The Major Histocompatibility Complex Class III Haplotype Ltab-Ncr3 Regulates Adjuvant-Induced but Not Antigen-Induced Autoimmunity.
Rheumatoid arthritis is a complex disease associated with >100 risk loci, with the strongest association from the major histocompatibility complex (MHC) region. Here, we analyzed a new genetic association in the MHC class-III region (MHC-III) using adjuvant- and antigen-induced arthritis models. In addition, we used models for multiple sclerosis for comparison and dissected the MHC-III-mediated mechanisms of importance for antibody and T-cell responses to antigens. With the use of a panel of MHC-III recombinant inbred strains, we found that the 33-kb Ltab-Ncr3 haplotype in MHC-III was linked to the induction of arthritis with incomplete Freund's adjuvant, with similar effects in arthritis induced by several oil adjuvants (hexadecane, heptadecane, squalene, arlacel). Adoptive T-cell transfer experiment showed that this arthritis-protective effect operated during the priming of T cells by controlling their arthritogenicity. Interestingly, Ltab-Ncr3 did not regulate autoimmune diseases induced with tissue-specific antigens emulsified in adjuvant oils, such as collagen-induced arthritis or experimental autoimmune encephalomyelitis. No effect on antibody or T-cell response to tissue antigens in the Ltab-Ncr3 could be demonstrated. The finding that Ltab-Ncr3 is specific in regulating adjuvant-induced arthritis but not antigen-induced autoimmunity, and with unique effects on priming of autoreactive and arthritogenic T cells, provides new insight for understanding the regulation of autoimmune diseases.
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Anthony C Y
ACY
Yau
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Jonatan
J
Tuncel
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Electronic address: rikard.holmdahl@ki.se.
Rikard
R
Holmdahl
D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D019540:Area Under Curve; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D003094:Collagen / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D008055:Lipids / Q000633:toxicity; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology*; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D008055:Lipids; D009419:Nerve Tissue Proteins; C000602563:Vangl2 protein, rat; C114843:incomplete Freund's adjuvant; D003094:Collagen; D005620:Freund's Adjuvant