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Review
Int Arch Allergy Immunol 2004;134:56–64
DOI: 10.1159/000077915
Rheumatic Fever: From Sore Throat to
Autoimmune Heart Lesions
Luiza Guilherme
a, b
Jorge Kalil
a–c
a
Heart Institute-InCor, University of Sa˜ o Paulo School of Medicine;
b
Institute for Investigation in Immunology,
Millenium Institute, and
c
Division of Clinical Immunology and Allergy, Department of Clinical Medicine,
University of Sa˜ o Paulo School of Medicine, Sa˜ o Paulo, Brazil
Published online: April 16, 2004
Correspondence to: Dr. Luiza Guilherme
Laborato´rio de Imunologia, Instituto do Coraça˜o-HC-FMUSP
Av. Dr. Eneas de Carvalho Aguiar, 44-9 andar
Sa˜o Paulo, SP 05403-000 (Brazil)
Tel. +55 11 3069 5901/3082 7730, Fax +55 11 3082 9350, E-Mail luizagui@usp.br
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2004 S. Karger AG, Basel
1018–2438/04/1341–0056$21.00/0
Accessible online at:
www.karger.com/iaa
Key Words
Autoimmunity
W Cytokines W Heart tissue proteins W
M protein W Rheumatic heart disease W T cell receptor
Abstract
Molecular mimicry between streptococci and heart com-
ponents has been proposed as the triggering factor lead-
ing to autoimmunity in rheumatic heart disease (RHD). In
this review, we present data from cellular autoimmune
responses, focusing on the interactions between HLA
class II molecules, streptococcal peptides and heart tis-
sue proteins and T-cell receptor (TCR) usage. HLA-
DR7DR53 associated with DQ molecules seem to be
related with the development of valvular lesions in se-
vere RHD patients. DR7DR53 molecules were also in-
volved in the recognition of an immunodominant M5
peptide in these patients. T cells infiltrating RHD hearts
displayed several oligoclonal expansions. Intralesional
T-cell clones presenting identical TCR-BVBJ AVAJ and
-CDR3 sequences were able to recognize several anti-
gens with little or low homology, showing an intramole-
cular degenerate pattern of antigen recognition. Periph-
eral blood mononuclear cells of rheumatic fever (RF)
patients produced proinflammatory cytokines, and in-
tralesional mononuclear cells from severe RHD patients
produced predominantly Th1-type cytokines. These re-
sults illustrate the complex mechanisms leading to heart
tissue damage in RF/RHD patients.
Copyright © 2004 S. Karger AG, Basel
Introduction
Rheumatic fever (RF) is an inflammatory disease me-
diated by humoral and cellular autoimmune responses
that occurs as a delayed sequelae of Streptococcus pyo-
genes infection in 3–4% of susceptible and untreated chil-
dren and adolescents (aged 5–18 years). Carditis affects
30–45% of RF patients and is the most serious manifesta-
tion of the disease, leading to valvular lesions mainly in
the mitral and aortic valves. It causes chronic rheumatic
heart disease (RHD) that still remains a major public
health problem in developing countries.
The pathogenic mechanisms involved in the develop-
ment of RF/RHD are not fully understood. It is be-
lieved that the molecular mimicry mechanism is respon-
sible for the cross-reactions between streptococcal anti-
gens and human tissue proteins, mainly heart tissue pro-
teins in susceptible individuals. It is now clear that the
Rheumatic Fever
Int Arch Allergy Imunol 2004;134:56–64
57
disease is mediated by both humoral and cellular im-
mune responses and that the cellular branch of the im-
mune response is more involved in the development of
RHD.
In this review, we will focus on the cellular branch of
autoimmune responses leading to heart lesions in RHD
patients. The three main components involved in the T-
cell responses: HLA class II molecules, antigenic peptides
and T-cell receptors (TCR; trimolecular complex) will be
discussed.
Trimolecular Complex
Early studies in animal models by Benacerraf [1]
showed that immunization with synthetic antigens were
able to induce the production of antibodies and that this
immune response was determined by certain MHC haplo-
types. Later experiments mapped the control of immune
responses to MHC class II genes [2]. Although several
HLA class II molecules have been associated with the
development of humoral or cellular-mediated diseases
and are considered as genetic markers of these diseases,
now we know that, in fact, the major role of HLA class II
molecules is to present antigens to Th (CD4+) cells. Anti-
gen-presenting cells (APC), e.g. macrophages, dendritic
cells and B lymphocytes, constitutively express HLA class
II molecules. When activated by specific cytokines such as
IFNÁ, these APCs express large amounts of HLA class II
molecules.
