Background/Purpose:

The pathogenesis of rheumatoid arthritis (RA) is thought to be influenced by a combination of genetic and environmental factors. Observations of microbial dysbiosis in patients with RA have raised interest in studying microbial-mucosal interactions as a potential trigger of RA. Using the murine collagen-induced arthritis (CIA) model, which is dependent upon generation of T and B cell reactivity to CII as well as complement activation, we hypothesized that microbiota are required for the development of robust autoimmune arthritis.

Methods:

Male 6-week old DBA/1j mice were immunized with bovine type II collagen (CII) in Complete Freund’s Adjuvant (CFA) on days 0 and 21. Microbiota depletion was performed by continuous administration of broad spectrum antibiotics in drinking water early (7 days preceding and throughout the study) or late (starting after day 21 throughout the study) in the disease process. Microbial depletion was confirmed by quantifying bacterial 16S rRNA by qPCR in feces. Sera were collected every 7 days during the study for autoantibody and cytokine testing. Mice were euthanized on day 35 and intestinal tissues were harvested for cytokine analyses by ELISA. Disease severity starting at day 21 was assessed by assigning a score for the degree of paw swelling.

Results:

Depletion of the microbiota prior to the induction of CIA resulted in ~50% reduction in disease severity associated with significantly reduced serum inflammatory cytokines and anti-CII antibodies. In intestinal tissue, we observed delayed IL-17A and IL-22 responses. Unexpectedly, microbial depletion during the late, effector phase of CIA resulted in >90% decrease in disease severity and 50% reduction in prevalence. In these mice, anti-CII antibodies were mildly reduced, but were significantly impaired in their ability to activate complement. In addition to reduced systemic inflammatory cytokines and intestinal IL-17A and IL-22, IL-23 was significantly reduced, suggesting it may link mucosal immune responses with systemic autoantibody effectivity. Studies are now aimed at understanding this mechanism.

Conclusion:

While future studies are needed to solidify the role of the microbiota in driving CIA, our data supports a model in which intestinal dysbiosis triggers mucosal immune responses that stimulate systemic B cell activities that are key for the development of inflammatory arthritis. Understanding the pathway by which microbiota and mucosal immune responses modulate systemic autoantibody production is pivotal, as targeting the microbiota during the preclinical, seropositive phase of RA may have potential for disease prevention.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gut-microbiota-modify-inflammatory-arthritis-through-autoantibody-generation-and-mucosal-cytokines-alteration/