Class II major histocompatibility complex–associated response to type XI collagen regulates the development of chronic arthritis in rats
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2537–2547, August 2012
How to Cite
Tuncel, J., Haag, S., Carlsén, S., Yau, A. C. Y., Lu, S., Burkhardt, H. and Holmdahl, R. (2012), Class II major histocompatibility complex–associated response to type XI collagen regulates the development of chronic arthritis in rats. Arthritis & Rheumatism, 64: 2537–2547. doi: 10.1002/art.34461
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 5 MAR 2012 03:43PM EST
- Manuscript Accepted: 28 FEB 2012
- Manuscript Received: 12 MAY 2011
- Crafoord Foundation
- Greta and Johan Kock Foundation
- Alfred Österlund Foundation
- Swedish Association Against Rheumatism
- Swedish Medical Research Council
- Swedish Foundation for Strategic Research
- European Union Seventh Framework Programme. Grant Numbers: project Masterswitch; Health-F2-2008-223404, project Euratrans; Health-F4-2010-241504, BMBF (ArthroMark; project 4, 01 EC 1009C
Chronic inflammation of the peripheral joints is a hallmark of rheumatoid arthritis (RA). The autoantibody response in RA has been shown to be directed mainly to ubiquitous antigens, whereas the response to cartilage proteins has been less extensively investigated. This study was undertaken to characterize the immune response in pristane-induced arthritis (PIA) in the rat to the cartilage-specific proteins type II collagen (CII) and type XI collagen (CXI) and to genetically fine-map their underlying major histocompatibility complex (MHC) associations.
The genetic control of CII and CXI immunity was mapped using intra-MHC–recombinant inbred strains immunized with the respective collagens. Reactivity with CII and CXI was tested in acute and chronic PIA and in 356 HLA-typed patients with recently diagnosed RA.
Mapping of arthritis susceptibility within the MHC region revealed a 144–223–kb locus containing <12 genes, including paralogs for HLA–DQ and HLA–DR. Susceptibility to CII and CXI was linked to haplotypes RT1av1 (DA) and RT1f (DA.1F), respectively. After injection of pristane, rats of both strains developed weak T cell and IgG responses to CII, but not to CXI. In chronic arthritis, however, collagen reactivity was stronger, specific for CXI, and restricted to rats with RT1f MHC. Among RA patients, 12% exhibited a specific IgG response to CXI, 6% to CII, and 6% to both collagens.
These findings demonstrate a shift in cartilage recognition in early and chronic arthritis in the rat, suggesting that CXI autoreactivity contributes to the perpetuation of chronic disease. The results provide evidence of the importance of joint antigens in arthritis development.