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Some of the People, Some of the TimeSusceptibility to Acute Rheumatic Fever

Penelope A. Bryant, MA, BM BCh, MRCP, MRCPCH, PhD;Roy Robins-Browne, MB BCh, PhD, FASM, FRCPA, FRCAPath;

Jonathan R. Carapetis, MB BS, FRACP, PhD;Nigel Curtis, MA, MBBS, MRCP, DTM&H, PhD

Abstract—Acute rheumatic fever is a major cause of heart disease in large parts of the world, but it remains unknown why

only a small fraction of those who are infected with rheumatogenic group A streptococci develop an abnormal immune

response that leads to acute rheumatic fever. An understanding of the mechanisms underlying host susceptibility can

provide important insights into pathogenesis that in turn can inform new treatments. Extensive searches for susceptibility

factors have been undertaken, including human leukocyte antigens, B-cell alloantigens, and cytokine genes. Although

significant associations have been found between genetic factors and acute rheumatic fever, study results often conflict

with each other. This review explores current understanding about host susceptibility to acute rheumatic fever and

provides an overall perspective to the number of studies that have recently addressed this subject. (Circulation. 2009;

119:742-753.)

Key Words: antigens genetics immunology rheumatic heart disease susceptibility

Acute rheumatic fever (ARF) remains a major cause of

heart disease and premature death in large parts of the

world (Figure 1). ARF is a systemic inflammatory autoim-

mune disease that follows throat infection with Lancefield

group A -hemolytic streptococci (Streptococcus pyogenes).

The pathogenesis of ARF is believed to involve the triad of a

genetically susceptible individual, infection with a rheumato-

genic strain of group A streptococcus, and an aberrant hostimmune response. There have been excellent recent reviews

addressing group A streptococcal virulence28 and the immuno-

pathogenesis of ARF.29 A key question that remains unanswered

is why only a small fraction of those infected with rheumato-

genic group A streptococci develop an abnormal immune

response that leads to ARF.

An understanding of the mechanisms underlying host

susceptibility can provide important insights into pathogene-

sis that in turn can inform new treatments and vaccine

development. The identification of individuals susceptible to

ARF would also help in the diagnosis of ARF. Currently, the

Jones criteria are not very sensitive or specific in countries

with a high incidence, and a test for susceptibility wouldincrease specificity. An appreciation of host susceptibility is

increasingly important with the imminent arrival of new

group A streptococcal vaccines that may offer protection

against ARF.30–32 The present review explores current under-

standing about host susceptibility to ARF and provides an

overall perspective to the number of studies that have recently

addressed this subject.

Epidemiological Support for a HereditarySusceptibility to ARF

The role of host factors in ARF is supported by the observa-

tion that different clinical outcomes occur during an outbreak of a single rheumatogenic group A streptococcal strain.33,34 In

populations exposed to rheumatogenic group A streptococci,

the lifetime cumulative incidence of ARF is remarkably

constant at 3% to 6%.23 This is regardless of geography or

ethnicity and suggests a strong genetic component to ARF

susceptibility. Rates of ARF similar to those found in devel-

oping countries today were documented in industrialized

countries during the early to mid 20th century.35 In most of

those countries, ARF has now become rare, yet the genetic

makeup of their populations has not changed dramatically.

Susceptible individuals are still present, but they are no

longer being exposed to rheumatogenic group A streptococci

as a result of factors such as living conditions.Early studies showed a family predilection for ARF.36,37 As

far back as 1889, Cheadle36 noted that the chance of an

individual with a family history of ARF acquiring the disease

is “nearly 5 times as great as that of an individual who has no

From the Departments of Paediatrics (P.A.B., N.C.), and Microbiology and Immunology (R.R.-B.), University of Melbourne, Parkville, Australia;Infectious Diseases Unit, Department of General Medicine (P.A.B., N.C.), and Infection, Immunity and Environment Theme, Murdoch Children’s

Research Institute (P.A.B., R.R.-B., N.C.), Royal Children’s Hospital Melbourne, Parkville, Australia; and Menzies School of Health Research (J.R.C.),Charles Darwin University, Casuarina, Australia.

Correspondence to Professor Nigel Curtis, University Department of Paediatrics, Royal Children’s Hospital Melbourne, Parkville, VIC 3052, Australia.