During throat infection by S. pyogenes, several strepto-
coccal peptides are generated by APC. These peptides,
mainly from the M protein, are associated with HLA class
II molecules and presented to Th cells triggering an
inflammatory or humoral response. In untreated individ-
uals with genetic predisposition to develop RF/RHD, T-
cell populations selected by some immunodominant
streptococcal peptides combined with HLA class II mole-
cules will be able to trigger an autoimmune reaction (dis-
cussed below – Molecular Mimicry).
In the case of acute rheumatic carditis, Aschoff’s bod-
ies, the pathognomonic sign of the disease, develop in the
myocardium and/or endocardium [3]. The Aschoff body
is constituted by an agglomeration of several cells, e.g.
monocytes/macrophages and B lymphocytes that are
probably acting as APCs. Furthermore, mononuclear cells
that also include APC (macrophages and B lymphocytes)
and T lymphocytes infiltrate the heart in patients with
both acute and chronic RHD.
The third component of the trimolecular complex is
the T lymphocyte. The majority of T cells (90%) present
an antigen receptor (TCR) composed of ·- and ß-chains.
The TCR ·- and ß-chain are produced by the assembly of
variable (V), joining (J) and constant (C) gene segments
and also diverse (D) gene segments for ß-chain. Combina-
tions of these genes generate around 10
18
TCRs. Both
chains have three regions designated as complementarity-
determining region (CDR1, CDR2, CDR3). CDR1 and
CDR2 of the TCR interact with MHC molecules. The
peptide side chains of the MHC-peptide complex on the
surface of APC interact most closely with the hypervari-
able region of the TCR (CDR3) encoded by the V-D-J
region on the TCR-ß-chain. The combinations between
HLA class II molecules and antigens will drive the T-cell
repertoire.
Genetic Susceptibility
Several genetic markers of susceptibility to RF/RHD
have been studied [4], and associations with different
HLA class II antigens have been observed in several popu-
lations, e.g. DR4/DR9 in American Caucasians and DR2
in American blacks [5, 6], DR4 in Arabians [7], DR3 in
Indians [8], DR1 and DR6 in Africans [9] and DR5 in
Turks [10]. Interestingly, DR7 was found to be associated
with the disease in different countries [11–15]. Associa-
tions of HLA-DR7 with some HLA-DQ antigens seem to
be related to the presence of multivalvular lesions in RHD
patients [14–15]. HLA-DR53 is another class II molecule
always associated with DR4, DR7 and DR9 molecules. In
our studies, DR53 was also associated with the disease
[11, 12]. The fact that several HLA class II antigens are
associated with the development of RF/RHD in different
countries is consistent with the possibility that different
strains of group A streptococci could be implicated in the
development of RF/RHD in different countries. The vari-
able association may also be due to the important role that
HLA class II antigens play in antigen presentation to the
TCR.
In order to analyze the role of HLA-DR7 molecules in
T-cell immune responses against the N-terminal region of
the M5 protein, we studied the T-cell reactivity in the
peripheral blood of RHD patients. Amongst the M5 pep-
tides tested, it was possible to map the immunodominant
regions recognized by severe and mild RHD patients.
Mild RHD patients recognized preferentially the region
of amino acid residues 1–25 of M5 protein by several
HLA class II molecules. However, severe RHD patients
58
Int Arch Allergy Imunol 2004;134:56–64
Guilherme/Kalil
Table 1.
HLA-DR7 and RF/RHD
Country Population HLA Clinical picture
of the disease
Functional
study
References
Brazil Mulatto DR7, DR53
allogenotope
a
TaqI
DRß 13.81 kb
RF/RHD M5(81–96) peptide
preferentially recognized by
DR7
+
severe RHD patients;
capacity of binding with the
HLA-DR53 molecule
11, 12, 16
Brazil Caucasian DR7 RF/RHD 13
Egypt Egyptian DR7 DQ A1 02 01 RHD-MVL 14
Latvia Latvian DR7 DQ B1 03 02
DR7 DQ B1 04 01
RF/RHD-MVL
RF/MVR Sydeham’s
chorea
15
a
Defined by restriction fragment length polymorphism, 13.81-kb fragment corresponding to the HLA-DR53 anti-
gen [12].
