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

Microbial Factors Contributing to the Generation of Autoimmunity at Mucosal Sites and Their Interaction with Environmental and Genetic Factors

As mentioned above, inconclusive studies have implicated infections with specific organisms in the pathogenesis of RA.[62,63,89,90] The emerging complexity of the human microbiome, coupled with new methods for culture-independent microbial DNA sequencing, today allows studies on how the microbiome interacts with genetic and environmental factors and contributes to disease.[60,91]

Microbiome composition is partially determined by the host genome, as first suggested by early studies in twins,[92,93] although some conflicting observations also exist.[94,95] Subsequent studies in congenic mouse strains have revealed that MHC genes might have a prominent effect in determining the composition of the gastrointestinal microbiota.[96] While these observations do not necessarily imply the same genetic associations as for RA, studies in HLA-DR transgenic mice have shown differences in the relative abundances of gut microbiota between arthritis-susceptible HLA-DRB1 0401 and arthritis-resistant HLA-DRB1 0402 transgenic mice.[97] Moreover, germ-free conditions lead to abrogation of spontaneous arthritis in IL-1 receptor antagonist knockout mice[59] and attenuation of spontaneous arthritis in K/BxN TCR transgenic mice. Interestingly, the wild-type animals do not develop arthritis, even in the presence of pro-arthritogenic gut flora.[48] It has also been shown that new-onset untreated seropositive RA patients have an overexpansion of gut Prevotella copri,[60] a recently described species with connection to IBD and atherosclerosis.[98] Curiously, RA patients with a greater abundance of P. copri are mostly those with negative SE alleles.

Beyond the gut, the oral and respiratory tract microbiome, and in particular changes in the oral microbiome related to PD, have long been implicated in the pathogenesis of RA. It is well known that PD shares multiple risk factors with RA, including smoking and the genetic association with HLA-DR, but the exact causality or association between these two disease states is not yet completely understood.[99] Interestingly, α-enolase of both bacterial (P. gingivalis derived) and human origin was immunogenic in HLA-DR transgenic mice, with generation of antibodies recognizing both native and citrullinated forms of human enolase. However, an arthritogenic effect could not be replicated. A possible explanation for this discrepancy may be attributed to local environmental conditions, in particular the pathogen status in different specific pathogen-free facilities.[100,101]

Importantly, despite data documenting a relevant role for the lower respiratory tract as a mucosal initiating site of RA-associated autoimmunity,[70,74,102] no study to investigate the lung microbiome in RA is currently available. Preliminary data suggest that the lung microbiome is different in asymptomatic subjects with elevated risk of future RA when compared with healthy controls.[103] It should be noted that environmental factors—and smoking in particular—have a large effect on the mucosal microbiome composition.[104–111] These are issues that will need to be explored in future studies.