title: Positional identification of RT1-B (HLA-DQ) as susceptibility locus for autoimmune arthritis.
abstract: 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.
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden;
authors: Sabrina
authors: S
authors: Haag
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden; Rikard.Holmdahl@ki.se Jonatan.Tuncel@ki.se.
authors: Jonatan
authors: J
authors: Tuncel
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden;
authors: Soley
authors: S
authors: Thordardottir
authors: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121;
authors: Daniel E
authors: DE
authors: Mason
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden;
authors: Anthony C Y
authors: AC
authors: Yau
authors: Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden; and Department of Chemistry, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden.
authors: Doreen
authors: D
authors: Dobritzsch
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden;
authors: Johan
authors: J
authors: Bäcklund
authors: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121;
authors: Eric C
authors: EC
authors: Peters
authors: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden; Rikard.Holmdahl@ki.se Jonatan.Tuncel@ki.se.
authors: Rikard
authors: R
authors: Holmdahl
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001665:Binding Sites / Q000235:genetics; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000276:immunology; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000276:immunology; D017434:Protein Structure, Tertiary; D051381:Rats; D012720:Severity of Illness Index; D013729:Terpenes / Q000276:immunology
chemical_list: D000596:Amino Acids; D019138:Antibodies, Blocking; D006649:Histocompatibility Antigens; D013729:Terpenes; C038353:histocompatibility antigens RT, rat; C009042:pristane