E-mail [email protected]

© 2009 American Heart Association, Inc.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.108.792135

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Basic Science for Clinicians

at VA MED CTR BOISE on September 4, 2015http://circ.ahajournals.org/ Downloaded from



such hereditary taint.” A more recent cohort study of children

raised separately from their parents in an Israeli kibbutz

showed that children whose parents had rheumatic heart

disease (RHD) had a relative risk of 2.93 for the development

of ARF compared with children whose parents did not have

RHD.37 An inherited susceptibility to ARF and RHD is

supported by twin studies that have found a significantly

increased concordance in monozygotic twins compared with

dizygotic twins38,39; however, the lower than expected con-

cordance (3 of 16 pairs) in these studies indicates that it is not

simple mendelian single-gene inheritance. The search for sus-ceptibility genes has been vigorous.

Human Leukocyte AntigensAs critical components in antigen processing, the major

histocompatibility complex human leukocyte antigen (HLA)

molecules are attractive candidate antigens that might confer

susceptibility to ARF. HLA class II molecules in particular

are associated with other autoimmune diseases (for example,

HLA-DR2 and systemic lupus erythematosus and HLA-DR3

and insulin-dependent diabetes mellitus).

In general, HLA class II molecules appear to have a closer

association with increased risk of ARF or RHD than class I

molecules, although no single HLA haplotype or combination

exists that is consistently associated with susceptibility

(Table 1). Similarly, intensive study of the DR locus in a

Brazilian population showed an association with RHD but

failed to find either a specific allele or unique nucleotide

sequence that conferred susceptibility.68 The authors pos-

tulated that this might be due to either the cross-reacting

peptide being indiscriminate or heterogeneity of the caus-

ative agent. Although most interest has been focused on

association with increased risk, several HLA molecules

have been found to be associated with decreased risk of

ARF.40,45,46,48,52,53,58– 61,63,64,67

A wide variation exists in results of studies in differentgeographic regions and ethnic populations, as well as incon-

sistent findings between different studies in similar popula-

tions. Some of the differences may be attributable to the

technique used for HLA typing. Earlier studies that used

serological methods are subject to potential inaccuracies and

are unable to distinguish between allelic subgroups; however,

results from more recent molecular studies that have

investigated allelic subgroups have also found differences

between ethnic groups, both in alleles and in haplo-

types.50,59– 61,63,64,66,67 Another potential source of variabil-

ity between studies is the selection of control subjects.

Where historical controls have been used, these may not berepresentative of the population from which the case

subjects came. It is also possible that differences in clinical

classification of ARF and RHD between studies are responsible

for some of the different results. Some support can be seen for

this in the finding that HLA associations are stronger in more

clinically homogenous patients.47,57,63 Also, some studies have

found HLA associations only with particular clinical features of

ARF; for example, in 1 study, a significant association was

found between HLA-A10 and HLA-DR11 in patients with

cardiac manifestations compared with ARF without cardiac

features, the latter group having a higher frequency of HLA-

C2.42 However, even with disease defined in exactly the same

way, ethnic differences in HLA association are apparent,47

which supports a genuine ethnicity-specific genetic susceptibil-

ity. Overall, most studies support the notion of an HLA associ-

ation with ARF/RHD.

The mechanism of HLA association is unknown. One

theory is that similarity exists between antigens from rheu-

matogenic group A streptococcal strains and HLA molecules.

If antigens from different strains of bacteria were structurally

similar to different HLA molecules, this would result in an

increased proportion of individuals of a specific HLA type

with ARF during an outbreak or in a geographic population

where a particular streptococcal strain dominates. To date, no

study has investigated people from 1 ethnic group who havemoved to a geographic area with a different predominant

Figure 1. Worldwide prevalence of RHD. Rates (in parentheses) are based on studies in school-age children unless indicated byan asterisk, in which case, they include adults. a, United States* (0.02)1; b, Native American* (4.6)2; c, Cuba (2.9)3; d, Brazil (3.6)4;e, Bolivia (7.9)5; f, Mali (3.8)6; g, Côte d’Ivoire (1.9)7; h, Egypt (5.1)5; i, Sudan (10.2)5; j, Ethiopia (6.4)8; k, Kenya (2.7)9; l, DPRCongo (14.3)10; m, Zambia (12.5)11; n, South Africa (1.0)12; o, Soweto, South Africa (6.9)13; p, Turkey (3.7)14; q, Saudi Arabia(2.4)15; r, Yemen (3.6)16; s, Bikaner, India (16.7)17; t, India (3.0)18; u, Nepal (1.2)19; v, Bangladesh (1.2)20; w, Sri Lanka (6.0)21;

x, China* (1.9)22

; y, Philippines (1.6)6

; z, Aboriginal Australian (6.8)23

; A, Maori New Zealand (6.5)24

; B, non-Maori New Zealand(0.9)24; C, Samoa (77.8)25; D, Tonga (2.7)26; E, Cook Islands (18.6)27; and F, French Polynesia (8.0).27

