/10.4049/jimmunol.212.supp.0012.4129.
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Abstract The innate immune system instructs adaptive immune activation to maintain host homeostasis, dysregulations of which underly many immune pathologies. Despite the multifold interactions, it is unclear whether innate immune responses are sufficient to enable adaptive activation and provoke disease. Breakdown of self-tolerance in T and B cells results in autoimmunity, yet innate immune control of self-reactivity is poorly understood. Mitochondrial DNA (mtDNA) recently has emerged in autoimmune disorders. However, it is unclear how mitochondrial stress associated with inflammation skews downstream aberrant adaptive responses. Here we show circulating cell-free (ccf-) oxidized (Ox-) mtDNA, induced during NLRP3 inflammasome activation, drives antibody mediated systematic autoimmunity. Abundant ccf-Ox-mtDNA in mice triggered by persistent peritonitis leads to SLE-like pathologies, development of which specifically relies on the oxidation of mtDNA. Although non-oxidized and Ox-mtDNA are both interferogenic to induce IFN-I signaling in pDCs, only Ox-mtDNA induces caspase-1 activation and IL-21 and IL-1β production, required for Tfh responses to support antibody production, leading to GC reactions and pathogenic antibodies deposition on kidney. This study establishes Ox-mtDNA ascribed by diverse chronic inflammatory diseases as a key to engage self-tolerance breach, highlights the innate immune origins of autoimmunity, and provides therapeutic targets for autoimmune disorders.
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Fritzler, M. J., and M. Salazar. "Diversity and origin of rheumatologic autoantibodies." Clinical Microbiology Reviews 4, no. 3 (July 1991): 256–69. http://dx.doi.org/10.1128/cmr.4.3.256.
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A hallmark of sera from patients with systemic rheumatic diseases is the presence of circulating autoantibodies directed against nuclear antigens. The identification of the antigens binding to these antibodies has provided the cell biologist and the immunologist with important tools to study cell structure, cell function, and the processes underlying the immune response. Through the elucidation of autoantibody specificities, the clinician has been provided with a better appreciation of the diagnostic and prognostic significance of autoantibodies. Many autoantigens, including those directed against components in the nuclear matrix, chromosomes, Golgi apparatus, and other intracellular antigens, are not yet characterized nor is their clinical significance established. The mechanisms leading to the breakdown of tolerance and the appearance of autoantibodies are not fully understood. Molecular mimicry at an interspecies or an intracellular level may be involved in altering immune tolerance. On the other hand, studies of epitopes on human autoantigens has provided compelling evidence that most autoantibody responses seen in systemic rheumatic diseases are driven by endogenous antigen.
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Porciello, Nicla, Martina Kunkl, and Loretta Tuosto. "CD28 between tolerance and autoimmunity: the side effects of animal models." F1000Research 7 (May 30, 2018): 682. http://dx.doi.org/10.12688/f1000research.14046.1.
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Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans.
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This, Sébastien, Stefanie F. Valbon, Marie-Ève Lebel, and Heather J. Melichar. "Strength and Numbers: The Role of Affinity and Avidity in the ‘Quality’ of T Cell Tolerance." Cells 10, no. 6 (June 17, 2021): 1530. http://dx.doi.org/10.3390/cells10061530.
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The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the ‘function’ and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the ‘quality’ of anergic and regulatory T cell populations.
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Robertson, Sarah. "Reproductive Immunology and Embryo Acceptance." Fertility & Reproduction 05, no. 04 (December 2023): 237. http://dx.doi.org/10.1142/s2661318223740511.
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Pregnancy is a test of the fundamental laws of transplantation immunology - the coexistence of genetically disparate tissues without host immune rejection. Advances over recent decades show that implantation and placental development depend on an active state of maternal immune tolerance, and breakdown of tolerance is a key contributor to infertility and recurrent pregnancy loss. Tolerance in pregnancy depends on regulatory T (Treg) cells, which are critical to inhibit effector immunity, constrain inflammation, and support maternal vascular adaptations that allow placental access to maternal nutrient supply. Treg cell defects are implicated in disorders of embryo implantation and placental development, but the origins of Treg cell dysfunction are unknown. In recent studies, we have comprehensively analysed the phenotypes and transcriptional profile of peripheral blood Treg cells in individuals with early pregnancy failure (recurrent miscarriage and recurrent implantation failure). Compared to fertile women, women with early pregnancy failure have fewer total Treg cells and altered Treg cell phenotypes, accompanied by lower Treg:Th1 and Treg:Th17 ratios. RNAseq demonstrates an aberrant Treg cell gene expression profile in early pregnancy failure, with upregulation of pro-inflammatory genes including CSF2, IL4, IL17A, IL21, and IFNG. Our data indicate that Treg cell defects in women with early pregnancy failure can arise due to loss of lineage fidelity associated with impaired FOXP3 regulation. Factors including metabolic function, luteal phase progesterone, and male partner seminal fluid components are all implicated in causing Treg cell deficit. Treg cells may be a useful target for therapeutic interventions to improve uterine receptivity, but this will depend on developing diagnostic tests that are informative. Moreover, safe, and effective interventions to modulate these cells are in their infancy, and personalized approaches matched to specific diagnostic criteria will be needed.
