Pathogenesis of autoimmune disease

Abstract

Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. Although T cells have a key role in pathogenesis, they are technically more difficult to assay. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways. Infection seems to be a common trigger for autoimmune disease, although the microbiota can also influence pathogenesis. As shown in seminal studies, patients may express autoantibodies many years before the appearance of clinical or laboratory signs of disease — a period called pre-clinical autoimmunity. Monitoring autoantibody expression in at-risk populations may therefore enable early detection and the initiation of therapy to prevent or attenuate tissue damage. Autoimmunity may not be static, however, and remission can be achieved by some patients treated with current agents.

The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronicTrypanosoma bruceiinfection

“…Interestingly, as observed in mice, we also detected the presence of autoantigens able to bind host proteins associated with either parasite control or pathology, such as proteins of the complement system (e.g., C1q, C3a) and nervous system-associated proteins (e.g., MBP and muscarinic receptor) ( Figure 9B ). Indeed, a total of 8 antigens (13.1% of the antigen array) were commonly identified by autoreactive antibodies in infected mouse serum and human CSF from 2 nd stage sleeping sickness patients, which are known to be diagnostic markers of autoimmune disorders such as systemic lupus erythematosus, Sjogren’s syndrome, scleroderma, rheumatoid arthritis, and multiple sclerosis 77–79 ( Figure 9C ). To further validate our findings, we examined the presence of circulating antibodies against MBP in an independent cohort of sleeping sickness patients from DRC that included both patients with an active infection (“cases”) and samples obtained from patients post-treatment (“treated) ( Figure 9D ).…”

The TCRs of pathogenic Th17 cells in arthritogenic mice are shifted toward a Treg-like repertoire

“…The development of autoimmune diseases is influenced by various factors, with the presence of self-reactive conventional T cells (Tconv) being a critical element. Equally important is the failure of regulatory T cells (Treg) to suppress self-reactivity and inflammation (Pisetsky 2023). Several mechanisms for Treg suppression, executed by cell-cell contact with target cells or by the production of soluble factors, have been reported in the literature, including production of inhibitory cytokines, cytolysis, metabolic disruption and indirect suppression by modulation of antigen presenting cell (APC) maturation or function (Vignali et al, 2008).…”

Integrative Mendelian Randomization approaches for therapeutic target prioritisation in immune-mediated diseases

“…Despite the substantial burden of autoimmune and inflammatory diseases, the pharmaceutical arsenal remains limited, owing to the complexity of the dysfunctional immune cascade underlying these heterogeneous conditions [4,5]. The absence of disease-specific biomarkers and need for chronic therapy compound the challenges of developing targeted agents.…”

“…Here, we propose a new intermediate trait category for use in proxying drug targets in IMD: immune cell abundance. There is substantial animal model, observational and MR evidence [21][22][23][24][25][26] implicating immune cell dysregulation in the pathogenesis of immune-mediated disorders, ranging from roles of T H 2 cells, eosinophils, and neutrophils in allergic conditions like asthma [27,28] and eczema [29,30] to expansion of certain T helper lymphocyte and B lymphocyte lineages in autoimmune diseases such as systemic lupus erythematosus (SLE) [31], multiple sclerosis [32] and rheumatoid arthritis [5]. Furthermore, approved drug targets for IMD are usually classed as immunosuppressants or immunomodulators, which alter the balance of immune blood cells in their course of on-target action.…”