Proteoglycan and DRB10401 transgenic mice

Similar to CII, proteoglycan is also a major structural component of the extracellular matrix of cartilage and has been suggested to be a target of RA autoimmunity. Years ago it was demonstrated that immunization of wild type BALB/c or C3H mice with human proteoglycan induced a progressive polyarthritis that shares many similarities with RA [31, 32]. Recently, BALB/c-DRB1*0401 and -DQ8 transgenic mice were developed to study the role of proteoglycan specific, DR4- and DQ8-restrict-ed immune responses [33]. In contrast to the humanized CII models in which introduction of DR4 and DR1 transgenes converted a CIA non-susceptible strain to a CIA susceptible strain [9, 10], proteoglycan induced arthritis (PGIA) only occurred in the humanized mice in which the transgene was expressed on the PGIA susceptible BALB/c background [33]. The incidence and severity of disease after immunization was lower compared to the standard BALB/c PGIA model, and arthritis onset occurred much later, but the histopathology was indistinguishable [33]. The trans-genic mice used in this model did not express human CD4 nor was the DR molecule chimeric for I-E, therefore the lack of a CD4 co-receptor for the DR molecule may have contributed to the reduced arthritogenicity of the proteoglycan in these trans-genic mice. Nevertheless, these humanized models allowed the investigators to identify antigenic components of human proteoglycan that are bound and presented by these RA alleles, and studies of RA patients with these proteoglycan peptides have indicated that T-cell immunity to these peptides exists in some patients [34].

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