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Vitale, Alessandra Maria, Letizia Paladino, Celeste Caruso Bavisotto, Rosario Barone, Francesca Rappa, Everly Conway de Macario, Francesco Cappello, Alberto J. L. Macario, and Antonella Marino Gammazza. "Interplay between the Chaperone System and Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus Pathogenesis: Is Molecular Mimicry the Missing Link between Those Two Factors?" International Journal of Molecular Sciences 25, no. 11 (May 21, 2024): 5608. http://dx.doi.org/10.3390/ijms25115608.
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Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by self-immune tolerance breakdown and the production of autoantibodies, causing the deposition of immune complexes and triggering inflammation and immune-mediated damage. SLE pathogenesis involves genetic predisposition and a combination of environmental factors. Clinical manifestations are variable, making an early diagnosis challenging. Heat shock proteins (Hsps), belonging to the chaperone system, interact with the immune system, acting as pro-inflammatory factors, autoantigens, as well as immune tolerance promoters. Increased levels of some Hsps and the production of autoantibodies against them are correlated with SLE onset and progression. The production of these autoantibodies has been attributed to molecular mimicry, occurring upon viral and bacterial infections, since they are evolutionary highly conserved. Gut microbiota dysbiosis has been associated with the occurrence and severity of SLE. Numerous findings suggest that proteins and metabolites of commensal bacteria can mimic autoantigens, inducing autoimmunity, because of molecular mimicry. Here, we propose that shared epitopes between human Hsps and those of gut commensal bacteria cause the production of anti-Hsp autoantibodies that cross-react with human molecules, contributing to SLE pathogenesis. Thus, the involvement of the chaperone system, gut microbiota dysbiosis, and molecular mimicry in SLE ought to be coordinately studied.
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Weyand, Cornelia M., and Jörg J. Goronzy. "Immunology of Giant Cell Arteritis." Circulation Research 132, no. 2 (January 20, 2023): 238–50. http://dx.doi.org/10.1161/circresaha.122.322128.
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Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1 + CD4 + T cells and the functional decline of NOTCH4 + T regulatory cells (Checkpoint 1). A defect in the endothelial cell barrier of adventitial vasa vasorum networks marks Checkpoint 2; the invasion of monocytes, macrophages and T cells into the arterial wall. Due to the failure of the immuno-inhibitory PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death ligand 1) pathway, wall-infiltrating immune cells arrive in a permissive tissues microenvironment, where multiple T cell effector lineages thrive, shift toward high glycolytic activity, and support the development of tissue-damaging macrophages, including multinucleated giant cells (Checkpoint 3). Eventually, the vascular lesions are occupied by self-renewing T cells that provide autonomy to the disease process and limit the therapeutic effectiveness of currently used immunosuppressants. The multi-step process deviating protective to pathogenic immunity offers an array of interception points that provide opportunities for the prevention and therapeutic management of this devastating autoimmune disease.
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Bam, Marpe, and Tamishraha Bagchi. "MART-1 transcript is absent in PBMCs from Vitiligo patients." Open Life Sciences 4, no. 4 (December 1, 2009): 528–35. http://dx.doi.org/10.2478/s11535-009-0057-6.
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AbstractMechanisms occurring in the thymus and periphery are responsible for the generation and maintenance of tolerance in the immune system. Various reports have shown that the existence of an antigen in the peripheral circulation results in tolerance induction towards that protein. These observations imply that the lack of a self antigen can lead to induction of autoimmunity. Previously we have reported that Tyrosinase related protein-2 (TRP-2) transcripts from peripheral blood mononuclear cells (PBMCs) are absent in vitiligo patients but present in healthy individuals. Here, we show that MART1 (Melanoma antigen recognized by T cells) transcripts are not detected in the PBMCs of vitiligo patients but is detected in healthy controls. Our result suggests that as MART1 is not expressed in the PBMCs, MART1 is also not available for induction and maintenance of peripheral tolerance in vitiligo patients. We therefore conclude that nonexpression of MART1 in PBMCs of vitiligo patients may be somehow responsible for the tolerance breakdown finally resulting in the induction of autoimmunity seen against these self antigens in vitiligo.
