T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients.
T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81-96) peptide] was most frequently recognized by PBMC from HLA-DR7+ DR53+ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81-103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.
Guilherme
L
L
Heart Institute, InCor, School of Medicine, University of São Paulo, São Paulo, Brazil. luizagui@usp.br
Oshiro
S E
SE
Faé
K C
KC
Cunha-Neto
E
E
Renesto
G
G
Goldberg
A C
AC
Tanaka
A C
AC
Pomerantzeff
P M
PM
Kiss
M H
MH
Silva
C
C
Guzman
F
F
Patarroyo
M E
ME
Southwood
S
S
Sette
A
A
Kalil
J
J
D017951:Antigen Presentation; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D015809:HLA-DR7 Antigen / Q000378:metabolism; D059845:HLA-DRB4 Chains; D006801:Humans; D016056:Immunodominant Epitopes; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D009206:Myocardium / Q000276:immunology*; D009218:Myosins / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D012214:Rheumatic Heart Disease / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D006684:HLA-DR Antigens; C050610:HLA-DR53; D015809:HLA-DR7 Antigen; D059845:HLA-DRB4 Chains; D016056:Immunodominant Epitopes; D010455:Peptides; C014689:streptococcal M protein; D009218:Myosins