Bryant et al Susceptibility to Acute Rheumatic Fever 743




Table 1. HLA Associations With ARF/RHD in Different Countries and Ethnic Populations

HLA Antigen Association Lack of Association Method Disease Country/Ethnicity No. in Study

Year and

Reference

HLA class I

A33 1 Rest of A, B S ARF/RHD North India 134 198640

A19 1 Rest of A, B, C S RHD Kashmir 54 199741

A10 1 Rest of A, rest of B, C, DR S ARF Turkey 100 199342

B35 1

B5 2 Rest of B, A, C S RHD Kashmir 50 199743

B35 1 Rest of B, A, C S ARF Martinique 88 198644

B14 2

B42 2

B16 1 Rest of B, A S RHD Turkey 107 199345

B51 2 Rest of B, A M RHD Turkey 85 200746

Cw*4 2 Rest of C

HLA class II DR

DR2 1 Rest of DR, A, B, C S ARF/RHD, especially with

cardiac features

USA: black 48 198647

DR4 1 USA: white 24

DR4 1 Rest of DR S RHD USA: white 33 198648

DR6 2

DR1-9 DR1-9 S RHD USA: white 57 199549

DR4 DR4 M

DRB1*16 1 Rest of DRB1 M ARF USA: white 33 199850

DR1 1 Rest of DR S ARF Martinique 88 198644

DR1 1 Rest of DR, A, B, DQ S Severe RHD Black South Africans 103 198751

DR6 1

DR3 1 Rest of DR S ARF/RHD North India 134 198640

DR2 2

DR2 2 Rest of DR, A, B S RHD North India 52 198952

DR2 2 Rest of DR, A, B, C S RHD North India 165 199053

DR3 1

DR4 1 Rest of DR, DQ S RHD Kashmir 54 199741

DR4 1 Rest of DR, DQ S RHD Kashmir 50 199743

DR4 1 Rest of DR, A, B, C S ARF/RHD Saudi Arabian Arabs 40 198754

DR7 1 Rest of DR1 10, DR52, A, B, DQ S ARF/RHD Brazil: white/light

mulatto

40 199155

DR53 1 37

DR7 1 DR53 S ARF/RHD Brazil: white 35 200056

DR4 1 Rest of DR, A, B S ARF, especially with

cardiac features

Turkey 93 199257

DR3 1 Rest of DR S RHD Turkey 107 199345

DR7 1

DR5 2

DRB1*01 2 Rest of DR M RHD Turkey 85 200746

DRB1*04† 2 Rest of DRB1 M ARF Turkey 55 200558

DRB1*13 2 Rest of DRB1, A, B, C, DRB4 DQB1 M RHD Turkey 100 200659

DRB3 2

DRB5 2

DRB1*07 1 Rest of DRB1*01-*18 M RHD Latvia 70 200360

DRB1*06 2

DRB1*07‡ 1 DRB1: 5 alleles M RHD Turkey 102 200661

DRB1*11 2

(Continued )

744 Circulation February 10, 2009




streptococcal type. This theory is supported by a study in a

population in which HLA-DR4 was associated with ARF.69

The investigators found that antistreptococcal serum caused

significantly increased toxicity to B lymphocytes bearing

HLA-DR4 compared with DR4-negative lymphocytes, and

they suggested that a strong antigenic similarity existed between

HLA-DR4 and the streptococcal antigen, which led to defective

antigen presentation by the HLA molecule (Figure 2). This inturn could lead to aberrant cytokine production and ultimately

antibody formation against proteins on valves, myocardium,

brain, and joint tissue.71 However, this occurred in lympho-

cytes both from individuals with ARF/RHD and from control

subjects, which left the progression to ARF in some individ-

uals unexplained. This study has not been repeated with any

other HLA types. An alternate theory is that structural

similarity causes streptococcal antigens to mimic HLA mol-

ecules, which initiates an aberrant immune response.70

More recently, it has been suggested that after binding to

the antigenic peptide, the particular HLA complexes may

initiate inappropriate T-cell activation72

(Figure 2). In thismodel, the HLA complex on the surface of the antigen-pres-

enting cell presents the streptococcal peptide to peripheral T

cells that have escaped immune tolerance. These T cells

recognize and are activated by the peptide, but then they

cross-react with similar self-antigens that they are unable to

identify as self, which initiates the autoimmune process. This

concept of an autoimmune process that is initiated by HLA-

specific antigen presentation is supported by a recent study

that used T-cell lines from valves of patients with severeRHD.72 In that study, an immunodominant peptide of the

streptococcal M5 protein bound to HLA-DR53 and was

recognized by an infiltrating T-cell clone from an HLA-

DR53–positive RHD patient, which suggests that the peptide

is presented to T cells in the context of HLA-DR53 in this

instance.

