T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes

Abstract

Type II collagen (CII) is of immunological interest because of its repetitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be identified. Multiple novel epitopes on mouse CII are here detected in the autoreactive T cell response. The major response is directed to an epitope with residues 707-721 located on the CB10 fragment. Some 25 other epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collagen. The cells reactive with mouse collagen peptides were of Th1 type, as judged by release of IFN-gamma. No significant reactivity was detected to mouse CII peptides during ongoing disease. Alignment of the mouse epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a nonamer core sequence. Binding of these epitopes was simulated in a computer model of the I-Aq molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best. The spacing of pockets and the fine structure of the binding surface of the I-Aq molecule meshes with the repetitive structure of the collagen (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes. Comparison with human DR binding motifs showed that the I-Aq motif resembles most closely that of the DR4 subtypes which predispose for rheumatoid arthritis.

Induction of Transient Arthritis by the Adoptive Transfer of a Collagen II Specific Th1 Clone to HLA-DR4 (B1*0401) Transgenic Mice

“…We have in fact, identified only one relatively strong binding site in either bovine or human CII for DR4 (B1*0401) using the predictive model of Hammer et al [3]. The MHC class II molecules of DBA/1J mice, however, have been reported to have 25 such relatively strong binding sites for CII [24]. There are also 16 T-cell epitopes from CII that can bind HLA-DQ8 (the human homologue of H-2 q in mice), and DQ8 transgenic mice are susceptible to CIA [25,26].…”

The Influence of HLA-DR4 (0401) on the Immune Response to Type II Collagen and the Development of Collagen Induced Arthritis in Mice

“…Thus, the failure of our DR4 Tg mice to develop CIA may reflect the fact that the APC of these mice may only bind a single peptide region of CII. In contast, CIA susceptible DBA/1J mice have at least 25 H-2 q restriction sites and it is also likely that there are additional H-2 f restriction sites for CII in DR4 Tg B10.M mice [17].…”

Chronic relapsing homologous collagen‐induced arthritis in DBA/1 mice as a model for testing disease‐modifying and remission‐inducing therapies

“…Two groups of investigators have reported that immunization of DBA/1 mice with homologous, rather than heterologous, CII led to a chronic relapsing and progressive form of CIA, which more closely resembled the clinical picture of RA in humans (16,17). The homologous CII model has subsequently been used to study autoimmune responses toward epitopes present on homologous and heterologous CII (18)(19)(20). However, homologous CIA has not been fully validated as a model for RA, in particular for the evaluation of antirheumatic therapies.…”