REVIEW ARTICLE

Understanding rheumatic fever

Pedro Ming Azevedo • Rosa Rodrigues Pereira •

Luiza Guilherme

Received: 21 April 2011 / Accepted: 10 September 2011 / Published online: 28 September 2011

� Springer-Verlag 2011

Abstract Through a comprehensive review of the recent

findings on rheumatic fever, we intend to propose a new

physiopathologic model for this disease. A Medline search

was performed for all articles containing the terms rheu-

matic fever or rheumatic heart disease in title or abstract

from 1970 to 2011. Best evidence qualitative technique

was used to select the most relevant. The scientific interest

on rheumatic fever has notably diminished throughout the

twentieth century as evidenced by the comparison of the

proportion of articles in which RF was a subject in 1950

(0.26%) and today (0.03%) [Pubmed]. However, RF

remains a major medical and social problem in the devel-

oping world and in the so-called hotspots, where it still

causes around 500.000 deaths each year, not too different

from the pre-antibiotic era. The role of genetic factors in

RF susceptibility is discussed. Familiar aggregation, simi-

larity of disease patterns between siblings, identical twin,

and HLA correlation studies are evidence for a genetic

influence on RF susceptibility. The suspect-involved genes

fall mainly into those capable of immunologic mediation.

Molecular mimicry explains the triggering of RF, but an

intense and sustained inflammation is needed to cause

sequels. Also, RF patients vary greatly in terms of symp-

toms. It is likely that a genetic background directing

immune response towards a predominantly Th1 or Th2

pattern contributes to these features. The recent findings on

rheumatic fever provide important insight on its physio-

pathology that helps understanding this prototype post-

infectious autoimmune disease giving insights on other

autoimmune conditions.

Keywords Rheumatic fever � Genetics � Immunology �Physiopathology

Introduction

Incidence of rheumatic fever has dramatically declined in

the developed world, where it remains around 0.2–1.9 per

100.000 habitants [1], mainly due to sporadic outbreaks.

The scientific interest on this disease has proportionally

diminished as evidenced by the comparison of the propor-

tion of articles in which RF was a subject in 1950 (0.26%)

and today (0.03%) [Pubmed]. However, RF remains a major

medical and social problem in the developing world and in

the so-called hotspots, where the incidence still is from 20

to 51 per 100.000 habitants, causing around 500.000 deaths

each year [2], not too different from the pre-antibiotic era.

Also RF is the prototype of post-infectious autoimmune

disease. It is likely that understanding RF will help to

decipher other autoimmune diseases.

Rheumatic fever (RF) is an inflammatory disease that

affects susceptible children and teenagers (aged 3–19 years)

[3]. It is mediated by humoral and cellular autoimmune

responses that occur as delayed sequelae of Streptococcus

pyogenes infection [4]. Bacterial factors are important

determinants of disease acquisition, but only 0.3–3% of

individual infected by a Streptococcus cepa known to be

rheumatogenic will develop disease [3, 5]. Environmental

factors such as poor quality of life and limited access to

medical facilities partially explain susceptibility, but indi-

vidual factors are known to play a role. A small proportion of

patients develop the full picture of symptoms (American

P. M. Azevedo (&) � R. R. Pereira � L. Guilherme

Universidade de Sao Paulo, Sao Paulo, Brazil

e-mail: pedroming@gmail.com

123

Rheumatol Int (2012) 32:1113–1120

DOI 10.1007/s00296-011-2152-z

Heart Association) [6], and only one- to two-thirds will have

carditis [7, 8]. Again, individual factor is determinant of

disease pattern and is poorly understood. Familiar aggrega-

tion [9, 10], similarity of disease patterns between siblings

and identical twin [11] and HLA correlation studies [8] are

evidence for a genetic influence on RF susceptibility and

manifestation. The suspect-involved genes fall mainly into

those capable of immunologic mediation. It is likely that a

genetic background directing immune response towards a

predominantly Th1 or Th2 pattern contributes to these fea-

tures. Molecular mimicry explains the triggering of RF, but

an intense and sustained inflammation is needed to cause

sequels. The purpose of the present article is to review the

recent findings on RF and to expose how they help to build a

physiopathological model for this disease.

Methods

A Medline search was performed for all articles containing

the terms rheumatic fever or rheumatic heart disease in title

or abstract from 1970 to 2011. ‘Best evidence’ qualitative

technique was used to select the most relevant.

