Enhanced interferon gamma response contributes to disease remission in Rheumatoid Arthritis.

Abstract

Abstract Rheumatoid arthritis (RA) is an autoimmune disease with debilitating bilateral inflammation in multiple joints. Although newer biologics are very effective in managing RA, critical gaps in immunopathogenic mechanism remain. We recently showed that increased expression of the interferon gamma (IFN-γ) receptor in PBMC associated with RA and increased radiographic severity. We hypothesized that enhanced IFN-γ signaling in specific subpopulations of mononuclear cells from patients with RA contributes to disease severity. To test this, we collected PBMC from healthy controls (HC) and RA patients in remission, low disease and moderate disease severity as per American College Criteria. As an autoimmune disease control, we compared PBMC from treatment naïve multiple sclerosis (MS) patients. We quantitated classical (JAK/STAT) and non-classical (ERK/MTOR) IFN-γ induced signaling in subpopulations of T and B cells within PBMC using phospho-flow cytometry. For analysis we utilized t-SNE and SPADE data visualization and clustering tools to interrogate changes in activation and marker expression within and between T and B cell populations. We observed IFN-γ-induced activation of STAT1 in CD4+ naïve and central memory T-cells from was greatest in RA patients in remission and lowest in individuals with moderate disease. IFN-γ induced activation of STAT1 in all CD8+ T-cell sub-populations of RA were similar to that from HC. Furthermore, the activation of STAT1 in all CD4+ T-cell sub-populations in PBMC from MS patients very generally greater than from RA patients and HC. From our results we infer that that while expression of IFNGR correlates with disease in RA, gain in response to IFN-γ is indicative of treatment response and RA remission.