The fact that different ethnic groups with ARF/RHD may

have different HLA associations suggests that cross-reactive

peptides may bind to several different HLA alleles that have

structural homology in the peptide-binding groove. Although

not inconsistent with this model, most researchers, however,

have concluded that the association between HLA and ARF/ RHD is through linkage disequilibrium and that an ARF

Table 1. Continued

HLA Antigen Association Lack of Association Method Disease Country/Ethnicity No. in Study

Year and

Reference

DRB1*07 1 DQA1, DQB1 M RHD Pakistan 114 200762

DRB1*0701 1 Rest of DRB1 M RHD, especially with

similar clinical features

Egypt 88 199963

DR16(DRB1*1602)

1 Rest of DR, DQA1, DQB1 M RHD Mexico 98 200364

DR11 2

DRB1 DRB1: 13 alleles M ARF Italy 25 200465

HLA class II DQ

DQ2§ 1 Rest of DQ S RHD North India 52 198952

DQA1 DQA1 M RHD USA: white 57 199549

DQB1 DQB1

DQA1*0104 1 Rest of DQA1 and DQB1, DRB1,

DPA1, DPB1

M RHD Japan 72 199666

DQB1*05031 1

DQA1*0101 1 Rest of DQA1 M ARF/RHD South China 54 199767

DQA1*0102 2

DQA1*0201 1 Rest of DQA1, DQB1 M RHD, especially with

similar clinical features

Egypt 88 199963

DQA1*0103 2

DQB1*0603 2

DQB1*302 1 Rest of DQB1 M RHD Latvia 70 200360

DQB1*0401-2 1

DQB1*0501 2

DQB1*0602-8 2

DQA1*03 2 Rest of DQA1, DQB1 M ARF Turkey 55 200558

DQB1*08 1 Rest of DQ M RHD Turkey 85 200746

S indicates serological; M, molecular.†Only in combination with DQA1*03.

‡Association also found with recurrent streptococcal pharyngitis.

§Only in D8/17-positive patients.





susceptibility gene exists that is mapped within or near the

HLA complex. This may explain ethnically defined differ-

ences. A cosegregation study of 22 families of different

ethnic background with multiple individuals with RHD sup-

ported this hypothesis, concluding that the inheritance

method was dominant with variable penetrance.74 This sup-

ports the original twin-study finding of lower than anticipatedconcordance in monozygotic twins.39

B-Cell AlloantigensThe idea that genetic determinants within the host immune

response may be relevant to susceptibility to ARF led

Patarroyo et al75 to use B-cell antiserum to distinguish

individuals with past ARF from control subjects. Using

alloantisera, they identified a novel B-cell alloantigen,

called 883, which was expressed on the B cells of 71% to

74% of rheumatic fever patients compared with only 17%

of control subjects.75 Monoclonal antibodies were devel-

oped to the alloantigen by Zabriskie et al76 and subse-

quently to another B-cell surface antigen that more accu-rately identified ARF patients.77 A number of studies have

investigated the association of this antigen, D8/17, and

ARF (Table 2).

In some studies, results have been expressed as the per-

centage of B cells that stain positive for the D8/17 antigen. In

others, a receiver operator curve or other method has been

Figure 2. Possible mechanisms for HLA association with ARF. The left side of thefigure (antibody theory) illustrates howantibodies may be central to the mecha-

nism through which the HLA associationis mediated, either through defective pre-sentation by the HLA molecule becauseof antigenic similarity,69 or through strep-tococcal antigens mimicking the HLA molecule.70 This is proposed to lead toaberrant cytokine production, poor anti-genic clearance, prolonged B cell stimula-tion and increased production of antibod-ies against the various tissues affected in

ARF.71 The right side of the figure (antigentheory) illustrates how streptococcal anti-gens may be presented to T cells in thecontext of specific HLA molecules, whichare cross reactive to epitopes on the tis-sues affected in ARF, initiating an aber-

rant T cell response.72,73

GpA indicatesgroup A; TCR, T-cell receptor.

