Session Type: ACR Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: The “Targeting Immune Responses for Prevention of RA” (TIP-RA) collaboration studies individuals at high risk for developing rheumatoid arthritis (RA) because of serum anti-citrullinated protein antibody (ACPA) positivity in absence of arthritis at baseline, and is focused on defining how they transition from at-risk to classifiable disease. One potential mechanism is the expansion of antigen specific T cells that recognize self-antigens and acquisition of disease associated T cell phenotypes. ACPA emerge years prior to clinically apparent disease and subsequently increase in their titer and breadth of specificity. However, few studies have characterized T cells during this transition. Therefore, individuals enrolled in the TIP-RA cohort were analyzed by multi-parameter flow cytometry to identify features associated with progression to RA.
Methods: HLA class II tetramer staining and flow cytometry were performed on peripheral blood samples from a baseline visit from CCP3- controls (n=34), CCP3+ at-risk (n=26), CCP3+ positive individuals who transitioned in the near-term to RA (called “RA converters”, n=4), and seropositive early-RA (n=21). Our staining panel allowed us to assess the frequencies of T cells specific for citrullinated alpha-enolase, aggrecan, cartilage intermediate layer protein, fibrinogen and vimentin. We then applied both supervised phenotyping and a cluster-based computational approach to compare the phenotypic landscape and specificity of CD4+ T cells in each cohort.
Results: In comparison with controls, we observed higher frequencies of T cells that recognize citrullinated epitopes in CCP3+ at-risk subjects (p< 0.05), suggesting that these T cells expand prior to disease onset. Supervised phenotypic analysis revealed an increase in CCR4+ CD4+ T cells in CCP3+ at risk subjects (p< 0.001) and a corresponding decrease in CXCR3+ CD4+ T cells that was most pronounced in RA converters and seropositive early-RA (p< 0.05). Cluster-based phenotypic analysis revealed a landscape of ten distinct immunophenotypes present within all subjects. Among these, a CCR4 immunotype was progressively enriched in ACPA+ at risk subjects, RA converters, and seropositive early-RA (p=0.007). Correspondingly, a CXCR3/CCR4/CCR6 immunotype was progressively depleted in ACPA+ at risk subjects, RA converters, and seropositive early-RA (p=0.05). Each of these ten immunotypes was shown to contain tetramer positive T cells that recognize citrullinated epitopes. However, the predominant immunotype varied for different antigens and unique phenotypic patterns were observed for different subject groups.
Conclusion: Our data suggest a progressive change in T cell phenotypes during disease development and subsequent transition to classified RA. Disease associated changes in the antigen specificity and phenotype of CD4+ T cells are present in CCP3+ at-risk subjects before the onset of symptoms and development of classified RA. This finding suggests that there is a continuum of immunologic changes that drive disease evolution and that exploring emerging antigen specificities and immunophenotypes will aid our understanding of risk and shape approaches for intervention.
To cite this abstract in AMA style:Muir V, Rims C, Deane K, Carlin J, Posso S, Nagpal S, Rao N, Baribaud F, Vratsanos G, Robinson W, Firestein G, Holers V, Linsley P, James E, Buckner J. Differences in the Phenotypic Landscape and Antigen Specificity of CD4+ T Cells Are Present in CCP+ Subjects Before the Onset of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/differences-in-the-phenotypic-landscape-and-antigen-specificity-of-cd4-t-cells-are-present-in-ccp-subjects-before-the-onset-of-rheumatoid-arthritis/. Accessed November 18, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differences-in-the-phenotypic-landscape-and-antigen-specificity-of-cd4-t-cells-are-present-in-ccp-subjects-before-the-onset-of-rheumatoid-arthritis/