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Frontiers in Immunology 2022The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to... (Review)
Review
The complement system (CS) is an ancient and highly conserved part of the innate immune system with important functions in immune defense. The multiple fragments bind to specific receptors on innate and adaptive immune cells, the activation of which translates the initial humoral innate immune response (IR) into cellular innate and adaptive immunity. Dysregulation of the CS has been associated with the development of several autoimmune disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis, and autoimmune bullous dermatoses (AIBDs), where complement drives the inflammatory response in the effector phase. The role of the CS in autoimmunity is complex. On the one hand, complement deficiencies were identified as risk factors to develop autoimmune disorders. On the other hand, activation of complement can drive autoimmune responses. The anaphylatoxins C3a and C5a are potent mediators and regulators of inflammation during the effector phase of autoimmunity through engagement of specific anaphylatoxin receptors, i.e., C3aR, C5aR1, and C5aR2 either on or in immune cells. In addition to their role in innate IRs, anaphylatoxins regulate humoral and cellular adaptive IRs including B-cell and T-cell activation, differentiation, and survival. They regulate B- and T-lymphocyte responses either directly or indirectly through the activation of anaphylatoxin receptors dendritic cells that modulate lymphocyte function. Here, we will briefly review our current understanding of the complex roles of anaphylatoxins in the regulation of immunologic tolerance and the early events driving autoimmunity and the implications of such regulation for therapeutic approaches that target the CS.
Topics: Anaphylatoxins; Autoimmune Diseases; Autoimmunity; Complement System Proteins; Humans; T-Lymphocytes
PubMed: 35958588
DOI: 10.3389/fimmu.2022.958392 -
Frontiers in Immunology 2022
Topics: Autoimmunity; Complement System Proteins
PubMed: 36466859
DOI: 10.3389/fimmu.2022.1085525 -
Internal and Emergency Medicine Oct 2021The innate immunity works as a defence bullwark that safeguards healthy tissues with the power of detecting infectious agents in the human body: errors in the context of... (Review)
Review
The innate immunity works as a defence bullwark that safeguards healthy tissues with the power of detecting infectious agents in the human body: errors in the context of innate immunity identify autoinflammatory disorders (AIDs), which arise as bouts of aberrant inflammation with little or no involvement of T and B cells and neither recognized infections, nor associated autoimmune phenomena. Hereditary AIDs tend to have a pediatric-onset heralded by stereotyped inflammatory symptoms and fever, while AIDs without an ascertained cause, such as systemic juvenile idiopathic arthritis, derive from the interaction of genetic factors with environmental noxae and are unevenly defined. A dysregulated inflammasome activation promotes the best-known family of AIDs, as well as several degenerative and metabolic disorders, but also nuclear factor κB- and interferon-mediated conditions have been framed as AIDs: the zenith of inflammatory flares marks different phenotypes, but diagnosis may go unnoticed until adulthood due to downplayed symptoms and complex kaleidoscopic presentations. This review summarizes the main AIDs encountered in childhood with special emphasis on the clinical stigmata that may help establish a correct framework and blueprints to empower young scientists in the recognition of AIDs. The description focuses inflammasomopathies as paradigms of interleukinopathies, nuclear factor-κB -related disorders and interferonopathies. The challenges in the management of AIDs during childhood have been recently boosted by numerous therapeutic options derived from genomically-based approaches, which have led to identify targeted biologic agents as rationalized treatments and achieve more tangible perspectives of disease control.
Topics: Autoimmune Diseases; Autoimmunity; Humans; Inflammation; Interferons
PubMed: 33999387
DOI: 10.1007/s11739-021-02751-7 -
Rheumatology (Oxford, England) Jun 2023Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the... (Review)
Review
Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.
Topics: Humans; Skin; Hematopoietic Stem Cell Transplantation; Scleroderma, Localized; Immune Tolerance; Autoimmunity; Scleroderma, Diffuse; Scleroderma, Systemic
PubMed: 36355455
DOI: 10.1093/rheumatology/keac628 -
Frontiers in Immunology 2022Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for... (Review)
Review
Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies.
Topics: Antineoplastic Agents; Autoimmune Diseases; Autoimmunity; Humans; Immunotherapy; Neoplasms
PubMed: 35634292
DOI: 10.3389/fimmu.2022.793234 -
Frontiers in Immunology 2022Various immune cell types, including monocytes, macrophages, and adaptive immune T and B cells, play major roles in inflammation in systemic autoimmune diseases.... (Review)
Review
Various immune cell types, including monocytes, macrophages, and adaptive immune T and B cells, play major roles in inflammation in systemic autoimmune diseases. However, the precise contribution of these cells to autoimmunity remains elusive. Transcriptome analysis has added a new dimension to biology and medicine. It enables us to observe the dynamics of gene expression in different cell types in patients with diverse diseases as well as in healthy individuals, which cannot be achieved with genomic information alone. In this review, we summarize how transcriptome analysis has improved our understanding of the pathological roles of immune cells in autoimmune diseases with a focus on the ImmuNexUT database we reported. We will also discuss the common experimental and analytical design of transcriptome analyses. Recently, single-cell RNA-seq analysis has provided atlases of infiltrating immune cells, such as pro-inflammatory monocytes and macrophages, peripheral helper T cells, and age or autoimmune-associated B cells in various autoimmune disease lesions. With the integration of genomic data, expression quantitative trait locus (eQTL) analysis can help identify candidate causal genes and immune cells. Finally, we also mention how the information obtained from these analyses can be used practically to predict patient prognosis.
