The Role of the Microbiome in Driving RA-Related Autoimmunity

Once referred to as "normal commensal flora" the human microbiome plays an integral role between health and disease. The host mucosal surface replete with a multitude of immune cells is a vast arena constantly sensing and responding to antigen presentation and microbial by-products. It is this key role that may allow the microbiome to prime or protect the host from autoimmune disease. Rheumatoid arthritis (RA) is a chronic, disabling inflammatory condition characterized by a complex multifactorial etiology. The presence of certain genetic markers has been proven to increase susceptibility to RA however it does not guarantee disease development. Given low concordance rates demonstrated in monozygotic twin studies there is a clear implication for the involvement of external players in RA pathogenesis. Since the historical description of rheumatoid factor, numerous additional autoantibodies have been described in the sera of RA patients. The presence of anti-cyclic citrullinated protein antibody is now a standard test, and is associated with a more severe disease course. Interestingly these antibodies are detectable in patient's sera long before the clinical signs of RA occur. The production of autoantibodies is driven by the lack of tolerance of the immune system, and how tolerance is broken is a crucial question for understanding RA development. Here we review current literature on the role of the microbiome in RA development including periodontal, gut and lung mucosa, with particular focus on proposed mechanisms of host microbiome interactions. We discuss the use of Mendelian randomization to assign causality to the microbiome and present considerations for future studies.