Table 2. Results of D8/17 Studies in ARF/RHD in Different Countries and Ethnic Populations

Proportion of

Individuals

Positive (%)

Proportion of B Cells Staining Positive

for D8/17 (Mean %1 SD)

Country/Ethnicity Patients Controls Patients Relatives Controls

Cutoff (% B Cells

Stained) Disease

No. of RHD Cases

in Study

Year and

Reference

United States and Tr inidad 98.8 14 33.58.5 13.75.8 7.54.3 11.8 RHD 84 198977

North India 62.9 12.5 RHD 54 198952

North India 66.4 14 40 RHD 90 199278

North India 68.8 14 10 ARF/RHD 63 199879

Mexico 89.7 11.1 34.613.2 12.55.7 7.56.9 14.4 ARF/RHD 39 199080

Brazil 90 0 38.817.8 16.29.4 4.62.8* 12 RHD 10 199281

Russia 88.9 10 ARF/RHD 117 199182

Russia 24.80.4† 11.11.0† ARF/RHD 40 199683

Israel 91 0 11.53.0 4.22.7 7.55 ARF 22 200284

Aboriginal Australian 94.7 4.4 39.311.8 22.55.2 11.67.3 22.1 ARF/RHD 41 200685

*Estimated SE.†Insufficient data available to confirm SE.





used to find a cutoff that is subsequently used to classifyindividuals as either positive or negative. With both methods,

a clear difference has been shown in the expression of this

antigen between RHD and control patients (Figure 3). How-

ever, substantial differences exist between studies in the

proportion of D8/17-positive B cells; for example, a study in

Israel84 reported the same mean percentage of D8/17-positive

B cells (11%) in the disease group as was documented in the

control groups in studies in Russia83 and Australia.85 Whether

this is a difference between study methodology or expression

in different populations remains unresolved. Regardless,

D8/17 antigen appears to be more robust than HLA typing as

a marker for RHD in geographically and ethnically diversepopulations.

D8/17 appears to be more than merely a marker of past or

current disease. In first-degree relatives, the proportion of

D8/17-positive cells or individuals classified as positive has

been found to lie between the proportions measured in

patients and control subjects with no family history of RHD

(Table 2).77,80,81,85 Khanna et al77 showed that D8/17 expres-

sion in healthy siblings of index case subjects depended on

their parents’ D8/17 results. The authors suggested that the

D8/17-positive phenotype is an inherited trait, possibly auto-

somal recessive with incomplete penetrance. An intriguing

finding in a study of family members of individuals with

RHD was that 1 unaffected sibling with a high level of positive B cells (30% positive, with 13% being the proportion

of D8/17-positive B cells that discriminated between rheu-

matic and nonrheumatic individuals) developed ARF shortly

afterward.86 This supports the hypothesis that it is a true

marker of susceptibility, which makes it an attractive prospect

for identifying potential recipients of a vaccine or early

preventative antibiotics.

Expression of D8/17 in patients with acute disease was

recently studied in Aboriginal Australians.85 A small number

of individuals with ARF had a significantly higher proportion

of D8/17-positive cells (83.710.1%) than individuals with

RHD (39.3

11.8%), who in turn had a higher proportionthan relatives (22.55.2%), with healthy control subjects

having the lowest proportion (11.67.2%; ANOVA between

means P0.001). The authors hypothesized that D8/17 was

expressed in susceptible patients and that this was augmented

by the process that leads to ARF.

Infectious stimuli such as pneumonia and gastroenteritis

have not been associated with increased D8/17 expression,

which suggests that D8/17 is not a nonspecific result of B-cell

activation.84 Studies showing an increasing percentage of

D8/17-positive B cells with age in both individuals with

RHD78 and their relatives86 suggest that expression may be a

result of cumulative exposure to group A streptococcal

antigens. However, in the Aboriginal population in northern

Australia, where infection with group A streptococci is

endemic, D8/17 expression was higher in relatives than in

control subjects, which suggests that inheritance is a more

important factor than exposure to streptococci.85 D8/17 ex-

pression appears to be specific to rheumatic fever, because no

association is present with other diseases such as poststrep-

tococcal glomerulonephritis, rheumatoid arthritis, or systemic

lupus erythematosus.77,87 However, a recent finding that 19patients with poststreptococcal reactive arthritis had higher

D8/17 expression than control subjects puts this into question

once again.88 It may suggest a shared genetic susceptibility

with ARF, but it could also support the streptococcal expo-

sure theory.

Most studies have reported D8/17-positive expression in

85% of individuals with previous ARF, but this is not

universal.52,78,79,89 In 1 study, antibodies to D8/17 were only

found to discriminate between ARF patients and control

subjects when staining of total lymphocytes (B and T cells)

was assessed, which led to the authors’ suggestion that the

discriminatory nature of D8/17 found in previous studies issimply a measure of B-cell numbers.89 In studies in which it

is not explicitly stated that only B cells were stained, this is a

possibility; however, in studies in which it is clear in the

methods that staining for D8/17 was only undertaken in B

cells,85 the discriminatory nature of D8/17 is unambiguous.

