T-cell molecular mimicry in Chagas disease:: identification and partial structural analysis of multiple cross-reactive epitopes between Trypanosoma cruzi B13 and cardiac myosin heavy chain

Chagas disease cardiornyopathy (CCC) is one of the few examples of post-infectious autoimmunity, where infectious episodes with an established pathogen, the protozoan parasite Trypanosoma cruzi, clearly triggers molecular mimicry-related target organ immune damage. CD4(+) T-cell clones infiltrating hearts from CCC patients cross-reactively recognize human cardiac myosin, the major heart protein, and the immunodominam B 13 protein from T. cruzi. Moreover, in vitro priming with B 13 leads to the recovery of cardiac myosin cross-reactive T-cell clones. In order to identify cross-reactive epitopes between B 13 protein and human cardiac myosin, we used B13 peptide S15.4, preferentially recognized by CCC patients, to establish a T-cell clone from an HLA-DQ7 individual. The B13 S15.4 peptide- specific CD4(+) T-cell clone 3E5 was tested in proliferation assays against 15 Lys/His-substituted S15.4-derived peptides for TCR/HLA contact analysis. Together with previous HLA-binding data and molecular modeling of the HLA-DQ7-peptide S15.4 complex, Lys/His scanning analysis showed eight TCR/HLA contact positions. Clone 3E5 was also tested against 45 15-mer peptides from human beta-cardiac myosin heavy chain bearing the central HLA-DQ7 binding motif. Clone 3135 recognized 13 peptides from cardiac myosin. The alignment of cross-reactive peptides in cardiac myosin showed very limited sharing of residues or side chains with similar chemical/structural features at aligned positions, indicative of a very degenerate TCR recognition pattern. The existence of degenerate intramolecular recognition, with multiple low-homology, cross-reactive epitopes in a single autoantigenic protein may have implications in increasing the magnitude of the autoimmune response in CCC and other autoimmune diseases. (c) 2005 Elsevier Ltd. All rights reserved.