Policondrite Ricorrente

IgG subclass use reflects both the type of antigen and the character of the cellular response to that antigen. Further, the IgG subclass of an autoantibody may influence the pathogenic role of that antibody. Antibodies to native type II collagen(CII) have been found in patients with both rheumatoid arthritis (RA) and relapsing polychondritis (RP). In patients with RA these antibodies are predominantly of the IgG3 and IgG1 subclasses. In RP the subclass use of anti-CII antibodies has not been previously examined. We have collected serum from a group of patients with RP and examined their antibody response to type II collagen, and compared the IgG subclass distribution of the anti-CII antibodies present in the sera of these patients to a group of sera from patients with RA.

Sera from 37 patients meeting criteria for RP were selected for this study. IgG antibodies directed against native human type II collagen were detected by ELISA. We found elevated antibodies to CII in 57% of RP patients, compared to 4% of 84 normal controls (p<0.0001). The 21 RP serum samples containing anti-CII IgG were then examined using a quantitative ELISA for the presence of anti-CII antibodies of the IgG1, IgG2, IgG3 and IgG4 subclasses. IgG1 and IgG2 were the predominant subtypes used with 14% of patients having a predominance of IgG1 (>70%), 28% using IgG2 predominantly (>70%) and 48% demonstrating an equal distribution of IgG1and IgG2. IgG4 was found at low levels in 50% of patients and only 2/21 produced IgG3 anti-CII antibodies. The differences between patient sera suggest that the IgG subclass use may reflect disease activity, severity or response to treatment. To test the validity of our assay system we examined the subclass distribution of anti-CII IgG in the serum of 12 RA patients known to have anti-CII antibodies. We found in these individuals a predominant use of IgG1 and IgG3 with no IgG2 or IgG4 detected, similar to previously published results. The lack of similarity between RA and RP patient’s anti-CII subclass distribution suggests that the immunologic response to CII is different in these two diseases. The dissimilarity may be due to alteration in the T-cell response to CII or differences of the micro-enviroment where the T-cells encounter the stimulant antigen, and as a consequence, the pathogenic role of these autoantibodies to CII in RA and RP may differ.

HLA-DQ8 transgenic B10 mice lacking endogenous class II molecules develop severe arthritis following type II collagen (CII) immunization and mount a strong invitro T cell response to CII. NOD mice develop spontaneous diabetes in a germ free colony. Immunization of NOD mice with CII does not lead to any clinical signs of arthritis. We have introduced HLA-DQ8 transgene in NOD mice lacking endogenous class II molecules to determine their susceptibility to arthritis. The mice were backcrossed to generate congenic NOD.DQ8.Abo line. All mice immunized with CII developed severe polyarthritis and auricular chondritis. The clinical and histologic manifestations of experimental polychondritis were similar to those symptoms in human relapsing polychondritis. Auricular chondritis was bilateral and histopathology revealed massive infiltration of ear by mononuclear cells and destruction of cartilage. HLA-DQ8 and Ag7 molecules share similarities, both carry non-Asp aa at position 57 of beta chain. However while Ag7 cannot present arthritogenic epitopes of CII, DQ8 molecule can do so leading to development of polyarthritis. Previously we have reported that expression of HLA-DQ8 and DQ6 molecules results in CII induced auricular chondritis while the parents are resistant. The finding with NOD.DQ8 mice show that complementation between NOD background genes and DQ8 molecules can result in severe CII-induced polyarthritis. These transgenic mice provide a model to study MHC/non-MHC genes as well as CII in relapsing polychondritis in human.

Type II collagen (CII) is a major component of cartilage and is a candidate autoantigen in both rheumatoid arthritis (RA) and relapsing polychondritis (RP). Animal models of collagen-induced arthritis and chondritis have been studied extensively, and animals transgenic for the RA associated class II alleles DR1 and DR4 have been used to establish the immunodominant epitope of CII. This epitope CII (261-273) has been shown to be immunodominant for both DRB1*0101 and DRB1*0401. T cell responses to this peptide have been seen in RA synovial fluid but T cells clones with this specificity have not yet been reported in patients with RA or RP.

Objective: In order to elucidate the mechanisms of cartilage destruction in polychondritis which often involves the external auricle and respiratory tract by immunological disorder, we analyzed 8 cases by immunohistochemical and in situ hybridization.

Summary: Cartilage destruction in polychondritis is induced not only by the inflammatory reaction around cartilage, but also the internal factors in chondrocytes themselves such as some kinds of proteolytic enzymes and apoptosis.