Inconsistencies in the results between D8/17 studies have also

been ascribed to technical difficulties with the D8/17

antibody.90

Differences between studies are more likely to be attribut-

able to population differences in B-cell alloantigen expres-

sion. In several studies in northern India, the proportion of

patients with RHD who were D8/17 positive was only 63% to

69%.52,78,79 Monoclonal antibodies (PG-12A, -13A, and-20A) were therefore developed against B-cell alloantigens in

local patients with ARF/RHD. In combination, these antibod-

ies identified 90% of north Indian patients with ARF/RHD

and were better than antibodies to D8/17 at discriminating

between RHD patients and control subjects.79 Like D8/17,

these population-specific B-cell alloantigens are most highly

expressed in ARF but remain positive in chronic RHD.91 This

study also showed that the proportion of D8/17-positive cells

in ARF diminished between the acute phase and 3-month

follow-up. It is not known whether the best way to discrim-

inate patients with ARF/RHD from control subjects in every

population is to use D8/17 or other monoclonal antibodiesdirected against markers in the local population.

Figure 3. Proportion of D8/17-positive B cells in studies in ARF/ RHD in different countries and ethnic populations. Error barsrepresent SEM.





It is not clear whether or how the expression of these

alloantigens on B cells relates to the host immune response to

group A streptococci. Williams et al92 showed that the

monoclonal antibody binds to sites on the surface of reactiveB cells very close to but distinct from sites that bind group A

streptococcal membrane antigens. This suggests a close

relationship between them, possibly involving recognition

and binding. A study on the tissue distribution of D8/17

antigen showed strong expression in cardiac, skeletal, and

smooth muscle in blood vessels, as well as various epithelial

and hepatic tissues.93 In the same study, a monoclonal

antibody to D8/17 bound to vimentin and myosin (cardiac

proteins) and to recombinant streptococcal M protein. This

suggests shared epitopes between the proteins, alluding to a

potential role in pathogenesis. It is possible that D8/17 could

be an anti-idiotype, mimicking the antigenic interaction withantibodies and T cells in ARF. The same group also showed

that cells from the pathognomonic rheumatic fever Aschoff

nodule expressed both HLA-DR and D8/17.94 However, no

correlation has been found between the presence of D8/17

and clinical outcome, and any role it may have in pathogen-esis remains uncertain.84

Immune Gene PolymorphismsThere have only been a limited number of studies investigat-

ing genetic susceptibility associated with other components

of the immune response (Table 3). In most cases, these

comprise single studies in 1 population. However, there have

been several studies examining the role of polymorphisms in

the promoter region of the tumor necrosis factor- (TNF-)

gene. These have shown associations with RHD in Mexican

patients, both in the allele (TNF--308A and -238G) and in

the genotype.95

An association was also found with valvedamage, but no relationship was found with the specific valve

Table 3. Associations With Immune Gene Polymorphisms and ARF/RHD

Immune Gene Allele Association Disease Country/Ethnicity No. in Study Year and Reference

Cytokine genes

TNF- promoter 308A 1 RHD Mexico 87 200395

1 ARF/RHD Turkey 71 200596

1 ARF/RHD Brazil 318 200697

None ARF Turkey 66 200698

1 RHD Egypt 50 200799

308G 2 RHD Mexico 87 200395

None ARF Turkey 66 200698

238G 1 RHD Mexico 87 200395

238A 2 RHD Mexico 87 200395

1 ARF/RHD Brazil 318 200697

TGF-1 509C* 2 RHD Taiwan 115 2004100

869T 1

IL-1Ra I/II/IV None RHD Taiwan 115 2005101

Intron 2 1 RHD Egypt 50 200799

IL-10 C/A None RHD Taiwan 115 2005101

1082A 1 RHD Egypt 50 200799

1082G 1 RHD Egypt 50 200799

IL-1 promoter C/T None RHD Taiwan 115 2005101

IL-1 E1/E2 None 115 2005101

IL-4 promoter C/T None 115 2005101

IL-4 RP1/RP2 None 115 2005101

IL-6 174G/C None RHD Egypt 115 2005101

Other immune genes

Fc RIIA R131 1 ARF Turkey 66 2004102

Fc RIIIB NA1/NA2 None

TCR C /V None RHD New Zealand: white and Maori 98 1995103

TCR V7/V8 None

TLR 753Gln 1 ARF Turkey 61 2005104

753Arg 2

677Arg/Trp None

TNF indicates tumor necrosis factor; TGF, transforming growth factor; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; TCR, T-cell receptor; and

TLR, Toll-like receptor.

