How an autoimmune reaction triggered by molecular mimicry between streptococcal M protein and cardiac tissue proteins leads to heart lesions in rheumatic heart disease.
Molecular mimicry between microbial antigens and host tissue is suggested as a mechanism for post-infectious autoimmune disease. In the present work we describe the autoimmune reactions of two severe rheumatic heart disease (RHD) patients, through an analysis of heart-infiltrating T-cell repertoire, antigen recognition, and cytokine production induced by specific antigens. T-cell clones derived from oligoclonally expanded T cells in the heart cross-recognized M5 peptides, heart tissue-derived proteins, and myosin peptides. We show, using binding affinity assays, that an immunodominant streptococcal peptide (M5(81-96)) is capable of binding to the HLA-DR53 molecule. The same peptide was recognized by an infiltrating T-cell clone from a patient carrying HLA-DR15, DR7, and DR53 molecules. This suggests that this peptide is probably presented to T cells in the context of the HLA-DR53 molecule. Cross-reactive heart-infiltrating T cells activated by the M5 protein and its peptides and by heart tissue-derived proteins produced predominantly inflammatory cytokines. Interleukin (IL)-4 was produced in small amounts by mitral valve intralesional T-cell lines and clones. Altogether, these results suggest that mimicry between streptococcal antigens and heart-tissue proteins, combined with high inflammatory cytokine and low IL-4 production, leads to the development of autoimmune reactions and cardiac tissue damage in RHD patients.
Faé
K C
KC
Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil.
Oshiro
S E
SE
Toubert
A
A
Charron
D
D
Kalil
J
J
Guilherme
L
L
D000941:Antigens / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000276:immunology; D006801:Humans; D008297:Male; D018716:Molecular Mimicry / Q000276:immunology*; D012214:Rheumatic Heart Disease / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology
D000941:Antigens; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D016207:Cytokines; C014689:streptococcal M protein