Washington University in St. Louis Saint Louis, MO, United States
Michael Paley1, Lynn Hassman2, Grace Paley2, Nicole Linskey2, Philip Ruzycki2, Jennifer Laurent2, Lacey Feigl2, Luke Springer2 and Wayne Yokoyama2, 1Washington University in St. Louis, Saint Louis, MO, 2Washington University School of Medicine, St. Louis, MO
Background/Purpose: HLA-B27 is genetically linked to Axial Spondyloarthritis (axSpA) and anterior uveitis (AU), an inflammatory ocular disease that can lead to cataract, glaucoma, and permanent vision loss. Whether HLA-B27-associated AU (B27AU) is driven by antigen-dependent autoreactive T cells or antigen-independent mechanisms remains unclear.
Methods: To evaluate these hypotheses, we performed single-cell RNA sequencing (scRNAseq) and T cell receptor sequencing (scTCRseq) on immune cells from the eye and blood during B27AU (n=5) and non-B27AU (n=14).
Results: We found evidence for both antigen-dependent and antigen-independent T cell responses in B27AU. Each B27AU sample contained one or more T cell clonotypes that had undergone clonal expansion, suggestive of antigen-specific stimulation, and was enriched in the eye compared to the blood by 10-fold or more, suggestive of tissue-specific recruitment. Additionally, in one patient, the clonally expanded and tissue-enriched clonotypes matched previously published TCR sequences specifically found in HLA-B27+ ankylosing spondylitis and reactive arthritis. These data suggest a role for pathogenic, antigen-specific T cells in axSpA.
In parallel, when compared to non-B27AU, B27AU contained greater than a 10-fold enrichment of mucosal-associated invariant T (MAIT) cells within the eye. MAIT cells are commonly found in enteric organs such as the colon and liver and do not recognize peptides, but rather riboflavin metabolites from bacterial synthesis. Compared to blood MAIT cells, ocular MAIT cells in B27AU showed evidence of JAK/STAT signaling, with upregulation of CISH and SOCS1, and evidence of tissue-specific recruitment, with upregulation of CXCR3 and CXCR6. The enrichment of activated MAIT cells in the eye during B27AU suggests antigen-independent mechanisms of inflammation.
Conclusion: Collectively, our data raise the possibility that HLA-B27-associated inflammation may be driven by a combination of (1) HLA-B27 presentation of autoantigens to self-reactive T cells and (2) microbial inflammatory stimuli from the gut.
Disclosures: M. Paley, AbbVie/Abbott, Priovant Therapeutics, Inc., Lilly, JK Market Research; L. Hassman, None; G. Paley, AbbVie/Abbott, Priovant Therapeutics, Inc., JK Market Research, Eli Lilly; N. Linskey, None; P. Ruzycki, None; J. Laurent, None; L. Feigl, None; L. Springer, None; W. Yokoyama, None.
