HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis

A novel model for human polyarthritis

Gerald H. Nabozny, Jeanine M. Baisch, Shen Cheng, Dominic E Cosgrove, Marie M. Griffiths, Harvinder S. Luthra, Chella S. David

Research output: Contribution to journalArticle

174 Citations (Scopus)

Abstract

Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA1*0301 and DQB1*0302 genes from an RA predisposing haplotype (DQ8/DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab0 mice, and their susceptibility to experimental collagen induced arthritis was evaluated. The HLA-DQ8+,H-2Ab0 mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4+ T cells expressing a normal repertoire of V(β) T cell receptors. Immunization of HLA-DQ8+,H-2Ab0 mice with bovine type II collagen (CII) induced a strong antibody response that was cross-reactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8+,H-2Ab0 mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2A(q)) controls. In contrast, HLA-DQ8, H-2Ab0 fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also establish a novel animal model for the study of human arthritis.

Original languageEnglish (US)
Pages (from-to)27-37
Number of pages11
JournalJournal of Experimental Medicine
Volume183
Issue number1
DOIs
StatePublished - Jan 1 1996

Fingerprint

Experimental Arthritis
Transgenic Mice
Arthritis
HLA-DQ Antigens
Rheumatoid Arthritis
HLA-DR Antigens
Genes
Collagen Type II
Antibodies
Linkage Disequilibrium
Genetic Predisposition to Disease
T-Cell Antigen Receptor
HLA-DQ8 antigen
Major Histocompatibility Complex
Transgenes
Haplotypes
Antibody Formation
Immunization
Animal Models
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology

Cite this

HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis : A novel model for human polyarthritis. / Nabozny, Gerald H.; Baisch, Jeanine M.; Cheng, Shen; Cosgrove, Dominic E; Griffiths, Marie M.; Luthra, Harvinder S.; David, Chella S.

In: Journal of Experimental Medicine, Vol. 183, No. 1, 01.01.1996, p. 27-37.

Research output: Contribution to journalArticle

Nabozny, Gerald H. ; Baisch, Jeanine M. ; Cheng, Shen ; Cosgrove, Dominic E ; Griffiths, Marie M. ; Luthra, Harvinder S. ; David, Chella S. / HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis : A novel model for human polyarthritis. In: Journal of Experimental Medicine. 1996 ; Vol. 183, No. 1. pp. 27-37.
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abstract = "Genetic studies have indicated that susceptibility to rheumatoid arthritis (RA) maps to the HLA-DR locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DR genes associated with RA, however, suggests that HLA-DQ molecules may also play a role in RA susceptibility. To examine the role of HLA-DQ molecules in arthritis, we generated transgenic mice expressing the DQA1*0301 and DQB1*0302 genes from an RA predisposing haplotype (DQ8/DR4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab0 mice, and their susceptibility to experimental collagen induced arthritis was evaluated. The HLA-DQ8+,H-2Ab0 mice displayed good expression of the DQ8 molecule, while no surface expression of endogenous murine class II molecules could be detected. The DQ8 molecule also induced the selection of CD4+ T cells expressing a normal repertoire of V(β) T cell receptors. Immunization of HLA-DQ8+,H-2Ab0 mice with bovine type II collagen (CII) induced a strong antibody response that was cross-reactive to homologous mouse CII. Also, in vitro proliferative responses against bovine CII, which were blocked in the presence of an antibody specific for HLA-DQ and mouse CD4, were detected. Finally, a severe polyarthritis developed in a majority of HLA-DQ8+,H-2Ab0 mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2A(q)) controls. In contrast, HLA-DQ8, H-2Ab0 fullsibs did not generate CII antibody and were completely resistant to arthritis. Therefore, these results strongly suggest that HLA-DQ8 molecules contribute to genetic susceptibility to arthritis and also establish a novel animal model for the study of human arthritis.",
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