Few spontaneous models of arthritic disease have been observed [14
], and none have as yet described all the manifestations necessary to be considered a spontaneous model of relapsing polychondritis – which is characterized not only by polyarthritis, but also by involvement of the ears, the nose and possibly the trachea. Hansson and colleagues have described a chondritic model in which matrilin-1 immunization induces involvement of the respiratory tract but in which peripheral joints and ears are unaffected [11
We describe herein a model of spontaneous autoimmune polychondritis that occurs in mice expressing the DQ6α8β transgene without the exogenous stimulation by antigen or adjuvant and the possible interference those substances may add. The mean onset of disease occurs about 6 months of age. Although difficult to directly correlate mouse years with human years, this places the onset of disease approximately at middle age, or near the fourth or fifth decade of life in human years, matching the mean onset of RP in humans. There is a strong female preponderance, which correlates with some reports of human relapsing polychondritis [1
] and autoimmune diseases in general. This would suggest that the gender-related factors that make females more prone to autoimmune responses may also be occurring in this newly identified model, and thus may be better understood. It is of note that enhanced female susceptibility is not observed in the CII-induced model of polychondritis or arthritis.
Human studies have shown that as many as two-thirds of RP patients do not develop antibodies to CII during the course of disease [17
], correlating to the finding that there was not a CII-specific immune response during SP. There are, however, significant total IgG responses in both SP and RP, suggesting a role for antibodies in the pathogenesis of disease. In addition, there is an increased infiltration of mast cells into the synovium and ears during SP, which also correlates with other recent reports suggesting a pathogenic role for the elevated IgG through mast cells in RA and animal models of arthritis [18
]. We are currently investigating the contribution the mast cells infiltrating into the cartilaginous tissues have toward the pathogenesis of SP. In addition, a strong antibody response to matrilin-1 is observed during SP, raising the possibility that matrilin-1 may be the putative autoantigen in the initiation of SP. This would correspond with an antimatrilin-1 antibody response observed in human RP patients [8
] and with the ability of heterologous matrilin-1 to induce a polychondritis-like disease in mice [11
There has been significant interest in another putative autoantigen, the ubiquitous protein glucose-6-phosphate-isomerase (G6PI), because antibodies specific for G6PI have been found deposited in the joints of RA patients as well as in mouse models of RA [22
]. There have not, however, been any reports of auricular chondritis in K/B × N mice or of anti-G6PI antibodies in RP patients. Both DQ6α8β tg expressing strains displayed high titers of anti-G6PI IgG1
regardless of the presence of clinical disease (Bradley and Wooley, personal communication), suggesting that while the deposition of antibody complexes into the joint may contribute to the overall destruction of synovial or auricular tissue, it is most probably not the initial trigger in pathogenesis of autoimmune damage in SP.
Treatment with transforming growth factor beta (TGF-β) has been shown recently to provide some protective effect against collagen-induced arthritis in young, susceptible mice, although the effects are not long-lasting. In aging mice, however, treatment with TGF-β has been shown to block induction of arthritis altogether [23
]. DQ6α8β tg expressing mice displayed an overall increase in the levels of TGF-β, regardless of the presence of disease, as compared with controls (naïve B10.T(6R) mice), with many samples reading high and out of range (Bradley and Cafruny, personal communication). It is unclear how this finding correlates with the immunoregulatory role of TGF-β in arthritis. It is possible, however, that the elevated TGF-β levels represent an active attempt by these mouse strains to downregulate the vigorous (auto)immune response. Alternatively, the TGF-β serum levels may represent another form of dysregulation, such as the role of TGF-β-specific antibodies in lupus-like diseases [24
Correlations have been made between the HLA genotype and the genetic predisposition to many autoimmune diseases, including rheumatoid arthritis (HLA-DR4, DQ8), insulin-dependent diabetes mellitus (DR4, DQ8), thyroiditis (DR3) and multiple sclerosis (DR4) [25
]. The occurrence of SP in a mouse expressing the DQ6α8β transgene and lacking endogenous MHC class II expression may provide insight into the potential contribution of mixed haplotype molecules to RP, and perhaps more generally to immune responses. It is of note that HLA-DR4 subtypes, some of which are linked with DQ8 due to linkage disequilibrium, have been associated with RP [2
]. This association is true of the DR4 subtypes linked with DQ8 and the subtypes not linked with DQ8, however, suggesting that the RP HLA-D association may be more complex than the allelic association. This may also suggest that one or more mixed haplotypes molecules (e.g. DQ6α8β) may be able to present the pathogenic epitopes responsible for polychondritis.