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Infection and Immunity, September 2001, p. 5345-5351, Vol. 69, No. 9
Heart Institute,
InCor,1 Children's
Institute,2 and Clinical Immunology and Allergy,
Department of Clinical Medicine,5 School of
Medicine, University of São Paulo, São Paulo, Brazil;
Instituto de Inmunologia, HSJD, Universidad Nacional de
Colômbia, Bogotá, Colombia3;
and Epimmune Inc., San Diego, California4
Received 30 January 2001/Returned for modification 17 April
2001/Accepted 6 June 2001
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.
Rheumatic fever (RF) is a sequel of
group A streptococcal throat infection and remains an important health
problem in developing countries. About 30% of RF patients develop
rheumatic heart disease (RHD), with high morbidity and cost to the
public health system.
Molecular mimicry between streptococcal antigens, mainly the M protein,
and heart tissue proteins is proposed as an important factor leading to
the heart lesions found in RHD patients. Several studies have been
performed with human peripheral blood mononuclear cells (PBMC)
showing reactivity against the streptococcal cell wall and tissue
antigens (20, 25). CD4+ T cells are
the predominant population at the site of heart lesions (23,
16).
Yoshinaga et al. (30) reported that T-cell lines derived
from heart valve specimens and PBMC from RF patients react with cell
wall and membrane streptococcal antigens. These lymphocytes did not
cross-react with M protein or mammalian cytoskeletal proteins. Autoreactivity to heart antigens caused by streptococcal infections was
also suggested by results of immunization in which peripheral T
lymphocytes from RHD patients stimulated in vitro with streptococci were able to recognize a 50- to 54-kDa myocardial protein fraction (7). Our group previously reported intralesional T-cell
clones, from surgical fragments of patients with severe RHD, capable of recognizing immunodominant M5 peptides and heart tissue proteins in a
cross-reactive way (13). Our results allowed us to
establish the significance of T-cell molecular mimicry between
beta-hemolytic streptococci and heart tissue and its implication in the
pathogenesis of RHD. Even though the identification of cross-reactive T
cells infiltrating the hearts of patients with severe RHD is taken as significant evidence for autoimmunity in pathogenesis
(26), further comparison of recognition repertoires in RHD
patients from different clinical groups with healthy controls may allow the identification of preferential antigenic targets for T cells from
RHD patients.
In the present study, we analyzed the reactivity of intralesional T
lymphocytes and PBMC from RHD patients and healthy individuals against
synthetic M5 peptides and human heart tissue protein fractions. Given
the previously reported association of the HLA-DR7, DR53 haplotype with
RF-RHD (12, 29), we also assessed the ability of
RHD-associated HLA molecules DR7 and DR53 to bind and present immunodominant M5 peptides.
Patients.
We studied 74 patients with RHD, from the Heart
Institute, Children's Institute, University of São Paulo,
selected according to Jones's modified criteria (5). The
average length of patient follow-up was 5 years. RHD patients were
divided into two groups: 41 patients with severe RHD and 33 patients
with mild RHD. Patients with severe RHD presented severe mitral and
aortic valve regurgitation; some presented congestive cardiac failure.
Patients with mild RHD presented mild mitral valve regurgitation. Two
patients with severe RHD presented chorea, while 19 patients with mild
RHD presented concomitant carditis and chorea. The mean age was 13.0 (standard deviation [SD], 2.7) years and 13.5 (SD, 3.5) years for
patients with severe and mild RHD, respectively. There were no
significant differences in gender distribution among these groups.
Eight patients with severe RHD and one patient with mild RHD had
recovered from disease reactivation 3 to 6 months before the study. The
blood samples were taken in absence of immunosuppressive drugs.
Thirty-five healthy adult individuals made up our control group for
peripheral blood reactivity studies, with a mean age of 32.5 (SD, 8.8)
years and without previous history of RF or recently documented
streptococcal throat infection. Blood samples and surgical fragment
collection procedures were cleared by the Committee of Ethics of the
Heart Institute, HC-FMUSP.
T-cell lines and T-cell clones.
Intralesional T-cell lines
were derived from in vitro culture of surgical fragments of
mitral valve, aortic valve, papillar muscle, or left atrium of eight
patients with severe RHD who submitted to surgery for valve correction.