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Blackburn, Kyle M., and Cynthia Wang. "Post-infectious neurological disorders." Therapeutic Advances in Neurological Disorders 13 (January 2020): 175628642095290. http://dx.doi.org/10.1177/1756286420952901.
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A multitude of environmental factors can result in breakdown of immune tolerance in susceptible hosts. Infectious pathogens are among the most important environmental triggers in the pathogenesis of autoimmunity. Certain autoimmune disorders have a strong association with specific infections. Several neurological autoimmune disorders are thought to occur through post-infectious mechanisms. In this review, we discuss the proposed mechanisms underlying pathogen-induced autoimmunity, and highlight the clinical presentation and treatment of several post-infectious autoimmune neurological disorders. We also highlight post-infectious neurological disorders in the setting of recent outbreaks.
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Nurieva, Roza, Guillermina Lozano, and Chen Dong. "Regulation of naïve T cell tolerance and regulatory T cell function by GRAIL (113.21)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 113.21. http://dx.doi.org/10.4049/jimmunol.186.supp.113.21.
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Abstract CD4+ T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self tolerance in CD4+ cells. Gene related to anergy in lymphocytes (GRAIL), the E3 ubiqutine ligase, has acknowledged as one of key molecules implicated in T cell activation and tolerance. In order to understand the physiological function of GRAIL in immune regulation, we have generated and analyzed GRAIL deficient mice. Naive T cells lacking GRAIL showed greatly enhanced proliferation and cytokine production after T cell receptor (TcR) activation. In addition, lack of GRAIL abrogated suppressive function of regulatory T (Treg) cells. We found that GRAIL deficient naive and Treg cells after TcR activation expressed substantially higher amounts of NFATc1 compared to wild-type cells, whereas the activation of other factors in AP-1 and NFκB pathways were normal. Our data also suggested that sustained TcR cell-surface expression in the absence of GRAIL led to selective NFATc1 expression in both naive T cells and Treg cells. In contrast to naïve T cells, GRAIL, through controlling NFATc1 expression, inhibits IL-21 production and upregulation of Th17-specific genes in Treg cells. Thus, the immune regulation by GRAIL in both naive and Treg cells is absolutely critical as evidenced by the failure of T cell tolerance induction and greatly increased susceptibility to autoimmune diseases of GRAIL deficient mice.
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Nurieva, Roza, Junmei Wang, and Andrei Alekseev. "Essential role of E3 ubiquitin ligase activity of GRAIL in T cell functions (P1111)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 122.7. http://dx.doi.org/10.4049/jimmunol.190.supp.122.7.
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Abstract T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self-tolerance in T cells. Understanding of the molecular mechanisms underlying T cell tolerance will lead to development of pharmacological approaches either to promote the tolerance state in terms of autoimmunity or to break tolerance in cancer. E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. We as well as other groups have reported that T cells activated in the absence of both CD28 and ICOS costimulation developed into tolerant T cells, associated with markedly upregulated expression of the E3 ubiquitin ligase GRAIL. In order to understand the physiological function of GRAIL, we generated mice deficient in Grail by replacing region that encompassing most of the RING domain and responsible for E3 ubiquitin activity. Remarkably, genetic inactivation of E3 ubiquitin ligase function of GRAIL led to T cell hyper-responsiveness to TCR/CD3z signaling and their independency to costimulation for activation. As a result, GRAIL-deficient mice were more predisposing to autoimmune diseases. On the other hand, modulation of GRAIL function helped to boost T cell immune responses to cancer, and, therefore, mediate tumor rejection. Thus, modulation of the E3 ligase activity of GRAIL might be an important approach to control T cell functions in autoimmunity or cancer.
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Yurasov, Sergey, Hedda Wardemann, Johanna Hammersen, Makoto Tsuiji, Eric Meffre, Virginia Pascual, and Michel C. Nussenzweig. "Defective B cell tolerance checkpoints in systemic lupus erythematosus." Journal of Experimental Medicine 201, no. 5 (February 28, 2005): 703–11. http://dx.doi.org/10.1084/jem.20042251.
