Category: General autoimmunity
IL-6 is a pleiotropic cytokine with multiple roles in the adaptive immune response resulting in the promotion of inflammation. Elevated IL-6 and membrane-bound IL-6R expression is associated with autoimmune disease, and therapeutics that target the IL-6 signaling pathway are effective in rheumatoid arthritis, yet little is known about how the increased expression of IL-6R affects the development of autoimmune disease. A genetic variant, IL6Rasp358Ala, is associated with T1D and RA and alters mbIL6RA expression on T cells. To better understand how differences in mbIL6RA may influence T cells, we performed bulk RNA-sequencing to assess the IL-6 response of CD4 and CD8 T cells from a cohort of 31 healthy individuals with IL6RAsp358Ala genotypes associated with either high (A/A; n=16) or low (C/C; n=15) mbIL-6R expression. T cell activation and differentiation pathways were enriched in the A/A but not C/C CD4 transcript signature after 4 hours of stimulation, while activation pathways were enriched in the C/C but not A/A CD4 signature after 24 hours, suggesting that higher mbIL6RA expression may affect IL-6 signaling kinetics. Genes differentially regulated by IL-6 in this experiment showed little overlap with gene sets previously identified under other activating conditions, indicating distinct gene regulation by IL-6 stimulation alone. These results suggest that increased mbIL-6R expression is associated with an enhanced, distinct response to IL-6. Future studies will determine the functional impact of signaling response differences in healthy and autoimmune subjects and investigate potential mechanisms by which enhanced mbIL6RA expression contributes to development of autoimmune disease.
Kirsten Diggins– Post Doc, Benaroya Research Institute
Britta Jones– Post Doc, Benaroya Research Institute
Megan Maerz– Research Technician II, Benaroya Research Institute
Peter Linsley– Systems Immunology Division, Benaroya Research Institute at Virginia Mason
Jane Buckner– Translational Research Program, Director, Benaroya Research Institute at Virginia Mason