DBA/1 mice develop a chronic peripheral arthritis after immunization with type II collagen termed collagen-induced arthritis. We have localized the main arthritogenic determinants of CB11, a CNBr-generated arthritogenic fragment of chick type II collagen (CII), using 3 smaller peptide fragments of CB11 generated by endoproteinase LysC, LysC1 (CII 124-290), LysC2 (CII 291-374) and LysC3 (CII 375-402) and a panel of monoclonal antibodies (mAb) specific to CB11. MAb specific to the arthritogenic region of CB11 were also used to study the synergistic effect of E. coli lipopolysaccharide (LPS) on antibody-mediated arthritis in naive DBA/1 mice. LysC2 contained a minimum essential arthritogenic fragment of type II collagen: LysC2 induced arthritis by active immunization, also, a combination of four mAb specific to LysC2 passively transferred arthritis to naive mice. A single i.p. injection of LPS (50 micrograms/mouse) reduced the threshold values of the arthritogenic dose of mAb from 1 mg to 50 micrograms/clone per mouse, and decreased the number of mAb required for inducing arthritis from 4 to 2 clones. These observations suggest that LysC2, an 84 amino acid residue fragment, contains the main arthritogenic determinants within chick CB11. Importantly, LPS, a strong inducer of pro-inflammatory cytokines, negates the required multiple epitope specificity of autoantibodies in the passive transfer model and acts synergistically in the induction of arthritis by autoantibody.

Identification of specific genetic loci that contribute to susceptibility to rheumatoid arthritis (RA) in humans has been hampered by several factors, including: i) multiple interacting genetic loci contributing to susceptibility; ii) complex interactions of environmental and genetic factors; iii) genetic heterogeneity; and iv) low penetrance. We have, therefore, mapped quantitative trait loci (QTLs) that control inflammatory arthritis susceptibility and/or severity in progeny of two inbred rat strains with significantly different susceptibilities to collagen-induced arthritis (CIA), an animal model for RA. Not surprisingly, we identified a major susceptibility factor, Cia1, on chromosome 20 in the vicinity of the rat major histocompatibility complex (MHC). However, by limiting the analysis to animals with arthritis-susceptible MHC genotypes and using genome-wide QTL analytic techniques, we also found four non-MHC QTLs-Cia2, 3, 4 and 5-on chromosomes 1, 4, 7 and 10, that contributed to disease severity. In addition, a QTL on chromosome 8 was suggestive for linkage. Characterization of the genes underlying these QTLs will facilitate the identification of key biochemical pathways regulating experimental autoimmune arthritis in rats and may provide insights into RA and other human autoimmune diseases. These genes may also represent novel targets for therapy.

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SummaryGenetic studies have indicated that susceptibility to rheumatoid arthritis (R.A) maps to the HLA-DP, locus of the major histocompatibility complex. Strong linkage disequilibrium between certain HLA-DQ genes and HLA-DP,. 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 DQA 1"0301 and DQB 1"0302 genes from an RA predisposing haplotype (DQ8/DR.4Dw4). The transgenes were introduced into mouse class II-deficient H-2Ab ~ mice, and their susceptibility to experimental collagen-induced arthritis was evaluated. The HLA-DQ8+,H-2Ab ~ 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~ T cell receptors. Immunization of HLA-DQ8+,H-2Ab ~ mice with bovine type II collagen (CII) induced a strong antibody response that was crossreactive 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-2Ab ~ mice, which was indistinguishable from the disease observed in arthritis susceptible B10.T(6R) (H-2Aq) controls. In contrast, HLA-DQ8-,H-2Ab ~ 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 estabhsh a novel animal model for the study of human arthritis.I t is widely accepted that a strong genetic component contributes to the susceptibility or resistance to certain human autoimmune diseases (1). Attempts to identify the particular genes involved in these disorders has been an area of major focus for many laboratories, and inroads have been clearly made. Among the numerous genes studied, one group that has garnered much attention are the genes encoding the class I and class II molecules of the HLA complex. Located on the short arm of chromosome 6, the primary function of HLA class I and II molecules is to bind and present processed antigenic peptides to T cells bearing receptors specific for the peptide-HLA complex. This presentation event plays a pivotal role in shaping the cellular immune repertoire and dictating the nature and scope of the immune response against a given antigen (2).A role for HLA molecules in the etiology of autoimmune disease derives from genetic studies showing a clear association between the presence or absence of certain HLA class I or II alleles, as well as increased or decreased susceptibility to a particular autoimmune disorder. A disease with a strong autoimmune foundation and HLA class II association is rheumatoid arthritis (RA) 1. In Caucasians, genetic studies initially showed a high prevalence of the HLA-DR4Dw4...