Tissue was finely minced with injection needles, placed in flat-bottom
96-well plates (Becton Dickinson Co.), with Dulbecco's modified Eagle
medium (Sigma Chemical Co.) supplemented with 2 mM
L-glutamine (Sigma), 10% pooled normal human serum, 10 mM
HEPES (Sigma), antibiotics (gentamicin, 40 mg/ml; Peflacyn, 20 mg/ml) and human recombinant interleukin 2 (IL-2) (40 U/ml; Biosource
Inc.), on an HLA-DR-matched feeder layer of PBMC at
105 cells/well, irradiated at 5,000 rads
(28). Peripheral T-cell lines were derived from one
patient with severe RHD (patient 8) and two patients with mild RHD
(patients 9 and 10) by PBMC stimulation with a pool of the N-terminal
M5 peptides (total final concentration, 10 µg/ml) in the presence of
IL-2 followed by phytohemagglutinin (PHA)-P stimulation. T-cell
clones were obtained by limiting dilution of intralesional and
peripheral T-cell lines using 0.3 cell/well in the presence of PHA-P (5 µg/ml) and 105 irradiated PBMC/well in an
IL-2-enriched growth medium as described (13). Plates that
had more than 15% positive wells were discarded. T-cell clones were
restimulated every 21 days and tested after up to three restimulations.
Peptide synthesis and preparation of human heart tissue protein
fractions and of human cardiac myosin.
Peptides based on the
published M5 protein sequence (19) were synthesized by the
"tea bag" method by tert-butoxycarbonyl chemistry and
checked by mass spectrometry and high-performance liquid
chromatography. Sequences for the following M5 peptides were as
indicated: M5 peptide encompassing residues 1 to 20 [M5(1-20) peptide], TVTRGTISDPQRAKEALDKY; M5(11-25),
QRAKEALDKYELENH; M5(62-82), LERKTAELTSEKKEHEAENDK; M5(81-96),
DKLKQQRDTLSTQKET; M5(83-103), KQQRDTLSTQKETLEREVQN; M5(91-103),
STQKETLEREVQN; M5(125-139), TRQELANKQQESKEN; M5(141-154),
KALNELLEKTVKDK; M5(163-177),
ETIGTLKKILDETVK. Tissue fractions from human
myocardium, aortic valve, purified human ventricular cardiac myosin
were obtained from lysates of postmortem normal tissue samples,
separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
and blotted onto nitrocellulose membranes from which nitrocellulose
suspensions containing heart protein fractions were obtained as
described (13). For molecular weight values, see Fig.
1.
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.9.5345-5351.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
T-Cell Reactivity against Streptococcal Antigens in the Periphery
Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic
Heart Disease Patients
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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FIG. 1.
Reactivity against N-terminal M5 peptides and heart
tissue proteins. (A) Intralesional T-cell clones from patients with
severe RHD; (B) peripheral T-cell clones from RHD patients.
PBMC-derived T-cell clones were not tested with myocardium protein
fractions. Abbreviations: LA, left atrium; Mi V, mitral valve; Ao V,
aortic valve; PM, papillar muscle. Black squares, M5 peptide-heart
tissue protein cross-reactive T-cell clones; gray squares,
non-cross-reactive T-cell clones recognizing either M5 peptide or heart
tissue proteins.
Proliferation assays
Proliferation assays
were performed in Falcon flat-bottom 96-well plates using
105 mononuclear cells/well isolated from peripheral blood
by centrifugation on a 1,077 density gradient for 120 h at
37°C in a humidified 5% CO2 incubator. Either of
streptococcal M5 peptides (5 µg/ml), heart tissue fractions (20 µl/well), or purified human myosin was added. Negative controls were
Dulbecco's modified Eagle medium for peptide experiments and 20 µl
of a protein-free nitrocellulose suspension for heart tissue fraction
and myosin experiments. PHA-P (5 µg/ml) was used for positive control
of proliferative responses. Triplicate wells were pulse-labeled with
0.5 µCi of tritiated thymidine (Amersham Pharmacia Biotech) per well
for the final 18 h of culture; cells were harvested and analyzed
in an automated gas phase beta counter (Matrix 96: Packard Co.). For
T-cell clones 2 × 104 T cells/well were incubated
with 105 HLA-DR-matched irradiated PBMC (5,000 rads) for
96 h. The proliferative response of PBMC and T-cell clones was
considered positive when the stimulation index (SI) (SI = mean
experimental cpm/negative control cpm) was 
2.5.
HLA class II antigens. Patients and controls were typed for HLA-DR by PCR amplification with sequence-specific primers (HLA-DR1 to DR18, HLA-DR51, DR52 and DR53) and for HLA-DQ by PCR amplification with sequence-specific oligonucleotides (12 and 22 different oligonucleotides for DQA1 and DQB1, respectively). DNA was isolated from proteinase K-treated peripheral blood leukocytes by salting-out extraction (21).
