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.

Fig. 1. Mechanisms of immune-mediated glomerulonephritis.

A common mechanism for immune-mediated kidney disease involves the formation and deposition of immune complexes followed by the activation of complement and ensuing inflammation. The mechanism for the formation of immune complexes varies among diseases and may involve: the formation of immune complexes in the blood followed by their glomerular deposition; binding of antibody to an autoantigen that is bound to the basement membrane (or has been ‘planted’); the formation of complexes within the glomerulus by locally generated antigen; or direct binding of antibody to a site on the basement membrane. Adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 2. The actions of autoantibodies in immunopathology.

Autoantibodies can disturb the function of cells or promote their damage or death through diverse mechanisms. These mechanisms include actions as receptor agonists (for example, as occurs in Graves’ disease), receptor antagonists (for example, as occurs in myasthenia gravis), ligand antagonists (for example, as occurs in immunodeficiency), cytotoxicity (for example, as occurs in haemolytic anaemia), neutrophil activation (with indirect damage to endothelium and epithelium) and acantholysis (for example, as occurs in pemphigus). ACh, acetylcholine; AChR, acetylcholine receptor; Fc, crystallizable fragment. Adapted from ref. , CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

Fig. 3. The stages of autoimmune disease.

Autoimmune disease develops over a time course and its trajectory may be affected by the presence of genetic, epigenetic and environmental factors. The presence of certain genetic risk factors, may, for example, cause disturbances in B cell and T cell signalling, even early in life. After a while, the impact of these disturbances becomes manifest, potentially as a consequence of environmental exposures (such as infection); in women, sex hormones may heighten these disturbances. Over time, evidence of autoimmunity (for example, elevated levels of autoantibodies or cytokines) increases and patients enter a stage that can be called asymptomatic or benign autoimmunity. The subsequent accumulation of other causative factors induces a transition to a stage of pre-clinical autoimmunity in which functional changes (for example, dysglycaemia) or symptoms (for example, arthralgia) occur but remain below a threshold that would cause the patient to seek medical attention or prompt the provider to order more testing. Once such a threshold has been reached, clinical autoimmune disease can be diagnosed and therapy started. The various stages probably represent a continuum, with more intensive screening moving each of the stages back in time. Post-clinical autoimmunity refers to the changes that may occur after clinical recognition and initiation of therapy. For diseases such as immune dependent diabetes mellitus, therapy might focus on agents such as insulin that aim to correct the functional disturbance without monitoring for autoimmunity or treatment with immunosuppressive agents. For other diseases, such as anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis and systemic lupus erythematosus, management may involve immunosuppressive therapy of varying intensity, in some instances guided by biomarkers such as anti-DNA, ANCA or complement. It is useful to distinguish between clinical autoimmunity and post-clinical autoimmunity because current therapy can induce remission in at least some diseases (for example, rheumatoid arthritis).