The IL-21 signaling pathway is enhanced in RA B cells and has the potential to alter development and cytokine production in RA B cells

Abstract

Abstract B cells have been implicated in the development of rheumatoid arthritis (RA) and IL-21 plays a central role in B cell maturation. Thus, in this study, we examined the response of B cells to IL-21 from RA subjects to determine if alterations in this response contribute to perturbations in B cell development and function in RA. Flow cytometric studies of PBMC from a cohort of RA and healthy subjects demonstrated an increase in the expression of the IL-21 receptor (IL-21R) on RA B cells as compare to those of healthy controls, and demonstrated a positive correlation between the IL-21R expression and the phosphorylation of STAT3 in response to IL-21. To further understand the molecular mechanisms involved in the altered signaling in RA B cells, we examined mRNA expression in B cell subsets with RNA flow cytometry. Using this approach we determined that IL-21R mRNA levels were enhanced in RA B cells and correlated with observed IL-21R protein expression. However, no alterations in the expression of SOC1 or SOCS3 were observed. Analysis of IL-21 induced activation of the Akt pathway demonstrated enhanced total FOXO1 protein expression in RA B cells with high IL-21R expression. This suggests that both STAT3 and Akt signaling pathways are enhanced in RA B cells that express elevated IL-21R levels. Further, we found that in vitro differentiation of naïve B cells to plasma cells was enhanced in RA B cells and that these plasma cells are IgM+ and produce increased quantities of IL-6. Together these findings suggest a mechanism by which the IL-21/IL-21R pathway may be contributing to alterations in B cell development and function in RA and point to a role for therapeutics targeting this pathway in these individuals.