Critical role of the major histocompatibility complex and IL-10 in matrilin-1-induced relapsing polychondritis in mice

Abstract

Relapsing polychondritis (RP) is an autoimmune disease that affects extra-articular cartilage. Matrilin-1-induced relapsing polychondritis (MIRP) is a model for RP and is useful for studies of the pathogenic mechanisms in this disease. There are indications that the major histocompatibility complex (MHC) class II plays a major role in RP, since DR4+ patients are more commonly affected than controls. We have now addressed the role of the MHC region, as well as the non-MHC contribution, using congenic mouse strains. Of the MHC congenic strains, B10.Q (H2q) was the most susceptible, the B10.P (H2p) and B10.R (H2r) strains developed mild disease, while B10 strains carrying the v, b, f, or u H2 haplotypes were resistant. A slight variation of susceptibility of H2q strains (B10.Q> C3H.Q> DBA/1) was observed and the (B10.Q x DBA/1)F1 was the most susceptible of all strains. Furthermore, macrophages and CD4+ T cells were the most prominent cell types in inflammatory infiltrates of the tracheal cartilage. Macrophages are the major source of many cytokines, such as interleukin-10 (IL-10), which is currently being tested as a therapeutic agent in several autoimmune diseases. We therefore investigated B10.Q mice devoid of IL-10 through gene deletion and found that they developed a significantly more severe disease, with an earlier onset, than their heterozygous littermates. In conclusion, MHC genes, as well as non-MHC genes, are important for MIRP induction, and IL-10 plays a major suppressive role in cartilage inflammation of the respiratory tract.

Figure 1

Disease course and weight in individual mice immunized with matrilin-1 to induce relapsing polychondritis. (a, b) Two QD ([B10.Q × DBA/1]F₁) mice (QD 1 and QD 2) and (c) a C3H.Q mouse (CQ 1) were scored for severity of disease on a scale from 0 to 5; see Materials and methods. All control mice (n = 4) were scored at the same time, and mean values of their weight are presented.

Figure 2

Tissue samples from a QD ([B10.Q × DBA/1]F₁) mouse immunized with matrilin-1 to induce relapsing polychondritis. (a) Section from the tracheal cartilage in the acute phase, showing inflammatory infiltrates and severe cartilage destruction. Cells detected in the infiltrates are macrophages, neutrophils, lymphocytes, and eosinophils. (b) Section from nasal septum, showing inflammatory infiltrates, fibrin deposition, and erosion of the cartilage. Staining with hematoxylin and erythrosine. Original magnification ×200.

Figure 3

Titers of antibodies to matrilin-1 in mice immunized with matrilin-1. Sera analyzed at day 35, with values expressed as relative titers in comparison with a positive control used on all plates assayed. For detailed information on the various strains and H2 haplotype, see Table 1.

Figure 4

Anticollagen type II antibody response after immunization with matrilin-1 in (B10.Q × DBA/1)F₁ B10.Q mice devoid of IL-10 through gene deletion, and their heterozygous littermates. Sera were analyzed for total IgG levels at day 35 after immunization. For detailed information on the experimental setup, see Materials and methods.