Pathotype-Specific Expression of Granzyme-Perforin Pathway Genes and their Association with Clinical Disease Activity in Early Rheumatoid Arthritis and in a Randomized Clinical Trial 2923

Abstract Description Rheumatoid arthritis (RA) is an autoimmune disease. Granzyme-perforin-serglycin is part of the exocytosis pathway with specialized granules to clear infection. We examined gene expression of five granzymes (GZMs), perforin (PRF-1) and serglcyin (SRGN) from tissues derived from two clinical studies; Pathobiology of Early Arthritis Cohort (PEAC) and R4RA. Information regarding gene expression of GZMs, PRF-1 and SRGN in synovium and blood pathotypes and their association with DAS28-ESR (Disease Activity Score-28 with erythrocyte sedimentation rate) and with DAS28-CRP (C-reactive protein) in Early RA (eRA) is lacking, as is the effect of RA drugs on these genes. To determine the expression of these genes in synovium and blood pathotypes, we analyzed synovial bulk RNA-seq data. The percentage of CD8+ T cells was determined in synovial tissue using multiplex immunohistochemistry, and the presence of Porphyromonas gingivalis (PG) antigen-reactivity (spackles) was examined in the synovium. The expression of GZM A, B, H, K, M, PRF-1 and SRGN was significantly higher in the lymphoid pathotype in the PEAC and R4RA synovium. No differences in blood were observed. The correlations among DAS28-ESR, DAS28-CRP and GZM A, B, K, H and M in the synovium were positive and significant, with few exceptions. The percentage of CD8 T cells was low, and minor spackles of PG antigen were detected in eRA synovium. Rituximab and Tocilizumab in R4RA decreased the expression of all GZMs, PRF-1 and SRGN. Funding Sources Supported by National Institutes of Health grant R01AR51749 to VMH (PI) and NKB (Co-I). By Institutional joint biology program to NKB (PI). Topic Categories Immune Mechanisms of Human Disease (HUM)