Altered Cytotoxicity Profile of CD8+ T Cells in Ankylosing Spondylitis

Abstract

Objective Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA–B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients. Methods Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence‐activated cell sorting (FACS). Results GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme‐positive and perforin 1–positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients. Conclusion Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.

Circulating Mature Granzyme B+ T Cells Distinguish Crohn’s Disease Associated Axial Spondyloarthritis from Axial Spondyloarthritis and Crohn’s Disease

“…Yet CD8 + T cells are signi cantly reduced in individuals with AS along with reduced expression of cytotoxic genes granzyme A (GZMA) and perforin (PRF1), but synovial uid levels of GZMA and GZMB were signi cantly elevated compared to the peripheral blood of the same patients. Intriguingly, the differences in cytotoxic gene expression were limited to men with AS [15,16]. In our study, while total CD8 + T cells were unchanged in axSpA, we identi ed a profound shift of cytotoxic cell populations in our study, and in particular, T cells expressing GZMB in the peripheral blood of individuals with CD-axSpA.…”

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis

“…Whether HLA-B27 could be mediating IEL activation in patients with SpA, and whether it is possible for these cells to home to the inflamed joints of these patients, is interesting to speculate. Relevant to this point, recent studies have revealed the presence of resident-like CD8 + T cells in axial spinal ligaments 134 , whereas other studies have demonstrated high frequencies of granzyme-producing CD8 + T cells with gut-related homing markers, in the peripheral joints of SpA patients 123,135 .…”

Serum immune modulators during the first cycle of anti‐PD‐1 antibody therapy in non‐small cell lung cancer: Perforin as a biomarker

“…Perforin and granzyme B also exist extracellularly in blood serum and plasma. There are only limited reports about the serum concentrations of perforin associated with pathophysiological status 18‐24 . In our study, perforin, but not granzyme B, was measured by ELISA.…”