Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Mar;55(3):391-402.
doi: 10.1093/rheumatology/keu469. Epub 2014 Dec 23.

Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis

Anca I Catrina  1 , Kevin D Deane  2 , Jose U Scher  3
Affiliations
Review

Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis

Anca I Catrina et al. Rheumatology (Oxford). 2016 Mar.

Abstract

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.

Keywords: break in tolerance; environmental risk factors; genetic susceptibility; microbiome; rheumatoid arthritis.

PubMed Disclaimer

Figures

F<sc>ig</sc>. 1
Fig. 1
Overview of the immune response in the tonsil and regional lymph node as an example of the mechanisms of immunity at mucosal sites Tonsils, adenoid tissue and the intestine contain M cells that mediate antigen uptake into the tissue rich with lymphoid follicles (A) in which the primary expansion of naive B cells occurs (dendritic cells can also uptake antigen at mucosal sites through processes that extend into the lumen). Antigen presentation is followed by the subsequent generation of memory B cells that populate other lymphoid tissues, especially regional lymph nodes. Dark and light zones containing centroblasts and centrocytes and the mantle zone, in which dendritic cells, B cells and T cells collaborate for B cell activation, are shown in the upper right of (B). A similar expansion of memory (and naive) B cells can occur with secondary exposure in the lymph nodes that are draining the airways as well as other mucosal sites. FDC: follicular dendritic cells; HEV: high endothelial venule. Figure reprinted from Kato A et al., B-lymphocyte lineage cells and the respiratory system. J Allergy and Clinical Immunol 2013;131:933-57 [17], with permission from Elsevier.
F<sc>ig</sc>. 2
Fig. 2
A schematic representation of how mucosal disequilibrium might lead to generation of autoimmunity and later to joint disease development Complex mechanisms dependent on environmental exposure and the host microbiome are responsible for maintaining homeostasis at mucosal surfaces (such as the respiratory and gastrointestinal tract). In genetically susceptible hosts, failure of these mechanisms may lead to mucosal disequilibrium and molecular changes such as post-translational modifications (citrullination), with subsequent antigen presentation by professional antigen presenting cells, activation of immune effector T cells (such as Th17) and relative deficiency of Tregs. These changes lead to activation of B cells and generation of antibodies (such as ACPAs) by plasma cells. These antibodies undergo somatic hypermutation and epitope spreading, leading to joint disease initiation and perpetuation through several mechanisms (complement activation, cell surface receptor activation, ligation of cell surface components and neutrophil activation).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aho K, Palosuo T, Heliovaara M, et al. Antifilaggrin antibodies within “normal” range predict rheumatoid arthritis in a linear fashion. J Rheumatol. 2000;27:2743–6. - PubMed
    1. Aho K, Heliovaara M, Knekt P, et al. Serum immunoglobulins and the risk of rheumatoid arthritis. Ann Rheum Dis. 1997;56:351–6. - PMC - PubMed
    1. Aho K, Palosuo T, Heliovaara M. Predictive significance of rheumatoid factor. J Rheumatol. 1995;22:2186–7. - PubMed
    1. del Puente A, Knowler WC, Pettitt DJ, Bennett PH. The incidence of rheumatoid arthritis is predicted by rheumatoid factor titer in a longitudinal population study. Arthritis Rheum. 1988;31:1239–44. - PubMed
    1. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–9. - PubMed

Publication types

MeSH terms