Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: the spark that lights the fire in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily manifests in synovial joints, such as those in the hands and feet. It can appear at any age in life and affects up to 1% of the population. While it is classified based on the presence of articular inflammation, a growing body of evidence indicates that RA autoimmunity begins outside of the joint. Circulating rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), anti-peptidylarginine deiminases (anti-PAD4), and anti-carbamylated proteins (anti-CarP) have been detected in many people years prior to the development of joint symptoms and an RA diagnosis. Several lines of investigation have implicated mucosal tissues of the lung and oral cavity as possible sites of initial autoantibody generation and inflammation. Mikuls et al. review the recent reports of this line of investigation (J Allergy Clin Immunol 2016; 137(1): 28-34).

In addition to harboring host inflammatory cells, mucosal tissues support a rich and diverse microbiome, which is increasingly understood to contribute to host immunity and autoimmunity. Mucosal tissues provide the first line of defense against environmental challenges such as invading pathogens and cigarette smoke. Both of these have been shown to be RA risk factors. Approximately one in six new cases of RA are attributable to smoking, with the risk highest among those who carry the HLA-DRB1 shared epitope. Disease-related autoantibodies in RA include IgA isotypes; the mucosal immune system and the ectopic lymphoid tissues that can develop at mucosal surfaces show dense infiltration by IgA-producing plasma cells.

Patients with RA often have extra-articular, pulmonary complications, and a number of reports of pulmonary involvement preceding joint symptoms in seropositive patients underscore the possibility that RA may be initiated in the lung. Disease-related antibodies have been detected in sputum, and in higher levels than in sera. Those with RA are also prone to disorders characterized by chronic oral inflammation, and the authors have recently found such patients showed a 50% greater prevalence of chronic periodontitis (PD) than those with osteoarthritis. The association was strongest among patients with ACPA-positive disease. 

The evolving evidence presented here suggests the lung and periodontium can be producers or reservoirs of RA-related auto-antigens. Much remains to be elucidated. Such questions include: a) What are the mechanisms through which this autoimmunity leads to the development of an articular disease? b) Does the same occur in other mucosal surfaces? c) Might the initiating site vary across individuals?