Results

Genetic contribution to susceptibility

Different HLA class II antigens associations have been

observed in several populations. The HLA-DR7 was the

most frequently associated with the disease [12]. The fact

that several HLA class II antigens are associated with the

development of RF/rheumatic heart disease (RHD) in

diverse countries is consistent with the possibility that

different strains of group A streptococci are implicated in

the development of RF/RHD in different countries. The

variable association may also be due to the important role

that HLA class II antigens play in antigen presentation to

the T-cell receptors (TCR) [4]. Accordingly, Guilherme

and colleagues studied the T-cell reactivity in the periph-

eral blood of 74 Brazilian RHD patients and found that on

those with severe RHD the immunodominant M5 (81–96)

epitope was preferentially presented to T cells in the con-

text of DR7 and DR53 molecules [13].

Since evidence of genetic influence on RF came into

light, many genes suspected to play a role in susceptibility

have been studied (Table 1). The great majority of them

Table 1 Gene polymorphisms

associated with RF and/or its

manifestations

MBL mannose-binding lectin,

TLR2 toll-like receptor-2, FCN2ficolin-2, TNFa tumor necrosis

factor-a, TGFb transforming

growth factor-b, CTLA-4cytotoxic T-lymphocyte

antigen-4, IL1RN interleukin-1

receptor antagonist gene, IL10interleukin-10, ACEangiotensin-converting enzyme,

AoR aortic regurgitation, MVLmultivalvular lesion, OCDobsessive compulsive disorder,

NS not significant, NC not

calculated

Gene polymorphisms Assoc. OR P Ref.

Innate immunity

MBL AA RHD 1.99 B0.02 [14]

MBL YA/YA & YA/XA RHD 2.48 & 2.42 0.035 & 0.001 [15]

MBL defectives alleles AoR 3.5 0.0022 [16]

TLR2 Arg753Gln & Arg753Arg RF 97.1 & 0.01 \10-3 & \10-3 [17]

FCN2 -986/-602/-4 G/G/A &

A/G/A

RHD 1.6 & 0.3125 0.021 & 0.008 [18]

Adaptive immunity

IL1RN A1 & A1A1 SRHD 0.11 & 0.092 0.031 & 0.017 [37]

IL1RN A1A1 RHD 2.2 \0.05 [39]

IL-10 -1082 AA & GG RHD/

MVL

3.1 & 5.2/5.2 & NS \0.05 & \0.05/\0.05 &

NS

[39]

FCc RIIA RR & RIIIB NA2 RF 4.98 & NS 0.0022 & NS [40]

TNFa G-308A & G-238A RF 1.4 & 1.9 0.026 & 0.015 [41]

TNFa G-308A RF/RHD 3.4/3.3 \0.0032/\0.0055 [42]

TNFa G-308A & G-238G RHD/

MVL

10.8 & 14.1/8.65 &

NS

\10-3 & \10-3/\10-3 &

NS

[43]

TNFa -308A & -238A OCD NC & NC \0.0005 & 0.0099 [44]

TNFa -308AA RHD/

MVL

5.7/10.6 \10-3/\0.05 [39]

TGF-b1 C-509T & T869C RHD 1.49 & NC \10-3 & 0.04 [49]

TGF-b1 C-509T & T869T &

T869TT

RHD 1.78 & 1.89 & 3.37 0.04 & 0.02 & 0.02 [45]

CTLA-4 ?49GG RHD 3.1 0.016 [28]

Others

ACE II RHD NC \0.003 [46]

ACE II RHD 2.12 0.02 [48]

1114 Rheumatol Int (2012) 32:1113–1120

123

are somehow involved with the regulation of the immune

system.

The innate immune response provides immediate

defense against infection, recruits immune cells to sites of

infection and activates the adaptive immune system

through antigen presentation, production of cytokines and

activation of the complement cascade. It is expected that

variations within genes codifying proteins involved in

innate immune response may influence the predisposition

to RF or it sequels. Of note, mannose-binding lectin (MBL)

is an innate pattern-recognition collectin, an acute-phase

protein known to play a key role in pathogen clearance

[14]. It binds to several pathogen’s surface sugars,

including N-acetylglucosamine (GlcNAc), the major im-

munoepitope of group A streptococcal cell wall carbohy-

drates that has immunological similarity with human heart

valve’s laminin [15, 16]. The toll-like receptors (TLRs)

family is a key player in host immunity by mediating

inflammatory reactions against a wide range of pathogens.

TLR-2 is reported to interact with different bacterial struc-

tures, including lipoproteins, peptidoglycan and lipoteichoic

acid, some of them present in Streptococcus’ structures [17].

