Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

Abstract

I propose a T-cell receptor (TcR)-based mechanism by which immunity mediates both "genetic self" and "microbial self" thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross-reactivity with "self," resulting in selection for a TcR repertoire mimicking "genetic self." Second, evolution has selected for a "microbial self" that mimics "genetic self" so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR-microbiome mimicry "holoimmunity" to denote immune tolerance to the "holobiont self." Logically, microbiome-host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross-react with host antigens producing "holoautoimmunity."

Holoimmunity Revisited

“…However, the immune mechanisms accounting for the establishment and maintenance of symbiotic bacterial populations are poorly understood. A promising hypothesis suggests that molecular mimicry, a condition in which different organisms share common antigens, is a mechanism of establishing tolerance between commensals and their hosts . On this view, certain bacteria may mimic the structural features of some of their host's T‐cell receptors (TCRs), namely those that survive thymic selection due to their lack of complementarity to self‐antigens.…”

“…Accordingly, analysis of genomic and metagenomic data suggests a tripartite mimicry between TCRs, self‐antigens, and commensal antigens that would serve as the basis for immune tolerance between these populations. And conversely, in an autoimmune scenario, both symbiotic microbes and the mimicked host tissue would be targeted for immune destruction …”

“…A promising hypothesis suggests that molecular mimicry, a condition in which different organisms share common antigens, is a mechanism of establishing tolerance between commensals and their hosts. [1] On this view, certain bacteria may mimic the structural features of some of their host's T-cell receptors (TCRs), namely those that survive thymic selection due to their lack of complementarity to self-antigens. With such "holoimmunity" the mimicking micro-organisms avoid immune recognition as the copied TCRs become mirror images of an extended super-organismal self, consisting of symbiotic and host antigens.…”

“…And conversely, in an autoimmune scenario, both symbiotic microbes and the mimicked host tissue would be targeted for immune destruction. [1] A recent report offers support for a large shared antigen pool: Calculations of the putative number of combinations of amino acids that TCRs can bind is 3.2 million, and 75.4% of these possible combinations are present in the human proteome and as many as 91.4% of them can be found on commensal bacteria as well. [2] This assessment has possible significance inasmuch as microbial peptides similar to human peptides are generally less immunogenic than other microbial molecules [3] and thus peripheral immune-modulation is likely.…”

A hypothesis: Establishing the microbiome through immune mimicry (comment on DOI 10.1002/bies.201600083)

“…While not strictly invoking immune regulation as such, this last means of avoiding immune attack may be the key to symbiotic entrenchment. But instead of camouflage, Root‐Bernstein (2016) suggests mimicry, whereby the immune system selects bacterial species because they are ‘seen’ as self, not foreign, and that correspondence then allows for hospitable host‐microbe co‐existence .…”