A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1)

Abstract

Relapsing polychondritis (RP) differs from rheumatoid arthritis (RA) in that primarily cartilage outside diarthrodial joints is affected. The disease usually involves trachea, nose, and outer ears. To investigate whether the tissue distribution of RP may be explained by a specific immune response, we immunized rats with cartilage matrix protein (matrilin-1), a protein predominantly expressed in tracheal cartilage. After 2-3 weeks, some rats developed a severe inspiratory stridor. They had swollen noses and/or epistaxis, but showed neither joint nor outer ear affection. The inflammatory lesions involved chronic active erosions of cartilage. Female rats were more susceptible than males. The disease susceptibility was controlled by both MHC genes (f, l, d, and a haplotypes are high responders, and u, n, and c are resistant) and non-MHC genes (the LEW strain is susceptible; the DA strain is resistant). However, all strains mounted a pronounced IgG response to cartilage matrix protein. The initiation and effector phase of the laryngotracheal involvement causing the clinical symptoms were shown to depend on alphabeta T cells. Taken together, these results represent a novel model for RP: matrilin-1-induced RP. Our findings also suggest that different cartilage proteins are involved in pathogenic models of RP and RA.

Figure 1

Sections of nasal and laryngeal cartilage from female LEW.1F rats. (a and b) Nasal septum from rats immunized with CMP. (a) Tissue taken at day 18 after immunization. Erosion of the nasal septal cartilage caused by inflammatory cells is seen. (b) Tissues taken in chronic phase, 120 days after immunization. Shown are irregular tissue and new formation of cartilage, i.e., new irregular cartilage tissue outside the original and normal cartilaginous structures. (c and d) Laryngeal tissue from rats immunized with CMP. (c) Tissue taken day 18 after immunization. A massive invasion of inflammatory cells is seen causing cartilage erosion. (d) Tissues taken in chronic phase, 120 days after immunization. Irregular tissue, new formation of cartilage, and a small area of inflammatory cells are seen. (a–d) Hematoxylin and erythrosin staining. (e and f) Staining with CMP-specific polyclonal antibodies. Tissue from a normal female LEW.1F rat showing positive staining in larynx (e) but not in the ear (f). (a–f) Original magnification: ×200.

Figure 2

Blocking of αβ TCR with mAb’s (R73). LEW.1F female rats, immunized with 150 μg of CMP, were treated with either PBS (open circles) or PBS + R73 (filled circles). Incidence (a) and mean clinical score ± SD (b). Clinical scores of respiratory distress. See Methods.