Ficolins (FCN) are pattern-recognition proteins involved in

innate immunity, which upon binding to their specific

pathogen-associated molecular patterns on the microbial

surfaces trigger the immune response either by binding to

collectin cellular receptors or by initiating the complement

lectin pathway. Ficolin-2 was shown to bind to lipoteichoic

acid, a cell wall constituent in all Gram-positive bacteria

such as Streptococcus [18]. Polymorphisms of the genes

codifying the above protein were associated with RF and/or

its manifestations (Table 1).

As further discussed later on, the adaptive immune

system plays a crucial role on the maintenance and

expansion of inflammation that leads to tissue damage seen

in RF. To date were associated with RF and/or manifes-

tations the genes for the interleukin-1 (IL-1) receptor

antagonist (IL1RN), tumor necrosis factor-a (TNFa),

transforming growth factor-b (TGFb) and cytotoxic

T-lymphocyte antigen-4 (CTLA-4) (Table 1). Interleukin-1

a and interleukin-1 b are produced by a wide variety of

cells only upon stimulation and promote the expression of

adhesion molecules and directly activate a number of cells

involved in immune response. An enhanced production of

IL-1 by peripheral blood mononuclear cells (PBMC) has

been implicated as the initial event of the cytokine dys-

crasias seen in RF [19]. Both IL-1a and IL-1b bind to the

same cellular receptor (IL-1R), which has a soluble

antagonist (IL1-RA). It acts by competitively linking to

IL-1 receptor without initiating the intracellular cascade

that signalizes the inflammation. The ratio IL-1ra/IL-1 is

important to determine the intensity and duration of the

inflammatory response [20]. The allelic variation of the

gene codifying IL1-RA (IL1RN) influences the leukocyte

IL-1RA production and immune response [21]. Most of the

studies associate IL-1RN’s allele 2 (A2) with an exacer-

bated immune response and the IL-1RN’s allele 1 (A1)

with a somehow milder immunological state [22]. Tumor

necrosis factor is one of the most important proinflamma-

tory cytokines. In RF and RHD, increased plasma levels of

TNF-a have been demonstrated [23–25]. TNF-a (also IL-1

and IL-2) production in the valvular lesions of RF patients

was correlated with Aschoff nodule progression [26]. It is

possible that TNF-a gene polymorphism interferes with

inflammatory response by influencing the levels of the

cytokine, but linkage disequilibrium with MHC class II

(both located on chromosome 6) is an alternative. Trans-

forming growth factor-beta (TGF-b) is a protein that con-

trols proliferation, cellular differentiation, and other

functions in most cells, including many within the immune

system and reparatory mechanisms. It was postulated that

TGF-b could be responsible for the increased valvular

fibrosis and calcification in the pathogenesis of RHD [27].

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is

a negative regulator of T-cell activation and proliferation

during the immune response. CTLA-4 gene polymorphism

has been shown to affect the inhibitory function of CTLA-4

[28]. Fc-gamma RIIA and Fc-gamma RIIIB are low-

affinity receptors for the FC region of immunoglobulin

gamma, present in many immune cells. Interleukin-10 (IL-

10) has pleiotropic effects in immunoregulation and

inflammation. It downregulates the expression of Th1

cytokines, MHC class II antigens, and costimulatory mol-

ecules on macrophages. It also enhances B-cell survival,

proliferation, and antibody production.

Triggering autoimmunity

The mechanism through which the group A Streptococcus

pyogenes pharyngeal infection triggers the autoimmunity

responsible to RF’s sequels is molecular mimicry. Several

streptococcal and human protein cross-reactive antibodies

found in the sera of RF patients and immunized rabbits and

mice have been described [29]. Antibodies against strep-

tococci’ wall GlcNAc display cross-reactivity against

laminin, a protein present in extracellular matrix that sur-

rounds heart cells and in the valves. Cardiac myosin and

vimentin are other major target antigens. Cunningham and

colleagues identified a 5 aminoacid residues’ epitope of the

Streptococcus N-terminal M5 and M6 proteins that cross-

reacts with cardiac myosin [30]. Antibodies from RF

patients were able to recognize several cardiac myosin

epitopes [31]. Sydenham’s chorea (SC) is mediated by

antibodies able to bind neuronal cells. Antibodies that

cross-react with lysoganglioside GM1 from neuronal cells

and streptococcal GlcNAc are capable of mediating signal

Rheumatol Int (2012) 32:1113–1120 1115

123

transduction, triggering dopamine release from neuronal

cells [32]. Cunningham’s group showed that in RF patients’

cross-reactive antibodies upregulate the adhesion molecule

VCAM-1 after binding to the endothelial surface leading to

cellular infiltration, inflammation, and valve scarring [33,

34]. These data establish that the antimyosin and antilami-

nin cross-reactive antibodies are implicated in the physio-

pathology of RF and bridge the early humoral immune

response to the later cellular infiltration and tissue damage.

