CII autoimmunity in DRB10101 and 0401 transgenic mice

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While several autoantigens have been proposed to be the target of the autoimmuni-ty of RA, most of the proteins that have been studied are found predominantly in joints, including type II collagen (CII), human cartilage glycoprotein 39, and proteoglycan. CII is the major structural protein in articular cartilage, and anti-CII antibodies have been found in a high percentage of RA patients [14-18] and the presence of CII-specific T-cells has also been reported in RA patients [19-21]. In order to experimentally test the relationship between RA and CII autoimmunity, several investigators have developed HLA-DR humanized mouse models to determine if the DR1 or DR4 susceptibility alleles mediate this CII-specific autoimmunity. CII immunization of humanized, transgenic mice expressing either DRB1*0101 or DRB1*0401 on B10.M or DBA/1 backgrounds induces an inflammatory autoimmune arthritis that shares significant clinical and histopathological similarities with RA [9, 10, 22]. Surprisingly, T-cells from both DRB1*0101 and DRB1*0401 trans-genic mice recognize the same dominant epitope in CII, located at amino acids 263-270 (CII263-270) [9, 10, 22]. This CII dominant epitope also binds to DRB1*0101 and DRB1*0401 in a very similar manner with the phenylalanine at amino acid 263 of the CII peptide fitting in the P1 binding pocket of both the DR1 and DR4 molecules [23]. The significance of this CII peptide is supported by recent studies in RA patients in which a T-cell response to CII263*270 was detected in patients with early disease (less than 3 years) but was less prevalent in RA patients with disease of longer duration [19].

Recently Latham et al. and Svendsen et al. demonstrated that DR1 and DR4 tetramers in which the respective peptide binding sites are loaded with the CII dominant peptide can be used to identify DR-restricted, CII-specific T-cells ex vivo using DR1 and DR4 humanized mouse models [12, 24]. This approach allowed for quantitation of the CII-specific T-cell response over time as arthritis develops as well as a means of isolating the pathogenic T-cell population for functional and molecular studies. The number of CII- specific T-cells reached a maximum around 10 days post immunization, and then gradually decreased, although CII-specific T-cells could still be detected at more than 100 days after immunization [12]. Cytokine analysis has revealed that these CII-specific T-cells express cytokines consistent with the Th1 phenotype [12, 24]. Moreover, these CII-specific T-cells are also present in the arthritic joints of the DR-transgenic mice but only at the early stages of disease, potentially indicating a direct role for CII-specific T-cells in the early pathogenic phase of CIA [12, 24]. DR4-CII tetramers have been also used to search for CII-spe-cific T-cells in the synovial fluid of RA patients [25], but to date, this approach has not yielded positive results. However, based on the data from the humanized models above, the use of samples from patients with late stage disease may have contributed to the inability to detect CII-specific T-cells. Alternatively, studies using human CII-transgenic, DR-humanized mice have suggested that glycosylated forms of CII, that were not present in the tetramers, may play an important role in the autoimmunity of RA [26].

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