Cgp39 and DRB10401 transgenic mice

Human cartilage glycoprotein 39 (HCgp39) is another cartilage-derived protein that has been studied in humanized mice as a potential autoantigen in RA. HCgp39 has received attention as a potential RA antigen because HCgp39-reactive T-cells have been detected in peripheral blood from RA patients [27]. Although HCgp39 is present in many tissues, it is undetectable in healthy cartilage explants [28, 29], but is abundantly present in inflamed arthritic joints where it is produced by synovial cells and articular chondrocytes [28, 29]. Cope et al. studied the immunogenicity of HCgp39 in both transgenic mice expressing the RA-susceptibility allele DRB1*0401 as well as mice expressing a non susceptible allele, DRB1*0402 [30]. Both of these humanized models incorporated a human CD4 transgene expressed by T-cells to function as a co-receptor for the DR molecule. Interestingly, although there was no difference in T-cell proliferation between DRB1*0401 and *0402 transgenic mice following stimulation with HCgp39, the cytokine profiles of HCgp39-specific T-cells from *0401- and *0402-transgenic mice were significantly different [30]. HCgp39-specific T-cells from *0401 mice produced high levels of IFN-y and TNF-a. In contrast, very little IFN-y was produced by *0402-restricted T-cells, and TNF-a production was undetectable in these cells. The immunodominant epitopes of HCgp39 in *0401 and *0402 mice have also been identified, and are distinct for each allele. There are three DRB1*0401-restricted dominant epitopes, HCgp39( 100-115), HCgp39(262-276), and HCgp39(322-337), while there are two major epitopes for *0402, HCgp39(22-37) and HCgp39(298-313) [30]. Additionally, proliferative responses to all three *0401-restricted immunogenic peptides have been observed in RA patients expressing the DRB1*04 susceptibility alleles

[30]. While immunization of the DRB1*0401 transgenic mice with HCgp39 induces a DR4-restricted T-cell response, these mice do not develop arthritis, in contrast to the other humanized models studying cartilage derived antigens. Despite this drawback, these mice still proved to be invaluable in testing the DR4-restricted immuno-genicity of HCgp39 and identifying its antigenic determinants.

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