Role of cellular immune response

As above described, humoral antibody–mediated autoim-

munity has an important role in initiating cardiac inflam-

mation and attracting cells that will perpetuate and expand

inflammation, now via cellular immune response. T lym-

phocytes CD4? are the major effectors of heart lesions in

RHD [35–37]. Molecular mimicry for T cells is manly

mediated by the recognition of bacteria and/or self-antigens

through HLA class II antigen presentation by antigen-

presenting cells (APCs), such as macrophages, dendritic

cells, and B lymphocytes. Pathogen epitopes that present

structural or sequential similarity to self-epitopes might

activate by the molecular mimicry mechanism autoreactive

T lymphocytes that have escaped immune tolerance. These

autoreactive T cells can also activate B cells that will

produce pathogen- and self-antigen-specific antibodies,

amplifying the process.

Several authors described peripheral and intracardiac

T cells capable of cross-recognizing a number of strepto-

coccus and self-epitopes, mainly derived from the immu-

nodominant bacterial M5 protein and cardiac myosin [31,

38–40], laminin, and tropomyosin [31, 40]. These M5

epitopes are also preferentially recognized by peripheral

T lymphocytes from RHD patients when compared to

normal individuals [13]. A high proportion (63%) of the

T-cell clones present in valvular tissue were reactive

against the LMM region of myosin in one study [13].

Guilherme and colleagues assessed the peripheral and int-

ralesional T-cell repertoire of RHD patients and found

evidence that some antigen-driven T-cell population

migrates from periphery to the heart where they are

expanded in an oligoclonal manner [41]. Several intrale-

sional T-cell clones present the same amino acid sequences

in the CDR3 region of the TCR conferring compatibility to

recognize numerous heart tissue proteins and LMM region

cardiac myosin peptides, indicating degeneracy in antigen

recognition [38, 42, 43]. Together, these data provide

support for the idea that antigen-specific peripheral T-cell

populations migrate to the heart tissue, expand locally, and

become capable of recognizing new self-antigens that are

distinct from the pathogen-inducing epitope, by an epitope-

spreading mechanism [44] (Fig. 1).

Intense and long-lasting immune response

One- to two-thirds of RF patients will have rheumatic

carditis [7, 8], and only a portion of them will suffer from a

severe and persistent form of this manifestation. It is not

rare that the initial heart inflammation subsides, leaving no

sequels. The factors determining the heart evolution are not

completely understood, but it is possible that some RF

patients will go through the epitope-spreading phenomena

and develop an intense and long-lasting cellular immune

response while others will not go much further on the initial

humoral-mediated inflammation. Accordingly, RF mild

carditis, as Sydenham chorea and arthritis, is believed to be

mediated by humoral immunity (Th-2-type immune

response) [3, 29, 32], while severe carditis is cellular

immunity–mediated (Th-1-type immune response) [35–37].

Cytokines in rheumatic fever

Antigen-activated CD4? T cells polarize to Th1 or Th2 or

Th17 subsets, depending on the cytokine secreted. Th1

cells are involved in the cellular immune response and

produce IL-1, IL-2, IFNc, and TNFa. Th2 cells mediate

humoral and allergic immune responses and produce IL-4,

IL-5, and IL-13. Th17 has more recently been described as

a type of proinflammatory response mediated by IL-17.

Streptococcus pyogenes throat infection triggers an

inflammatory reaction that involves several proinflamma-

tory cytokines, such as IL-1, IL-6, and TNFa.

Several evidence suggest that FR patients have a more

severe and long-lasting immune reaction. Acute RF (ARF)

patients’ lymphocytes have exacerbated in vitro cellular

reactivity as compared to patients with acute post-strepto-

coccal glomerulonephritis peaking at 1–6 months and

Fig. 1 Epitope spreading

1116 Rheumatol Int (2012) 32:1113–1120

123

lasting for at least 2 years after onset [45]. Upon stimula-

tion, acute ARF patients’ peripheral blood mononuclear

cells (PBMC) produce larger amounts of IL-1 and IL-2

than PBMC from normal controls, streptococcal pharyn-

gitis (SP), or chronic rheumatic heart disease (CRHD)

patients, and the IL-2 overproduction persisted after

48 weeks. ARF and acute rheumatic heart disease (ARHD)

patients’ PBMC also expressed higher proportions of IL-2

receptors (CD25). The IL-1 is considered to be an amplifier

of IL-2 and IL-2r production, and thus, the author specu-

lated that IL-1 is the major responsible factor for the per-

sistent inflammatory process [19]. In other study, the

plasma concentration of IL-1 and IL-2 was higher in ARF

than those in SP, CRHD, or normal controls, and the pro-

duction of IL-2 in ARF and CRHD directly correlated with

increased percentages of CD4? (T helper) and CD25?

cells in the peripheral blood [25].