MVL = Multivalvular lesions; MVR = mitral valve regurgitation.
recognized the region of amino acid residues 81–96,
defined as an immunodominant M5 epitope. Interest-
ingly, 70% of severe RHD patients that recognized this
M5 peptide were HLA-DR7+ DR53+, suggesting that
M5(81–96) peptide was preferentially presented to the T
cells in the context of DR7 and DR53 molecules. The
analysis of the capacity to bind streptococcal M5 peptides
showed that the M5(81–96) peptide was also able to bind
to the DR53 molecule [16]. These results are presented in
table 1.
Molecular Mimicry
Antigenic mimicry between streptococcal antigens,
mainly M-protein epitopes and heart components, has
been proposed as the triggering factor leading to autoim-
munity in RF. M protein is the major antigen of S. pyo-
genes and extends from the cell wall. It is composed of
approximately 450 amino acid residues showing antigenic
variations but high homology on the amino-terminal (N-
terminal) region, except for the 11 first amino acid resi-
dues that define the different serotypes, nowadays ap-
proximately 100 strains. The carboxyterminal (C-termi-
nal) region contains multiple repeat regions and is con-
served [17].
Molecular mimicry was first demonstrated in studies
on humoral immune responses. Anti-streptococcal anti-
bodies cross-reacted with several human tissues, includ-
ing the heart, skin, brain, glomerular basement mem-
brane, and striated and smooth muscles [18, 19].
One intersection point between humoral and cellular
immune responses in RHD patients could be the fact that
cross-reactive antibodies in the heart tissue may bind to
the valvular endothelium leading to inflammation, cellu-
lar infiltration and valve scarring [20]. Once activated, the
valvular endothelium expressed increased amounts of the
adhesion molecule VCAM-1, that facilitates the binding/
adhesion of T cells and consequently extravasation into
the valves, leading to the cycle of scarring, neovasculariza-
tion and infiltration of lymphocytes [21].
The presence of CD4+ T cells at lesion sites in the heart
of RHD patients has been demonstrated, suggesting a
direct role of these cells in the pathogenesis of RHD [22,
23].
We showed the significance of molecular mimicry
between ß-hemolytic streptococci and the heart tissue,
analyzing the T-cell repertoire leading to local tissue dam-
age in RHD. We demonstrated the capacity of infiltrating
T cell clones from heart lesions of severe RHD patients in
recognizing M protein peptides and heart tissue-derived
proteins. Our results pointed out three M5 immunodomi-
nant regions (residues 1–25, 81–103 and 163–177) that
cross-reacted to several heart protein fractions, mainly
those derived from valvular tissue with a molecular mass
of 95–150, 43–63 and 30–43 kD [24]. Peripheral T lym-
Rheumatic Fever
Int Arch Allergy Imunol 2004;134:56–64
59
Fig. 1.
Shared sequences of human and murine M5 epitopes recognized by T cells. Several T-cell immunodominant
M5 protein peptides were described and here we presented only peptides with shared sequences. The sequences of M5
peptides [M5(1–25), M5(81–96), M5(83–103) and M5(163–177)] from references 16 and 24 were based on the
sequence of the M5 protein published by Manjula et al. [29]. Sequences used on murine studies from reference 27
(peptides NT4, NT5, NT6, B1B2, B2, B2B3A and B3A) were from Miller et al. [30] and reference 28 [M5(1–35)
peptide] refers to a mutant M5 protein published by the authors. Human and murine amino acid residues of overlap-
ping peptides are underlined; murine amino acid residues of overlapping peptides are in bold type.
phocytes also recognized these immunodominant M5
peptides and valve proteins. The M5(81–96) mentioned
above is included in the M5(81–103) region peptide and
was preferentially recognized by HLA-DR7+DR53+ in
severe RHD patients (table 1) [16]. By using a proteomic
approach, we were able to characterize some mitral-valve
proteins identified by molecular weight and isoelectric
point (pI). Several valve-derived proteins were recognized
by peripheral blood and intralesional T-cell clones from
severe RHD patients. Amongst them, we identified vi-
mentin (molecular weight 53 kD/pI 5.12, recognized
mainly by peripheral T cells) and other cytoskeleton pro-
teins (recognized by both peripheral and intralesional T
cells) [manuscript in preparation]. In line with these
results, previous work showed the recognition of a 50- to
54-kD myocardial-derived protein by peripheral T lym-
phocytes from RHD patients [25].