Full textAbstract:
A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.
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Wanchoo, Rimda, Leonardo V. Riella, Nupur N. Uppal, Carlos A. Lopez, Vinay Nair, Craig Devoe, and Kenar D. Jhaveri. "Immune Checkpoint Inhibitors in the Cancer Patient with An Organ Transplant." Journal of Onco-Nephrology 1, no. 1 (January 2017): 42–48. http://dx.doi.org/10.5301/jo-n.5000006.
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The use of immune checkpoint inhibitors (ICI) in several cancers is expanding; however, their use in patients with cancer and an organ transplant is very limited. In this review, we summarize the literature and the experience of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) inhibitors in the organ transplant patient. The immunology of CTLA-4 and PD-1 inhibitors and their role in tolerance breakdown is also reviewed. While CTLA-4 inhibitors have been successfully used in kidney, liver, and heart transplant patients without rejection, the uses of PD-1 inhibitors and the combination therapy of CTLA-4 and PD-1 inhibitors have been associated with cellular- and antibody-mediated rejection. While immunosuppression minimization is needed for ICI to provide the best response when managing transplant patients who develop malignancy, this can lead to rejection episodes. Prevention strategies, such as the use of ongoing steroids and sirolimus, could prevent rejection while sustaining tumor response. As the experience grows with these agents, we will learn more about tolerance and the use of ICI in the organ transplant patient. Therefore, the use of an immune checkpoint blockade in transplantation is extremely difficult, and future research should focus on finding the right balance between unleashing the immune system to provide an anti-tumor effect but at the same time sustaining tolerance so that rejection is suppressed. Also, the ability to identify biomarkers that may predict rejection early and allow for the fine tuning of doses and frequencies of drug administration would be very helpful.
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Lu, Kun-Lin, Ming-Ying Wu, Chi-Hui Wang, Chuang-Wei Wang, Shuen-Iu Hung, Wen-Hung Chung, and Chun-Bing Chen. "The Role of Immune Checkpoint Receptors in Regulating Immune Reactivity in Lupus." Cells 8, no. 10 (October 8, 2019): 1213. http://dx.doi.org/10.3390/cells8101213.
Full textAbstract:
Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune responses interacting with genetics and the environment. The close connections between co-signaling pathways and SLE have gradually been established in past research. Also, the recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the co-inhibitory receptors in cancer immunotherapy. Moreover, immune checkpoint blockade could result in substantial immune-related adverse events that mimic autoimmune diseases, including lupus. Together, immune checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. Therefore, it appears reasonable to treat SLE by restoring the out-of-order co-signaling axis or by manipulating collateral pathways to control the pathogenic immune responses. Here, we review the current state of knowledge regarding the relationships between SLE and the co-signaling pathways of T cells, B cells, dendritic cells, and neutrophils, and highlight their potential clinical implications. Current clinical trials targeting the specific co-signaling axes involved in SLE help to advance such knowledge, but further in-depth exploration is still warranted.
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Than, Nwe Ni, Hannah C. Jeffery, and Ye H. Oo. "Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy." Canadian Journal of Gastroenterology and Hepatology 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/7181685.
Full textAbstract:
Autoimmune hepatitis (AIH) is an immune mediated liver injury. The precise aetiology of AIH is still unknown but current evidence suggests both genetic and environmental factors are involved. Breakdown in peripheral self-tolerance, and impaired functions of FOXP3+regulatory T cell along with effector cell resistance to suppression at the tissue level seem to play an important role in AIH immunopathogenesis. AIH is predominantly a T lymphocytes driven disease but B lymphocytes are also involved in the immunopathology. Innate immune cells are crucial in the initial onset of disease and their response is followed by adaptive T (Th1, Th17, and cytotoxic T cells) and B cell responses evidenced by liver histology and peripheral blood serology. Standard treatment regimens involving steroid and immunosuppressive medications lead to global immune suppression requiring life-long therapy with many side effects. Biologic therapies have been attempted but duration of remission is short-lived. Future direction of diagnosis and treatment for AIH should be guided by “omics” and the immunology profile of the individual patient and clinicians should aim to deliver personalised medicine for their patients. Cell therapy such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance may soon be a potential future treatment for AIH patients.
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Mellanby, Richard J., David C. Thomas, and Jonathan Lamb. "Role of regulatory T-cells in autoimmunity." Clinical Science 116, no. 8 (March 16, 2009): 639–49. http://dx.doi.org/10.1042/cs20080200.
Full textAbstract:
There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.