Background/Purpose:  HLA-B27 is the strongest known genetic risk factor for ankylosing spondylitis and other spondyloarthropathies (SpAs). We have shown previously that Fisher 344 rats that express the human HLA-B27/β2m transgene (33-3 locus) develop a globally altered intestinal microbiome relative to wild type (WT) control animals. This mirrors the altered gut microbiota of SpA patient populations and indicates intestinal dysbiosis may be a functionally significant event in SpA pathogenesis. Intestinal IgA responses are known to shape the intestinal microbiota. We hypothesized that microbiota-specific IgA responses may be significantly impacted by HLA-B27 expression. Moreover, since IgA responses can regulate microbial translocation from the gut to the periphery, we examined B27-associated translocation of gut microbes to the joint – a site predisposed to inflammation in the HLA-B27/β2m rat.

Methods:  For IgA analysis, we used IgA-SEQ sequencing methodology, whereby fecal bacteria are flow-sorted based upon their coating with IgA and the IgA+ve and IgA-ve fractions subjected to 16s rRNA gene sequencing. The relative enrichment of each bacterial operational taxonomic unit (OTU) in the IgA+ve vs IgA-ve fraction was then calculated to profile the microbiota-specific IgA response in 16wk old HLA-B27/β2m or WT control rats. The frequency of IgA+ve B cells in intestinal lamina propria, mesenteric lymph node (MLN) and bone marrow (BM) was also enumerated by flow cytometry. We collected small and large intestinal contents (ileum, cecum and colon), MLN and ankle tissue from 16wk old HLA-B27/β2m rats and WT controls. DNA was extracted and subjected to 16s rRNA gene sequencing to profile microbial DNA at these intestinal and peripheral sites.

Results: HLA-B27 expression was associated with a markedly altered IgA response to the intestinal microbiota, with pronounced IgA-enrichment of many microbial OTUs vs WT animals. Amongst the most disproportionately IgA-coated fecal microbes in B27+ rats were Prevotella, Blautia and Akkermansia spp. and Segmented Filamentous Bacteria (SFB) – the latter of which is a known arthritogenic agent in rodents. These changes were accompanied by a B27-associated expansion of IgA+ve B cells specifically in the gut. Interestingly, we observed a highly polymicrobial DNA signature in joint tissue, including many microbes of putative intestinal origin. B27 expression was associated with a significant expansion of Suturella, Roseburia, Akkermansia, Prevotella and Coprobacillus spp.DNA at this tissue site.

Conclusion: The dysbiosis observed with HLA-B27 expression may be a result of highly perturbed mucosal IgA responses to the intestinal microbiota. The presence of microbial DNA in joint tissue implicates the translocation of gut microbes to joint may be a relevant mechanism in SpA pathogenesis. Further functional studies will provide valuable insight as to the relationship between these observations and their respective contribution to B27-associated spondyloarthropathy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-b27-expression-is-accompanied-by-a-profoundly-altered-iga-response-to-the-intestinal-microbiota-and-microbial-translocation-to-the-joint/