We have also analyzed the intralesional T-cell re-
sponses against synthetic peptides from human cardiac
myosin ß-chain, and we found that 29% of these intrale-
sional T-cell clones derived from both myocardium and
valves were reactive. Taken together, our results indicate
that several autoantigens were recognized, and vimentin
could be the initial target of RF lesions resulting from
polyarthritis reactions, while myosin could also be an
immunodominant target during carditis episodes. The
phenomena of epitope spreading described by Sercaz et
al. [26] that lead to a broad diversity of recognition and
triggers an amplification and diversification of immune
responses could explain these results.
Myosin/M5 protein cross-reactive T-cell epitopes were
also investigated in mice immunized with intact cardiac
myosin [27]. Lymph node T cells were tested against over-
lapping M5 peptides named NT5/6/7 and B1B2/B2 and
B2B3A/B3A aligned with the M5 regions identified by us,
the M5(81–96) and M5(163–177), respectively. Robinson
et al. [28] obtained lymph node T-cell clones from mice
immunized with recombinant M5 protein that were able
to recognize M5 epitopes. Amongst the M5 epitopes rec-
ognized by the mouse T-cell clones, only the M5(1–35)
60
Int Arch Allergy Imunol 2004;134:56–64
Guilherme/Kalil
Table 2.
TCR analysis of cross-reactive intralesional T cell clones
T cell clone
identification
TCR BV BJ CDR3
(N-D-N) sequences
Antigens recognized mitral-valve-derived
protein, LMM or M5 peptides
Lu 3.1.3 SGRQGRYEQY-10aa 35 kD/pI 8.84
Lu 3.1.8 BV13 BJ2S7
AV2 AV3
SGRQGRYEQY-10aa 35 kD/pI 8.84, LMM 28 (1647–1664)
LMM 28B (1660–1677), LMM 32 (1699–1716)
Lu 3.1.29 SGRQGRYEQY-10aa 56–53 kD/pI 6.76
Lu 3. 2. 12.9 BV13 BJ2S7
AV2 AV7
SGRQGRYEQY-10aa 56–53 kD/pI 6.76
Lu 3.1.85 BV3 BJ2S1
AV5
SFTGRLDNEQF-11aa 79 kD/pI 5.12
M5 (1–20), M5 (11–25), M5 (81–96)
M5(111–130), M5(121–140)
M5(163–177), M5( 183–201)
LMM = Light meromyosin peptides; LMM28 = SLQSLLKDTQIQLDDAVR; LMM28B = DDAVRANDDLKE-
NIAIVE; LMM32 = RSRKL
AEQELIETSERVQ; M5 peptides: 1–20 = VTRGTISDPQRAKEALDKY; 11–25 =
QRAKEALDKYELENH; 81–96 = DKLKQQRDTLSTQKET; 83–103 = QQRDTLSTQKETLEREVQN; 111–
130 = TRQELANKQQESKENEKALN; 121–140 = ESKENEKALNELLEKTVKDK; 163–177 = ETIGTLKKI-
LDETVK; 183–201 = LDETVKDKLAKEQKSJQNI; NT = not tested. Shared sequences are underlined (adapted
from Faé et al. [43]).
region aligns with the M5(1–25) region recognized by the
human infiltrating T-cell clones. Figure 1 summarizes
both human and murine reactivity against M protein, the
N-terminal portion [29, 30].