Topics: Autoimmune Diseases; Autoimmunity; Gene Expression Profiling; Humans; Inflammation; Monocytes
PubMed: 35663941
DOI: 10.3389/fimmu.2022.857269 -
The Journal of Experimental Medicine Oct 2023Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite...
Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite numerous efforts to distinguish the homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells remains poorly understood. In this study, we demonstrate that the inflammatory Th17 cells involved in autoimmune colitis and those activated during colitogenic infection are distinguishable populations characterized by their differential responses to the pharmacological molecule, clofazimine (CLF). Unlike existing Th17 inhibitors, CLF selectively inhibits proautoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells partially by reducing the enzyme ALDH1L2. Overall, our study identifies two distinct subsets within the inflammatory Th17 compartment with distinct regulatory mechanisms. Furthermore, we highlight the feasibility to develop disease-promoting Th17 selective inhibitor for treating autoimmune diseases.
Topics: Humans; Autoimmunity; Th17 Cells; Autoimmune Diseases; Inflammation; Colitis
PubMed: 37367944
DOI: 10.1084/jem.20221911 -
Archives of Medical Research Oct 2021Virus infection can alter immune regulatory activity, and thus may be involved in the occurrence of autoimmune diseases. Recently, the pandemic of COVID-19 has posed a... (Review)
Review
Virus infection can alter immune regulatory activity, and thus may be involved in the occurrence of autoimmune diseases. Recently, the pandemic of COVID-19 has posed a huge threat to public health and emerging evidence suggests that coronavirus may be implicated in the development and pathogenesis of autoimmune diseases. However, how coronavirus infection impacts the risk of autoimmune disease remains largely unknown. In this review, we focused on the association between coronavirus and autoimmunity, and elucidated the molecular mechanisms linking coronavirus exposure to autoimmunity. Additionally, we briefly introduced the role that coronavirus plays in several autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and idiopathicthrombocytopenic purpura (ITP).
Topics: Autoimmune Diseases; Autoimmunity; COVID-19; Humans; Lupus Erythematosus, Systemic; SARS-CoV-2
PubMed: 33875273
DOI: 10.1016/j.arcmed.2021.03.012 -
International Journal of Molecular... May 2021Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this... (Review)
Review
Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this relationship because activated and differentiated B cells produce secretory immunoglobulin A (sIgA), which binds commensals to preserve a healthy microbial ecosystem. Mounting evidence shows that changes in the function and composition of the gut microbiota are associated with several autoimmune diseases suggesting that an imbalanced or dysbiotic microbiota contributes to autoimmune inflammation. Bacteria within the gut mucosa may modulate autoimmune inflammation through different mechanisms from commensals ability to induce B-cell clones that cross-react with host antigens or through regulation of B-cell subsets' capacity to produce cytokines. Commensal signals in the gut instigate the differentiation of IL-10 producing B cells and IL-10 producing IgA+ plasma cells that recirculate and exert regulatory functions. While the origin of the dysbiosis in autoimmunity is unclear, compelling evidence shows that specific species have a remarkable influence in shaping the inflammatory immune response. Further insight is necessary to dissect the complex interaction between microorganisms, genes, and the immune system. In this review, we will discuss the bidirectional interaction between commensals and B-cell responses in the context of autoimmune inflammation.
Topics: Autoimmunity; B-Lymphocytes; Cell Differentiation; Humans; Immunoglobulin A; Inflammation; Interleukin-10; Microbiota
PubMed: 34063669
DOI: 10.3390/ijms22094846 -
International Journal of Molecular... Apr 2021Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival... (Review)
Review
Immune homeostasis is a tightly regulated system that is critical for defense against invasion by foreign pathogens and protection from self-reactivity for the survival of an individual. How the defects in this system might result in autoimmunity is discussed in this review. Reduced lymphocyte number, termed lymphopenia, can mediate lymphopenia-induced proliferation (LIP) to maintain peripheral lymphocyte numbers. LIP not only occurs in normal physiological conditions but also correlates with autoimmunity. Of note, lymphopenia is also a typical marker of immune aging, consistent with the fact that not only the autoimmunity increases in the elderly, but also autoimmune diseases (ADs) show characteristics of immune aging. Here, we discuss the types and rates of LIP in normal and autoimmune conditions, as well as the coronavirus disease 2019 in the context of LIP. Importantly, although the causative role of LIP has been demonstrated in the development of type 1 diabetes and rheumatoid arthritis, a two-hit model has suggested that the factors other than lymphopenia are required to mediate the loss of control over homeostasis to result in ADs. Interestingly, these factors may be, if not totally, related to the function/number of regulatory T cells which are key modulators to protect from self-reactivity. In this review, we summarize the important roles of lymphopenia/LIP and the Treg cells in various autoimmune conditions, thereby highlighting them as key therapeutic targets for autoimmunity treatments.
Topics: Animals; Autoimmune Diseases; Autoimmunity; COVID-19; Cell Proliferation; Homeostasis; Humans; Lymphopenia; T-Lymphocytes, Regulatory
PubMed: 33923792
DOI: 10.3390/ijms22084152