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Abstract Number: 1828

Gut-Joint T Cell Trafficking in a Model of Bacteria-Driven Murine IBD-Spa

Eric Norman1, Adam Lefferts1 and Kristine A Kuhn1,2, 1Rheumatology, University of Colorado Denver, Aurora, CO, 2Mucosal Inflammation Program, University of Colorado Denver, Aurora, CO

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: inflammatory bowel disease (IBD), microbiome and spondylarthritis, T cells

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Session Information

Date: Monday, October 22, 2018

Title: 4M088 ACR Abstract: Spondyloarthritis Incl PsA–Basic Science (1828–1833)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Significant bacterial dysbiosis occurs in individuals with IBD and SpA, and individuals with SpA have evidence of circulating intestinal-derived cells, lending credence to the gut-joint hypothesis. In order to understand the mechanistic linkage between microbiota, mucosal immune development, and subsequent pathogenic targeting of joints in SpA, we utilized the TNFΔARE/+ murine model of ileitis and arthritis, which spontaneously develop around 6 weeks of age due to increased TNF-α mRNA stability. We hypothesized that bacteria are required to generate disease, and that gut-joint trafficking could be observed in this model.

Methods: The microbiome was evaluated in 4-8 week old mice by sequencing the V3V4 region of bacterial 16S rRNA in fecal samples from TNFΔARE/+ mice and littermate controls. Then microbiota were depleted by administration of broad-spectrum antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) in the drinking water from 4-8 weeks of age. Assessment of ileitis and arthritis was done by histology. Cells from intestinal tissue and Achilles’ entheses were evaluated by flow cytometry. To demonstrate trafficking of cells from the intestine to the joints, we utilized transgenic KikGR mice, which contain a transgene for a photoconvertible green-to-red fluorescent protein, that were crossed with the TNFΔARE/+ line. Endoscopy-guided violet light allowed photoconversion of the distal colon in vivo. Trafficking of photoconverted lymphocytes was determined by flow cytometry.

Results: TNFΔARE/+ mice become increasingly dysbiotic as disease develops between 4 and 8 weeks of age. Ileitis and arthritis were dependent upon an intact microbiota as mice treated with antibiotics had significantly decreased histologic damage. At 4 weeks of age, TNFΔARE/+ mice had significantly expanded colon TCRβ+ and TCRγδ+ intraepithelial lymphocytes (IELs, T cells residing in the epithelium) compared to littermate controls, that decreased to control numbers by 8 weeks of age. These IELs produced significant TNF-α as compared to littermate controls. At 8 weeks of age, both TCRβ+ and TCRγδ+ T cells were significantly expanded in the Achilles entheses of TNFΔARE/+ mice compared to littermate controls. Finally, we observed trafficking of TCRγδ+ IELs from the colon to the joint in both TNFΔARE/+ mice and littermate controls within 72 hours and sustained up to 1 week after photoconversion.

Conclusion: These data demonstrate a key role of bacterial dysbiosis in the development of both ileitis and arthritis as mice depleted of bacteria through the administration of antibiotics had significantly reduced tissue damage. Furthermore, we observe an expansion of colon IELs prior to disease onset that return to control numbers at the time when T cells are expanding in the inflamed joints. TCRγδ+ IELs specifically were identified to traffic from the colon to the joint. These data suggest a working hypothesis that bacteria educate T cells in the gut that traffic to the joint where they may initiate inflammation. Studies are now directed at understanding the specific mechanisms underlying this hypothesis.


Disclosure: E. Norman, None; A. Lefferts, None; K. A. Kuhn, None.

To cite this abstract in AMA style:

Norman E, Lefferts A, Kuhn KA. Gut-Joint T Cell Trafficking in a Model of Bacteria-Driven Murine IBD-Spa [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/gut-joint-t-cell-trafficking-in-a-model-of-bacteria-driven-murine-ibd-spa/. Accessed .
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