T-Cell Repertoire
In the 90s, some researchers described a superantigenic
effect of streptococcal M5 protein preparations (pepsin
cleaved fragment – pepM5) for human T cells expressing
TCR-BV2, BV4, and BV8 [31–35]. Superantigens are
proteins that polyclonally activate T cells by an MHC
class II-dependent, but haplotype-unrestricted mecha-
nism. Proliferative responses to superantigens are limited
to T cells expressing a particular TCR-BV gene but inde-
pendent of antigen specificity. M protein has an impor-
tant role in the host anti-streptococcal immune response,
and for this reason it has been ascribed superantigenic
properties. However, the superantigenic effect was later
dismissed by some studies showing that the superantige-
nicity of pepM1 and pepM5 were due to contamination
with pyrogenic exotoxins that had themselves a potent
superantigen effect on BV2-bearing human T cells [36–
39].
In a recent work, we compared the TCR-BV usage in
peripheral blood and heart-infiltrating T cell lines (HIL)
from severe RHD patients, looking for oligoclonal ß-
chain expansions in line with antigen-driven immune
responses. T-cell receptor ß-chain family (TCR-BV) usage
and the degree of clonality were assessed by the analysis of
the length of the ß-chain CDR3. Our results showed
expansion of several BV families with oligoclonal profiles,
mainly in heart-infiltrating T-cell lines, and favor no
superantigenicity of M proteins in RHD patients. Few
oligoclonal BV expansions were shared by mitral valve-
and left atrium-derived T-cell lines in the same individu-
al. However, in this study, we described a case of 1 patient
that presented a BV5 expansion with the same BJ2S3 seg-
ment in both valve and myocardium tissues. However,
these T cells presented different amino acid CDR3 se-
quences, suggesting that different antigenic peptides
could be predominantly recognized by T cells that infil-
trate mitral valve and myocardium tissues [40]. The high
frequency and the persistence of T-cell oligoclonal expan-
sions in the damaged heart valves seem to be associated
with the progression of the disease [41], probably due to
the T-cell recognition of several heart tissue proteins
exposed by local lesions. In agreement with these data, it
has been described that it is possible to detect T-cell
Rheumatic Fever
Int Arch Allergy Imunol 2004;134:56–64
61
expansions in damaged heart valves even 20 years after
the acute RF episode [42].
Recently, we described intralesional T-cell clones with
a degenerate pattern of reactivity [43]. Five heart tissue-
derived T-cell clones (three from the mitral valve and one
from the myocardium) obtained from a patient with
severe RHD presented the same TCR-BV13 BJ2S7 with
identical CDR3 sequences. They expressed two ·-chains
at the RNA level and recognized M5 epitopes or human
cardiac ß-chain synthetic myosin peptides or mitral valve-
derived proteins. Interestingly, a mitral valve-derived
protein (53–56 kD/pI7.76) was recognized by two intrale-
sional T-cell clones, one from mitral valve tissue and the
other from myocardial tissue. These T-cell clones ex-
pressed only one different ·-chain. We also found other
T-cell clones that recognized several different antigens
bearing the same TCR-BV3 BJ2S1. These results are sum-
marized in table 2. Our data are in agreement with those
done by Mason [44, 45], in which the flexibility of T-cell
antigen recognition was evaluated by the analysis of the
immune response pattern against pathogens in experi-
mental models. Using a mathematical approach, he esti-
mated that T cells can react with a very large number of
peptides. The high frequency of cross-reactivity was pos-
tulated as essential for keeping the T-cell repertoire active
against the large number of foreign antigens that an indi-
vidual can encounter and respond to in his/her life [44,
45]. Thus, it appears that the major role of degeneracy of
T cells is to maintain the physiological immunity. How-
ever, our report is the first to identify intramolecularly
degenerate pattern of recognition.
It is known that among autoreactive T cells it is possi-
ble to differentiate T-cell subsets triggering pathological
compared to what could be called ‘physiological autoim-
munity’ [46–48]. However, the mechanism used by de-
generate T cells to recognize selected peptides without
pathological potential and, on the other hand, the mecha-
nism of degenerate T-cell reactivity leading to pathologi-
cal autoimmunity in individuals with genetic susceptibili-
ty remain unknown.
