Mechanisms of human autoimmunity

Abstract

R e v i e w S e R i e S : A u t o i m m u n i t y2 2 2 9 jci.org Volume 125 Number 6 June 2015theories have been proposed to explain this association, including epitope spreading, antigenic complementarity, and excessive innate/pattern recognition receptor activation. For example, evidence of EBV infection in postmortem brain tissue has been associated with MS but not other inflammatory disorders (17). Additionally, systemic infections have been reported to trigger relapses in patients with relapsing-remitting MS through enhancement of myelin-specific T cell responses (15). Another example of the association of infections with autoimmunity is that of periodontal infections and rheumatoid arthritis (18). In contrast, infections are also postulated to protect against some autoimmune diseases. For example, infection of germ-free mice with Bacteroides fragilis has been reported to protect against experimental autoimmune encephalomyelitis, the mouse model of MS, through induction of Treg cells (19). Additionally, a higher incidence of MS and type 1 diabetes is correlated with a decreased number of infections in developed countries (20). Recent interest has focused on the possible role of the microbiome in influencing local and systemic immune responses. Much of the emphasis has been on the gut microbiome. It is now believed that inflammatory bowel disease (IBD) is initiated by dysregulated and exaggerated immune responses to intestinal commensal microbes. In fact, the major manifestations of IBD may be caused by antimicrobial immune reactions and not by true autoimmunity (i.e., directed at tissue self-antigens). There are also several studies in mice that implicate commensal microbes in autoimmune disease, including type 1 diabetes (reviewed in ref. 21).A well-recognized nonmicrobial environmental trigger is UV irradiation for cutaneous lupus. A possible explanation for this connection is that UV radiation induces apoptotic death of many cell types and increases the burden of nuclear antigens, especially if the dead cells cannot be efficiently cleared (22). It has been suggested that low-level natural cell death in tissues is a mechanism for maintaining peripheral tolerance to tissue antigens through tolerance-promoting dendritic cell populations (23). It is plausible that lupus patients have a genetic predisposition for this system to become easily overwhelmed and are thus unable to maintain tolerance in the presence of continual UV exposure.Defective regulation as the cause of autoimmunity. If failure of self-tolerance is the fundamental abnormality in autoimmune diseases, the central question becomes -which mechanisms of tolerance fail in specific diseases, and why? In patients with SLE, defects in deletion of immature B cells in the bone marrow, in receptor editing, and in control of mature B cells in peripheral tissues have all been proposed (24). In humans with SLE, mature naive B cells can produce autoantibodies even before encounter with antigen, suggesting that defects in early B cell tolerance checkpoints m...

Follicular Helper T Cells in Autoimmunity

“…The identification of disease-relevant initiation factors is a difficult task because clinical symptoms develop considerably after the incidence of the abnormal immune reaction. However, it is generally accepted in the field that autoimmune diseases originate from a combination of several contributing factors that can be classified as follows: polymorphisms in various genes result in defective regulation or reduced threshold for lymphocyte activation and environmental factors trigger activation of selfreactive lymphocytes that have escaped control [3].…”

“…An example for a well-accepted abiotic trigger of autoimmunity is UV radiation, especially in the context of cutaneous lupus. Cell apoptosis caused by UV radiation leads to an excessive supply with selfantigens which can, based on a genetic predisposition, provoke the loss of peripheral tolerance [3,24].…”

“…This is due to the fact that ongoing tissue damage leads to an accumulation of self-antigens again exacerbating the autoimmune reaction and the coexisting inability to eliminate the self-antigens [3]. Furthermore, the autoimmune reaction as such attracts additional immune cells and induces cytokine secretion, leading to a catastrophic inflammatory loop [3].…”

“…This is due to the fact that ongoing tissue damage leads to an accumulation of self-antigens again exacerbating the autoimmune reaction and the coexisting inability to eliminate the self-antigens [3]. Furthermore, the autoimmune reaction as such attracts additional immune cells and induces cytokine secretion, leading to a catastrophic inflammatory loop [3]. With ongoing autoimmunity, the accumulation of effector T cells leads to an imbalance in the ratio of effector T cells to Tregs which, accompanied by Tregs with diminished functionality and effector T cells with a resistance towards suppression, also drives disease progression [27].…”

A systems approach to renal inflammation in SLE

“…The murine and human immune systems are remarkably similar and there is no doubt that animal models can be useful for studying human disease and identifying new therapies (18–20). The translation of pre-clinical studies to a successful therapeutic for humans has occurred in a large number of autoimmune diseases including rheumatoid arthritis, psoriasis, inflammatory bowel disease, uveitis and multiple sclerosis.…”