Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritis
Article first published online: 28 MAY 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 6, pages 1683–1693, June 2009
How to Cite
Campbell, I. K., Kinkel, S. A., Drake, S. F., Nieuwenhuijze, A. V., Hubert, F.-X., Tarlinton, D. M., Heath, W. R., Scott, H. S. and Wicks, I. P. (2009), Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen-induced arthritis. Arthritis & Rheumatism, 60: 1683–1693. doi: 10.1002/art.24501
- Issue published online: 28 MAY 2009
- Article first published online: 28 MAY 2009
- Manuscript Accepted: 12 FEB 2009
- Manuscript Received: 10 SEP 2008
- Reid Charitable Trusts
- National Health and Medical Research Council of Australia
- Rebecca L. Cooper Medical Research Foundation
- European Union Sixth Framework Programme EuroThymaide and EURAPs Projects
Autoimmune regulator (Aire) promotes the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study was undertaken to determine whether loss of central tolerance renders Aire-deficient (Aire−/−) mice more susceptible to the induction of autoimmune arthritis.
Medullary TECs were isolated from Aire−/− and wild-type C57BL/6 mice for gene expression analysis. Collagen-induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) in adjuvant. Cellular and humoral immune responses to CII were evaluated. Chimeric mice were created by reconstituting lymphocyte-deficient mice with either Aire−/− or wild-type CD4 T cells and wild-type B cells.
Wild-type, but not Aire−/−, mTECs expressed the CII gene Col2a1. Aire−/− mice developed more rapid and severe CIA, showing elevated serum anti-CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire−/− mice; however, Aire−/− CD4 T cells were more efficient at stimulating wild-type B cells to produce anti-CII IgG following immunization of chimeric mice with CII.
Our findings indicate that Aire-dependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire−/− mice manifests as increased CD4 T cell help to B cells for cross-reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross-reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.