The role of T follicular helper cell molecules, and environmental influences, for autoantibody production and progression to inflammatory arthritis
OBJECTIVE: Antibody-mediated autoimmunity involves cognate interactions between self-reactive T- and B-cells during germinal centre (GC) reactions. The aim of the study was to determine the role of essential T follicular helper (TFH ) molecules (CXCR5, SAP) on auto-reactive CD4+ , and the role of certain environmental influences, that may determine GC-driven autoantibody production and arthritis development. METHODS: We transferred self-reactive KRNtg CD4+ to recipient mice, which induced autoantibodies and auto-inflammatory arthritis. This model allowed for manipulation of environmental effects such as inflammation, and the use of transferred cells genetically deficient in important TFH -associated molecules. RESULTS: Deficiency of SAP from KRNtg CD4+ completely protected against arthritis, indicating that stable T-B interactions were required for GCs, autoantibody production and disease. In contrast, CXCR5 deficiency from KRNtg CD4+ still induced disease when transferred to wild type mice, suggesting that T-cell help for B-cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28-/- recipients (reduced disease), or use of inflammation-inducing Complete Freund's adjuvant (CFA) (progression to arthritis). We also examined the capacity of pre-existing GCs with a non-autoimmune specificity to co-opt autoimmune T-cells, and found no evidence for any influence. CONCLUSION: In addition to the quality and quantity of cognate CD4+ help, external factors such as inflammation and non-cognate CD4+ bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances. This article is protected by copyright. All rights reserved.
|Authors||Chevalier, N. ; Macia, L. ; Tan, J. K. ; Mason, L. J. ; Robert, R. ; Thorburn, A. N. ; Wong, C. H. ; Tsai, L. M. ; Bourne, K. ; Brink, R. ; Yu, D. ; Mackay, C. R.;|
|Publisher Name||Arthritis & Rheumatology|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26501485|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13141|