title: MHC class II alleles associated with Th1 rather than Th17 type immunity drive the onset of early arthritis in a rat model of rheumatoid arthritis.
abstract: Polymorphisms in the MHC class II (MHCII) genes are strongly associated with rheumatoid arthritis, supporting the importance of autoreactive T helper (Th) cells for the development of this disease. Here, we used pristane-induced arthritis (PIA), induced by the non-antigenic hydrocarbon pristane, to study the impact of different MHCII alleles on T-cell activation and differentiation. In MHCII-congenic rats with disease-promoting MHCII alleles, pristane primarily induced activation of Th1 cells, whereas activated T cells were Th17 biased in rats with protective MHCII alleles. Neutralization of IFN-γ during T-cell activation abrogated the development of disease, suggesting that Th1 immunity is important for disease induction. Neutralization of IL-17, by contrast, suppressed arthritis only when performed in rats with established disease. Adoptive T-cell transfers showed that T cells acquired arthritogenic capacity earlier in strains with a prevailing Th1 response. Moreover, upon pristane injection, these strains exhibited more Ag-primed OX40+ and proliferating T cells of polyclonal origin. These data show that T cells are polarized upon the first encounter with peptide-MHCII complexes in an allele-dependent fashion. In PIA, the polyclonal expansion of autoreactive Th1 cells was necessary for the onset of arthritis, while IL-17 mediated immunity contributed to the progression to chronic disease.
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Tuncel
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Sabrina
authors.identifier: 0000-0003-3714-6268
authors.initials: S
authors.lastname: Haag
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000483:Alleles; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D011110:Polymorphism, Genetic; D051381:Rats; D011919:Rats, Inbred Strains; D013729:Terpenes; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000949:Histocompatibility Antigens Class II; D020381:Interleukin-17; D013729:Terpenes; C009042:pristane; D007371:Interferon-gamma
keywords: Animal models; Autoimmunity; Immune responses; MHC; Rheumatoid arthritis; T helper (Th) cells