Positional Identification of RT1-B (HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis

Haag, Sabrina (author)

Tuncel, Jonatan (author)

Thordardottir, Soley (author)

Mason, Daniel E. (author)

Dobritzsch, Doreen, 1972- (author): Uppsala universitet,Biokemi,Structural Biochemistry

Peters, Eric C. (author)

(creator_code:org_t)

2015-03-15
2015
English.
In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:6, s. 2539-2550

Related links:: https://www.jimmunol...; show more...; https://urn.kb.se/re...; https://doi.org/10.4...; http://kipublication...; show less...

Abstract Subject headings

Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.

By the author/editor: Haag, Sabrina; Tuncel, Jonatan; Thordardottir, S ...; Mason, Daniel E.; Yau, Anthony C. ...; Dobritzsch, Dore ...; show more...; Backlund, Johan; Peters, Eric C.; Holmdahl, Rikard; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Other Chemistry ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Immunology

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