Gene, Environment, Microbiome and Mucosal Immune Tolerance in Rheumatoid Arthritis

Anca I. Catrina; Kevin D. Deane; Jose U. Scher


Rheumatology. 2016;55(3):391-402. 

In This Article

Abstract and Introduction


RA is a complex multifactorial chronic disease that transitions through several stages. Multiple studies now support that there is a prolonged phase in early RA development during which there is serum elevation of RA-related autoantibodies including RF and ACPAs in the absence of clinically evident synovitis. This suggests that RA pathogenesis might originate in an extra-articular location, which we hypothesize is a mucosal site. In discussing this hypothesis, we will present herein the current understanding of mucosal immunology, including a discussion about the generation of autoimmune responses at these surfaces. We will also examine how other factors such as genes, microbes and other environmental toxins (including tobacco smoke) could influence the triggering of autoimmunity at mucosal sites and eventually systemic organ disease. We will also propose a research agenda to improve our understanding of the role of mucosal inflammation in the development of RA.


RA is one of the most common forms of inflammatory arthritis. Notable advances in the understanding of its pathogenesis have been achieved in recent years. One of the major concepts developed by multiple lines of investigation posits that there is a period in the development of seropositive RA during which there is elevation of autoantibodies, including RF and ACPAs, several years prior to a diagnosis of RA. This autoantibody production occurs in the absence of synovitis (as determined either by physical examination, imaging or, in some cases, synovial biopsy).[1–13]

While the specific aetiology of RA remains elusive, this preclinical period of RA development implies that the disease is initiated at a site outside of the joints. While the exact location is unknown, established and emerging data discussed below support the central hypothesis for our current studies, namely that events leading to RA autoimmunity might originate at a mucosal site.

In this review we will discuss this hypothesis by first succinctly describing the structure, development and function of mucosal surfaces. In particular we will examine the role of microbes in shaping mucosal and systemic immune responses. We will also outline how microbes, as well as other factors such as smoking, can trigger immune responses at mucosal sites and eventually lead to RA. Finally, we propose a research agenda for greater understanding of the role of mucosal immune responses in the initiation of autoimmunity and RA.