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 |
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Authors: | Bayrak S; Holmdahl R; Travers P; Lauster R; Hesse M; Dolling R; Mitchison NA |
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Institution: | Deutsches Rheuma-Forschungszentrum Berlin, Germany. |
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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.
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