HLA binding assay. The binding assay was performed for HLA-DR7 and DR53 molecules purified and then incubated with 125I-radiolabeled peptides as described (18). The data were then plotted, and the dose yielding a 50% inhibitory concentration (IC50) was measured. Each peptide was tested in two to four completely independent experiments.
Statistical analysis.
Differences in the frequency of
positive proliferative responses of PBMC from patients in different
clinical groups and healthy individuals were evaluated using Fisher's
exact test. A P value of 
0.05 was considered significant.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Presentation and T-cell response to streptococcal M5 peptides,
heart tissue fractions and human myosin.
PBMC reactivity against
N-terminal M5 peptides was found in 54 and 57% of patients with severe
and mild RHD, respectively, and 26% of healthy individuals. Six
peptides were more frequently recognized by PBMC from RHD
patients than by those from controls (Table 1). PBMC
from severe RHD patients preferentially recognized peptides in the
regions of residues 1 to 20 and 81 to 103. Peptide M5(81-96) was
recognized by PBMC from 46% of patients with severe RHD versus those
from 8.6% of controls (P = 0.0005). This peptide was
also twice as frequently recognized by PBMC from severe than those from
patients with mild RHD (46 versus 27%, P = 0.08). The overlapping peptides M5(91-103) and M5(83-103) were recognized by
24.3% of patients with severe RHD and 3.0% of controls
(P = 0.01) (Table 1) and by 27% of patients with
severe RHD and 11.4% of controls (P not significant),
respectively. Peptide M5(1-20) was recognized by PBMC from 35.1% of
patients with severe RHD and those from 8.6% of controls,
(P = 0.01) (Table 1). Peptides M5(11-25) and
M5(125-139) were predominantly recognized by PBMC from patients with
mild RHD compared with controls (P = 0.008 and
P = 0.01, respectively) (Table 1). Although 54.5% of
patients with mild RHD and 5.4% of patients with severe RHD presented
Sydenham chorea (P < 0.001) we could not identify any
specific antipeptide reactivity among these patients. Rates of
recognition of the M5(163-177) peptide (Table 1) were comparable in
patients with mild and severe disease.
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35,000 nM). However, binding with
intermediate affinity (IC50 in the 100 to 1,000 nM range) was detected for M5(81-96) peptide with the HLA-DR53
molecule (IC50 = 670 nM) (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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We have found that peripheral T cells from more than 50% of RHD patients and 26% of healthy individuals are able to recognize N-terminal streptococcal M5 epitopes. This indicates that PBMC from RF-RHD patients display a vigorous recall response to previous streptococcal infection. The ability of normal adult individuals to respond to streptococcal peptides is in all probability related to previous streptococcal throat infection.
We have identified five immunodominant M5 peptides comprised in the N-terminal M5 protein regions that are not only preferentially recognized by PBMC from patients with severe or mild RHD but also by intralesional and peripheral T-cell clones. The M5(81-103) region was recognized by several intralesional T-cell clones obtained from five of eight patients with severe RHD, along with peripheral T-cell clones obtained from one patient with severe RHD (Fig. 1). It has been shown that immunized mice display strong T-cell proliferative responses against the M5(81-103) region (4), further supporting the argument for immunodominance of this region. The trend towards increased recognition of M5(81-103) by peripheral T cells from severe rather than mild cases of RHD (Table 2) is in line with its frequent recognition by heart-infiltrating T-cell clones (Fig. 1A). Together, our data support a role for the M5(81-103) region containing an immunodominant epitope of the N-terminal portion of streptococcal M protein and suggest a role for differential T-cell recognition in the development of severe carditis.
The fact that heart tissue fractions were recognized by PBMC from 61% of patients with severe RHD and only 15 to 20% of patients with mild RHD or controls (Table 2) suggests either that (i) recognition is nonspecific and secondary to heart tissue damage or (ii) recognition of specific heart antigens is pathogenetically relevant. The finding of preferential recognition of selected myocardial along with aortic valve protein fractions (Table 2), by PBMC and several intralesional T-cell clones from patients with severe RHD (Fig. 1), supports the second hypothesis. These data are in line with our previous results showing the presence of streptococcal and heart tissue protein cross-reactive T-cell clones in the heart lesions (13). It has been suggested that antiheart responses found in peripheral blood may be secondary to molecular mimicry with streptococcal M protein (22). We have previously shown that oligoclonal T-cell expansions are more frequently observed in the heart lesions than in the PBMC of patients with severe RHD. The frequency of these oligoclonal infiltrating T cells was variable in the analyzed patients. Our findings could suggest a differential epitope recognition at the two lesional heart sites after a common initial bacterial challenge (14).
