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

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."

T-cell receptors (TcR) and antibodies are selected to mimic "self" antigens. The microbiome avoids immunity by mimicking "self" antigens and TcR ("holoimmunity"). Pathogens, however, are complementary to "self," TcR, and the microbiome. A pathogen that also mimics "self" can trigger autoimmunity to the host, TcR, and microbiome simultaneously ("holoautoimmunity").

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