*Only significant as CC genotype.





affected.95 A study in Turkey confirmed the TNF--308A

polymorphism association in RHD and showed that these

patients also had increased production of TNF- compared

with those with the TNF--308G allele.96 A recent study in

Brazil confirmed that patients with ARF/RHD were more

likely to have the TNF--308A polymorphism,97 but an

Egyptian study99 found that this was only true in individuals

homozygous for the TNF--308A allele; heterozygous A/G

genotypes were significantly less common in patients with

RHD.99 An association with the TNF--238 polymorphism

was also found, but in this population,99 it was with the

TNF--238A allele rather than the G allele found in Mexican

patients.95 In addition, when patients were clinically stratified

in the Egyptian study,99 the polymorphisms were found to be

present in patients with RHD and valvular lesions but not in

those with Sydenham’s chorea. One study in Turkish children

showed no association between polymorphisms in the TNF-

gene and risk of ARF or disease progression.98 However, in

general, there does appear to be a risk association with

polymorphisms in the TNF- promoter region. Althoughcytokines are thought to play a role in ARF, the TNF- gene

maps close to the major histocompatibility complex region,

and as yet, it is unclear whether the association is related to

the effects of TNF- or linkage disequilibrium with HLA or

other possible risk-associated genes. If it is a marker for

development of particular clinical features, as has been

suggested, there may be therapeutic implications.97

Noncytokine components of the immune response have

received less attention. One study found associations between

immunoglobulin Fc RIIA gene polymorphisms and concom-

itant genotypes in susceptibility to ARF.102 A possible mech-

anism for the association is a genetically determined failure

of removal of immune complexes. Circulating immune com-plexes previously have been found in the sera of RHD

patients along with raised IgG.58 Conversely, no association

was found between RHD and polymorphisms in the T-cell

receptor - and -chains in a study in Caucasian and Maori

populations.103 The discovery of Toll-like receptors (TLR),

key components of the innate immune response to bacteria,

has introduced new avenues for research in disease associa-

tions. The only TLR polymorphism to be studied in relation

to ARF/RHD to date, TLR-2, showed a strong association

with ARF in children.104

Other Gene AssociationsFamilial Mediterranean fever is an inflammatory condition

characterized by recurrent fever, abdominal pain, and arthritis

that is caused by mutations in the MEFV gene that encodes

pyrin. Polymorphisms in the MEFV gene are associated with

a number of inflammatory conditions, including juvenile

rheumatoid arthritis105 and psoriatic arthritis.106 Patients with

familial Mediterranean fever have a higher prevalence of

RHD than the general population,107 and polymorphisms in

the MEFV gene are associated with ARF.108 However, a

recent study found that the polymorphisms in the TNF-

promoter region that are associated with ARF are not asso-

ciated with familial Mediterranean fever, which suggests the

association is by an alternate mechanism.109

The most con-sistent feature in all of these diseases is arthritis, and in

rheumatoid arthritis, MEFV mutations are associated with

more severe joint symptoms.110 It has been suggested that

MEFV polymorphisms cause impaired control of the type 1

helper T cell (Th1) immune response, which is consistent

with the proposed pathogenesis of ARF.

Most studies have investigated gene associations with

susceptibility to ARF rather than disease severity; however,

polymorphisms of the ACE gene have recently been associ-

ated with chronic valvular fibrosis and calcification in

RHD.111,112 These polymorphisms are strongly associated

with valvular damage compared with individuals with previ-

ous ARF but normal valves.113

Genetically Determined HostResponses in ARF

Despite the burgeoning number of studies, it remains uncer-

tain whether the associations between ARF/RHD and HLA

molecules, B-cell alloantigens, and immune and other gene

polymorphisms have a role in pathogenesis or simply repre-

sent disease markers. Although the molecular pathogenesisand immunopathogenesis of ARF have been explored in

extensive detail,29,114 there has been less work to date at-

tempting to link the potential susceptibility factors described

above with current knowledge about pathogenesis. Defining

the role of susceptibility factors in pathogenesis will allow us

to understand more than the mode of inheritance of ARF.

Recent studies of the pathogenesis of other severe strepto-

coccal diseases hint at how host genetic susceptibility might

influence disease outcome. It is well described that the same

invasive streptococcal strain can cause disease of varying

severity in different individuals.115 Certain HLA types protect

individuals against severe invasive disease caused by supe-

rantigens, whereas others confer susceptibility.116,117 More-over, different combinations of HLA allelic variations pres-

enting different superantigens result in different in vitro

proliferative effects and production of cytokines.117 This has

been further explored in a study that showed that binding of

the superantigen streptococcal pyrogenic exotoxin B is de-

pendent on an HLA-DQ -chain polymorphism, which went

on to show this affected T-cell proliferation and cytokine

production.118 In a mouse model, genetic differences affected

the deposition of anti-myosin autoantibodies and the subse-

quent development of myocarditis.119 Whether any of these

mechanisms are involved in the pathogenesis of ARF is not

known.