Cytokines
The cytokine pattern produced by Th cells in response
to defined antigens is crucial to drive the humoral or cellu-
lar immune responses. In addition, the concept of patho-
logical or physiological autoimmune reactions depends on
the cytokine produced in response to the autoantigens
that are being recognized by T cells. RF manifests differ-
ent clinical pictures such as arthritis, chorea, carditis, ery-
thema marginatum and/or subcutaneous nodules [49]. All
these manifestations involve particular autoantigens as
targets of pathological autoimmunity. Arthritis, chorea
and mild RHD are in part due to a pathological autoim-
mune reaction probably mediated by Th2-type cytokines,
leading to an exacerbated humoral response, as reported
in several studies [19]. On the other hand, severe RHD is
mediated mainly by T lymphocytes [16, 22–24]. The pro-
duction of TNF·, IL-1 and IL-2 in the peripheral blood of
acute RF and active RHD patients have been described
[50, 51]. Other authors have confirmed these findings and
have also noted increased plasma levels of TNF· in RF/
RHD patients [52–54].
In heart lesions during the acute phase of RHD, the
production of IL-1, TNF· and IL-2 was correlated with
progression of the Aschoff nodule [55] localized mainly in
the endocardium, subendocardium or perivascular re-
gions of the myocardial interstitium.
Recently, we have shown that intralesional mononu-
clear cells from heart lesions predominantly secret IFNÁ
and TNF· in both acute RF and chronic RHD patients,
with a scarce production of IL-4 [submitted]. When stim-
ulated with streptococcal M5 antigens, mitral valve-
derived intralesional T-cell lines produced IFNÁ but not
IL-4, while myocardial intralesional T-cell lines produced
IFNÁ, IL-10 and IL-4. The predominant Th1-type cyto-
kine produced mainly by CD4+ T cells infiltrating valve
tissue could mediate the severe RHD valve lesions, and
the fact that myocardial-infiltrating cells were able to pro-
duce regulatory cytokines could have a role in the mild-
ness of myocardial damage in RHD.
Conclusions
The development of RF/RHD involves a complex net-
work of autoimmune reactions comprising the following
major points. (1) Molecular mimicry between streptococ-
cal antigens and human tissues, mainly heart tissue, leads
to rheumatic heart lesions in RHD patients. (2) CD4+
T lymphocytes are the major effectors of heart lesions
and display a degenerate pattern of antigen recognition.
(3) Several streptococcal immunodominant peptides gen-
erate cross-recognition of vimentin, myosin and several
mitral valve-derived proteins, possibly resulting from an
epitope-spreading mechanism. (4) Several HLA class II
molecules are associated with the disease, and HLA-DR7/
DR53 combined with some HLA-DQ molecules seem to
be associated with the development of multiple valvular
62
Int Arch Allergy Imunol 2004;134:56–64
Guilherme/Kalil
Fig. 2.
Model of the development of RF/RHD. After group A strep-
tococcal throat infection, untreated susceptible individuals (5–18
years old) developed RF/RHD. Humoral and cellular immune
responses against S. pyogenes trigger an autoimmune attack to
human tissues by molecular mimicry. The autoimmune reaction is
initiated in the periphery where T cells recognize immunodominant
M5 peptides presented by APC (macrophages/monocytes) in the con-
text of HLA class II molecules. Proinflammatory cytokines were pro-
duced in the periphery. Activated T CD4+ cell clones expanded and
migrate to the heart (myocardium and valvular tissues as shown in
the picture), and several heart tissue proteins are recognized by
molecular mimicry. Epitope spreading amplifies the autoimmune
response. Several autoreactive T cell clones are generated and display
degenerate TCR capable of recognizing several different antigens.
Intralesional mononuclear cells also produced predominant Th1-
type cytokines (IFNÁ and TNF·). Mitral valve picture from 1 RHD
patient shows verruca lesions as indicated by the arrow. On the lower
left, a fragment of the mitral valve lesions (HE, !20) shows infiltrat-
ing mononuclear cells in the endocardium. In vitro growing of T cells
shows lymphoblasts as ‘flowers’. !100.
lesions in RHD patients. (5) T-cell recognition displays an
intramolecular degenerate reactivity against streptococcal
and human protein epitopes with low homology. (6) Th1-
type cytokines seem to be predominant in heart lesions,
especially valvular lesions.
All these points extend the knowledge on the develop-
ment of RHD (summarized in fig. 2) and may open new
possibilities of immunotherapy.
Rheumatic Fever
Int Arch Allergy Imunol 2004;134:56–64
63
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