In the heart tissue (myocardium and valves) of acute and

chronic RHD patients were identified by immunohisto-

chemistry a large number of mononuclear cells that were

able to secrete inflammatory cytokines (TNFa and IFNc)

and the regulatory cytokine IL-10. The analysis of the

cytokine profile of these cells suggested that the regression

of myocardium inflammation does not depend solely on the

regulatory function of IL-10. The differential cytokine

polarization in the atrium versus valvular tissue was

speculatively attributed by the authors to immigrant auto-

reactive T cells, local chemokines produced by inflamma-

tory cells, and adhesion molecules. The predominant IFN-cand TNF-a expression in the heart suggested that Th1-type

cytokines could mediate chronicity of RHD. The

production of IL-4 (antiinflammatory cytokine) seemed to

be crucial for a protective role by the fact that in the valves

there are only few cells producing this cytokine and the

lack of this cytokine probably leads to the worsening of

valvular lesions [46]. Fraser and colleagues divided the

progression of the Aschoff nodules into 3 chronologic

stages: macrophages only, accumulation of first T lym-

phocytes, and finally B lymphocytes. They concluded that

TNF-a and IL-1 secretion in macrophages is required for

T and B lymphocytes activation and aggregation, sug-

gesting that the macrophages arrive at the scene of rheu-

matic injury prior to lymphocytes. Il-2 is usually expressed

later and was found only in the lymphoid aggregates [26].

The previously mentioned associations between genes

polymorphism RF and/or its manifestations suggest that

genetic variation of cytokine genes influences their pro-

duction, the cytokine profile, and finally RF outcome. Our

group found a protective association (OR = 0.092,

P = 0.017) of the A1A1 IL1RN genotype, classically

connected to a milder immune response, with the devel-

opment of severe carditis in 84 RF Brazilian patients [47].

This is interesting because severe carditis is Th-1-mediated

and IL1-RA production is a major signal to inflammation

end in Th-1 immune response [48], diminishing the pos-

sibility of chronification and epitope-spreading. Also,

Morris and colleagues suggested an enhanced production

of IL-1 by peripheral blood mononuclear cells (PBMC) as

the initial event of the cytokine dyscrasias seen in RF [19],

and Guilherme et al. pointed the importance of the local

Th1-type cytokines produced by infiltrating inflammatory

cells in mediating chronicity of RHD [46].

Fig. 2 Rheumatic fever

physiopathology

Rheumatol Int (2012) 32:1113–1120 1117

123

Physiopathological model of disease

Under the light of the mentioned findings, a model of RF

physiopathology can be proposed (Fig. 2), where a pharynx

infection by a Streptococcus pyogenes bearing epitopes

similar to human structures (molecular mimicry) is initially

fought by the innate immunity that triggers local adaptive

immunity that will produce exacerbated quantities of pro-

inflammatory cytokines and antibodies, some of them

capable of cross-recognize human and bacterial epitopes.

The cytokines act systemically, activating and expanding

multiple lymphocytes clones. At the joints, the antibodies

precipitate in form of immunocomplex and activate com-

plement-inducing arthritis. Few antibodies recognize basal

ganglia neurons and induce dopamine secretion leading to

Sydenham’s chorea and probably obsessive compulsive

disorders in some patients. Autoantibodies against heart

structures, mainly derived from myosin, laminin, and

tropomyosin, promote adhesion molecules as VCAM-1

expression recruiting initially monocytes and macrophages.

These mononuclear cells produce a gamma of cytokines

that acts locally with proinflammatory and antiinflamma-

tory properties. The balance between these cytokines can

be influenced by host genetic background and will deter-

mine whether peripheral lymphocytes will be attracted to

the heart, where epitope spreading phenomena may occur,

leading to persistent and intense inflammation and heart

damage. If antiinflammatory cytokines overcome inflam-

mation end, no heart damage occurs.

Conclusion

Rheumatic fever is a prototype of post-infectious autoim-

mune disease and offers important clues to understand

other immune conditions. The accumulation of information

about RF now permits a construction of a physiopatho-

logical model that hopefully will be soon traduced into

befits to millions that still are affected by this disease.

Acknowledgments The work was supported only by academical

grants. RMRP receives funds by CNPQ #300559/2009-7.

Conflicts of interest We have no financial or other relationships

that could lead to a conflict of interest.

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