The lack of significant recognition of cardiac myosin by PBMC from RHD patients is in line with reports on idiopathic dilated cardiomyopathy (3) and may indicate that cardiac myosin is not a relevant heart antigen in the context of RHD. This contrasts with several reports showing the presence of cardiac myosin and streptococcal antigen cross-reactive antibodies in sera of patients (10, 17) and from animal models as well as cross-reactivity by murine and human monoclonal antibodies (6, 9, 15).
HLA class II DR7 or DR53 antigens have been linked with genetic
susceptibility to RF (12, 29, 2, 1, 24). Recently, it was
shown that DRB1*0701 and DQA1*0201 are associated with mitral valve
disease in Egypt (11). In our group of patients with
severe RHD only a few patients presented the DR7, DQA1*0201 haplotype
(data not shown). The immunodominant M5(81-96) peptide was
preferentially recognized by peripheral T cells from RHD a patients
coexpressing DR7,DR53 molecules (Fig. 2), in line with the previously
reported association. The fact that intralesional T-cell clones from
some DR7+ DR53+ patients
failed to recognize peptide M5(81-96) may be due to the limited number
of T-cell clones analyzed per individual. On the other hand,
recognition of the peptide M5(81-96) by T-cell clones from
DR7
DR53 patients
indicates that other HLA molecules are also able to present this
peptide. Interestingly, none of the nine N-terminal peptides studied
bound to HLA-DR7, and only the M5(81-96) peptide was able to bind to
HLA-DR53 molecules within the range of affinity associated with T-cell
recognition in the context of HLA-DR molecules (27). This
may imply that HLA-DR53 preferentially presents immunodominant peptide
M5(81-96) to T cells from RHD patients. However, given the recent
demonstration that certain self-peptides with undetectable MHC binding
values can induce experimental T-cell autoimmunity (8),
one cannot exclude the possibility that HLA-DR7 and other HLA-DR
molecules can in fact present M5 epitopes. On the other hand, no PBMC
from healthy individuals carrying HLA-DR7 or HLA-DR53 molecules
recognized this peptide (Fig. 2). Healthy individuals may or may not
have had previous contact with streptococci, but if they had they
certainly did not develop tissue-damaging T cells to trigger lesions in
their hearts. Thus, it is possible that DR7,
DR53 restricted M5(81-96)-reactive T cells are indeed
related to disease progression. The lower number of M5(81-96)
peptide-responder individuals carrying HLA-DR7 or -DR53 among patients
with mild RHD in comparison to those in the group with severe RHD may
indicate that recognition of the M5(81-96) peptide in the context of
the mentioned HLA-DR alleles is related to heart tissue damage. It is
likely, however, that individuals lacking response to M5(81-96) may
target other pathogenic epitopes in the streptococcal M protein
(13).
Together with the finding of streptococcal M5 peptide-heart protein cross-reactive T-cell clones in the heart lesions of RHD patients (13), the present data lend support to the idea that T cells sensitized in the periphery by M5 protein during streptococcal infection, in particular the M5(81-96) peptide, in HLA-DR7+ DR53+ RHD patients, migrate to the heart and initiate heart tissue damage after activation due to cross-reactive recognition of the relevant heart antigen. The identification of several M5(81-96) peptide-reactive T-cell clones recognizing valve fractions of 90 to 150 kDa and 30 to 65 kDa (Fig. 1A) further indicates the role of cross-reactivity between streptococcal and valve proteins in the pathogenesis of RHD. The nature of these target heart proteins is presently under investigation using bidimensional T-cell Western blotting and a proteomics approach. The identification of antigenic and/or pathogenic epitopes in streptococcal M protein may lead to the development of safe synthetic peptide-based vaccines and novel immunotherapeutic strategies aiming to control heart damage.
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ACKNOWLEDGMENTS |
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This work was supported by grants 620087/94.3 from PADCT-CNPq and 75197-555101 from HHMI.
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FOOTNOTES |
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* Corresponding author. Mailing address: Laboratório Imunologia, Instituto do Coração-HC-FMUSP, Av. Dr. Eneas Carvalho Aguiar, 500 3° andar, 05403-000 São Paulo SP, Brazil. Phone and fax: 55-11-30829350. E-mail: luizagui{at}usp.br.
Editor: E. I. Tuomanen
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Infection and Immunity, September 2001, p. 5345-5351, Vol. 69, No. 9
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.9.5345-5351.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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