Early upregulation of Socs1 contributes to antigen-specific tolerance in collagen-induced arthritis

Abstract

Master thesis, Programme in Medicine. TITLE: Early upregulation of Socs1 contributes to antigen-specific tolerance in collagen-induced arthritis. AUTHOR: Olof Turesson INTRODUCTION: To study tolerogenic immunological mechanisms we use lentiviral based gene therapy in collagen-induced arthritis. In our tolerogenic model, collagen type II expression is enhanced on MHC class II on all types of antigen-presenting cells. After this treatment only 5% of mice develop arthritis at the same time as >95 % of control mice do. This study’s focus is before immunisation and days 3 and 5 after. METHOD: Gene expression analysis in draining lymph nodes was performed using an immune card array, where the mRNA expression of 96 inflammation related genes was determined by quantitative PCR. Differences in relative quantification was investigated using multivariate analyses OPLS-DA and PLS. The presence of regulatory T cells in spleen and draining lymph nodes was determined by CD4 and Foxp3 expression using flow cytometry. RESULTS: At day 3 mRNA expression of both Socs1 and Il10 was positively while Ifng and Il6 was negatively associated to tolerance. At the same time the frequency of CD4+FoxP3+ cells where significantly increased in tolerant mice. CONCLUSIONS: In tolerant mice, overexpression of collagen type II on MHC II leads to upregulation of SOCS1 at day 3 after CIA induction. SOCS1 inhibits the JAK/STAT pathway. Simultaneously, we see down-regulation of pro-inflammatory cytokines such as IFN-g and IL-6 as well as to increased levels of immunoregulatory IL-10. These findings coincide with an expansion of regulatory T cells. Thus, the arthritogenic immune response is switched of during an early stage of CIA and aborts arthritis develoment.