In a disease as complex as ARF, which involves different

potential bacterial antigenic triggers, humoral and cellular

arms of the immune response, and damage to multiple

specific tissues, it is doubtful that a single gene holds the key

to understanding the intricacies of its pathogenesis. This

complexity is underlined by the fact that although strong

associations exist between susceptibility and disease, geneti-

cally susceptible individuals (defined by a previous episode

of ARF) do not invariably develop ARF after exposure to

rheumatogenic strains of group A streptococci.120 The advent

of microarray technology has provided an ideal tool for the

investigation of complex diseases such as ARF/RHD through

the global analysis of genes and gene expression. To date,there have been no studies analyzing the entire host genome





in relation to susceptibility to ARF/RHD. There have, how-

ever, been 4 global gene expression studies that investigated

the host response to group A streptococci; 2 of these studies

analyzed gene expression in human cells after stimulation

with the bacteria in vitro, and 2 investigated gene expression

in vivo in mice.

A comparison of gene expression responses in neutrophils

after in vitro stimulation with various bacteria showed that

group A streptococci induce a unique gene expression profile

in addition to the changes induced by all bacteria.121 Phago-

cytosis of group A streptococci caused differential expression

of 393 genes in neutrophils that differed significantly from

those induced by other bacteria. These included altered

expression of 71 genes involved in apoptosis and cell fate and

26 genes regulated by interferon- . The authors postulated

that as a result of decreased neutrophil survival, this favors

pathogen survival and consequently the likelihood of disease.

Pharyngeal adherence by rheumatogenic group A strepto-

cocci is thought to be a necessary virulence mechanism in the

pathogenesis of ARF. A study of gene expression in humanepithelial cells after in vitro stimulation with M49 group A

streptococci (a nephritogenic strain) found that the Fas-2

component signal transduction system induces massive cyto-

kine gene expression, apoptosis, and cytotoxicity.122 The

response induced by a rheumatogenic strain has not been

investigated, but it would be interesting to determine whether

differences in immune response exist at this early stage of

infection that might explain rheumatogenicity.

Macrophages are part of the cellular infiltrate in acute

valvular disease in ARF, which implies their involvement in

the pathogenesis of the disease.94 Investigation of murine

peritoneal macrophages after in vivo peritoneal injection of

group A streptococci revealed a gene expression pattern thatdid not contain all components of either the classic or the

alternative pathway of macrophage activation, although it

reflected both.123 Upregulation of phagocyte oxidase led the

authors to propose that this might mediate phagocytic killing

of the bacteria, which was confirmed in subsequent experi-

ments with knockout mice. Animal arthritis models have been

used to investigate inflammatory and autoimmune processes.

In a study in which cell-wall antigen from group A strepto-

cocci was injected into rat joints in vivo, analysis of total

RNA from the synovial fluid showed upregulation of genes

involved in chemotaxis and the inflammatory response.124 In

addition, 10 genes were upregulated that had not previously

been associated with arthritis, and these were found to map to

genomic loci associated with autoimmune diseases, such as

systemic lupus erythematosus and multiple sclerosis. Al-

though these studies provide tantalizing clues to pathogen-

esis and autoimmunity, to date, no studies have been

published that have used microarrays to investigate ARF or

RHD.41,43,44,49,51,54 –56,62,65,82,100,101

The series of immunologic events that occur in a suscep-

tible individual when infected with rheumatogenic group A

streptococci but do not occur in a nonsusceptible individual

remain to be fully delineated. Future research should include

large studies in multiethnic populations, particularly in mi-

gratory populations, of the association between the variousgenes and markers described in the present review, to

determine whether associations are primarily genetic or

geographic. In addition, it would be revealing to use global

genome analysis to investigate ARF and to determine how

host responses differ between individuals who are susceptible

and nonsusceptible. These types of studies would provide

insight into the multiple genes and other susceptibility factors

that are involved in the interplay between rheumatogenic

bacteria and the host immune system that leads to the aberrant

autoimmune response underlying the immunopathogenesis

of ARF.

Sources of FundingThis work was supported by a grant from the National Heart

Foundation of Australia and the Australian National Health and

Medical Research Council. Dr Bryant was the recipient of a

European Society of Pediatric Infectious Diseases Fellowship Award

and a University of Melbourne Research Scholarship.

DisclosuresNone.

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Penelope A. Bryant, Roy Robins-Browne, Jonathan R. Carapetis and Nigel CurtisSome of the People, Some of the Time: Susceptibility to Acute Rheumatic Fever

Print ISSN: 0009-7322. Online ISSN: 1524-4539Copyright © 2009 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation

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