The microbiome in systemic autoimmune disease: mechanistic insights from recent studies

Abstract

Purpose of review: The resident bacterial communities and the host immune system have coevolved for millennia. However, recent changes in modern societies have disrupted this coevolutionary homeostasis and contributed to a rise in immune-mediated conditions. The purpose of this review is to provide an overview of recently elucidated mechanisms of how certain taxa within the bacterial microbiome propagate autoimmunity.

Recent findings: Interactions between the bacterial microbiome with innate and adaptive immune cells propagate autoreactivity, chronic inflammation, and tissue damage in susceptible hosts. These interactions contribute to autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, which are the focus of this review. Recent findings suggest that autoimmune manifestations in genetically susceptible individuals can arise through cross-reactivity with commensal orthologs of autoantigens or commensal-mediated posttranslational modification of autoantigens. Physiologic responses to gut, oral, or skin commensal bacteria can thus be misdirected toward such autoantigens in susceptible hosts. In addition, recent studies highlight that a breach of the gut barrier and translocation of commensal bacteria to non-gut organs can trigger several autoimmune pathways that can be prevented by commensal vaccination or dietary interventions.

Summary: Complex host-microbiota interactions contribute to systemic autoimmunity outside the gut. On a molecular level, posttranslational modification of, and cross-reactivity with, autoantigens represent mechanisms of how the microbiota mediates autoimmunity. On a cellular level, translocation of live gut bacteria across a dysfunctional gut barrier allows for direct interactions with immune and tissue cells, instigating autoimmunity systemically.

Figure

Examples of microbiota in RA and SLE that propagate systemic autoimmunity through innate and adaptive immune pathways. A. Examples of pathobionts linked to rheumatoid arthritis (RA). In the oral cavity, P. gingivalis and Aggregatibacter actinomycetemconitams (A. actino.) contribute to the pathogenesis of RA. P. gingivalis skews autoimmune responses through innate signaling via TLR2 leading to inflammatory cytokines(38). Complement activation by P. gingivalis contributes also to innate inflammation (not shown)(36,37). Posttranslational modification of autoantigens in RA is mediated by a toxin, leukotoxin A, from A. actino. This toxin induces citrullinated peptides in neutrophils, which can be recognized as neo-epitopes by the adaptive immune system(39). A. actino. also mediates neutrophil-specific cytolysis leading to neutrophil extracellular traps or NETosis. This process contributes to innate inflammation, not shown here(39). In the colon, P. copri promotes Th17 differentiation, engaging both innate and adaptive signaling pathways(30, 31). B. Examples of pathobionts linked to systemic lupus erythematosus (34) and subacute cutaneous lupus erythematosus (SCLE). In the ileum, L. reuteri promotes pDC and type I IFN innate pathways in genetically prone hosts leading to SLE-related manifestations (53). E. gallinarum colonizes the jejunum and ileum but drives autoimmunity by translocating to extraintestinal organs(52). E. gallinarum induces thereby autoreactive Th17 and Tfh responses and generation of autoantibodies. Monocolonization with E. gallinarum further induces pDCs, not shown here. Commensal organisms such as B. thetaiotaomicron (B. theta.), P. propionicum, or Corynebacterium amycolatum (not shown), express orthologs of the human Ro60 autoantigen targeted by SLE and Sjogren`s syndrome patients(19). These Ro60 ortholog-expressing commensals reside on the skin and mucosal sites, where they may stimulate and sustain autoreactive T and B cells in genetically predisposed hosts, contributing to the pathogenesis of both SLE and SCLE.