Rheumatic Fever and Rheumatic Heart Disease

C H A P T E R

63 Rheumatic Fever and Rheumatic Heart Disease Luiza Guilherme1,2 and Jorge Kalil1,2,3 1

Heart Institute (InCor), School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil 2Immunology Investigation Institute, National Institute for Science and Technology, University of Sa˜o Paulo, Sa˜o Paulo, Brazil 3Clinical Immunology and Allergy Division, School of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, Brazil

O U T L I N E Clinical, Pathological, and Epidemiologic Features

1255

Autoimmune Features

1257

Genetic Features 1258 Innate Immune Response 1260 Adaptive Immune Response 1260 Major Histocompatibility Complex: DRB1, DRB3, DQB1, DQA1 Genes 1261 Both Innate and Adaptive Immune Response 1261

In Vivo and In Vitro Models In Vivo Model of Myocarditis and Valvulitis In Vitro Model of Rheumatic Heart Disease Autoimmune Reactions

1262 1262

Pathologic Effector Mechanisms

1263

Autoantibodies as Potential Immunologic Markers

1264

Concluding Remarks—Future Prospects

1265

References

1265

1262

CLINICAL, PATHOLOGICAL, AND EPIDEMIOLOGIC FEATURES The clinical profile of rheumatic fever (RF) was first described by Cheadle in 1889, and the manifestation of the disease follows defined criteria established by Jones in 1944, which were updated in 1992 and remain useful today (Dajani et al., 1992). Briefly, the disease follows an untreated Streptococcus pyogenes infection in children and teenagers that present some genetic factors that predispose to the diverse clinical manifestations. The diagnosis is made in a clinical basis. The major manifestations include polyarthritis, carditis, chorea, subcutaneous nodules, and erythema marginatum. The minor manifestations are fever, arthralgia (clinical), and prolonged PR interval, increased erythrocyte sedimentation rate, and presence of C-reactive protein. Polyarthritis and carditis are the most frequent manifestations of the disease and occur in around 70% of the children. Arthritis is one of the earliest and most common features of the disease, present in 60% 80% of the patients. It usually affects the peripheral large joints; small joints and the axial skeleton are rarely involved. Knees, ankles, elbows, and wrists are most frequently affected. The arthritis is usually migratory and very painful. Carditis is the most serious manifestation of the disease, occurring a few weeks after the infection, and usually present as a pancarditis. Endocarditis is the most severe sequel and frequently leads to chronic rheumatic heart disease (RHD). Mitral and aortic regurgitation (AR) are the most common events caused by valvulitis. Sydenham’s chorea is less common (30% 40%) characterized by involuntary movements, especially of the face

The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00063-4

1255

Copyright © 2020 Elsevier Inc. All rights reserved.

1256

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

and limbs, muscular weakness, and disturbances of speech, gait, and voluntary movements. It is usually a delayed manifestation, and often the sole manifestation of acute RF. Other manifestations such as subcutaneous nodules and erythema marginatum can also occur during RF episodes and are characterized by nodules on the surface of joints and skin lesions, respectively (Mota et al., 2009). S. pyogenes, or group A streptococci, was identified in 1941 by Rebecca Lancefield through serology based on its cell wall polysaccharide that is composed by carbohydrates such as N-acetyl-β-D-glucosamine linked to a polymeric rhamnose backbone. Group A streptococci contain M, T, and R surface proteins and lipoteichoic acid, involved in bacterial adherence and invasion to throat epithelial cells (Fig. 63.1). The M protein, which extends from the cell wall, is composed by two polypeptide chains with approximately 450 amino acid residues, in an alpha-helical coiled-coil configuration. The amino-terminal (N-terminal) portion is composed by two regions, A and B, which present variable numbers of amino acid residues. The A region shows high polymorphism and defines the different M types, currently more than 225 according to CDC (Centers for Disease Control and Prevention; http://www.cdc.gov/ncidod/biotech/strep/strepblast.htm). These M types were more recently grouped in 48 emm-clusters based on their structural and binding properties. The C-terminal portion (regions C and D) is highly conserved (Smeesters et al., 2010). Epidemiological studies indicate the emm1, emm 12, and emm 28 as the most common emm types found in both high- and low-income countries (Steer et al., 2009b). It is interesting to note that some strains are predominant in different regions of the world (Table 63.1) and could be related with population migrations and genetic background (Arya et al., 2014; Areˆas et al., 2014; Baroux et al., 2014; Boyd et al., 2016; Dundar et al., 2010; Engel et al., 2014; Espinosa et al., 2003; Freschi de Barros et al., 2015; Fria˜es et al., 2012; Hraoui et al., 2011; Imo¨hl et al., 2010; Koutouzi et al., 2015; Lindsay et al., 2016; Lopardo et al., 2005; Luca-Harari et al., 2008; Ma et al., 2009; Meisal et al., 2010; O’Brien et al., 2002; O’Grady et al., 2007; Rogers et al., 2007; Seale et al., 2016; Shea et al., 2011; Shulman et al., 2009; Smeesters et al., 2006; Steer et al., 2009a; Tamayo et al., 2014; Tanaka et al., 2016; Tapia et al., 2015; Tartof et al., 2010; Turner et al., 2016; Williamson et al., 2014). The incidence of ARF in some developing countries exceeds 50 per 100,000 children. The worldwide incidence of RHD is of at least 15.6 million cases and the major cause of around 233,000 deaths/year. However, since these estimates are based on conservative assumptions, the actual disease burden is probably substantially higher. The incidence of ARF can vary from 0.7 to 508 per 100,000 children per year in different populations from several countries (Carapetis et al., 2005). More recently, it was showed that the prevalence of RHD varied from less than 50,000 cases to more than 8,000,000 depending on the region of the world (Carapetis et al., 2016). In Brazil, according to the WHO epidemiological model and data from IBGE (Brazilian Institute of Geography and Statistics), the number of Streptococcal pharyngitis infections is around 10 million cases, which could lead to 30,000 new cases of RF, of which around 15,000 could develop to cardiac lesions (Barbosa and Mu¨ller, 2009).

FIGURE 63.1 Streptococcus pyogenes throat colonization. S. pyogenes (red) invasion and adherence into throat epithelial cells leads to colonization and invasion into human pharynx cells. Source: Image obtained by emission scanning EM, kindly provided by Prof. Dr M. Rhode, HZI, Braunschweig, Germany.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1257

AUTOIMMUNE FEATURES

TABLE 63.1 Streptococcus pyogenes Distribution Around the World References North America

Canada: 1, 2, 3, 4, 6, 12, 28, 77, 89

Shea et al. (2011)

United States: 1, 2, 3, 4, 12, 28

Espinosa et al. (2003) Shulman et al. (2009) O’Brien et al. (2002)

Europe/United Kingdom

Africa

South America

Mexico: 1, 2, 3, 4, 12, 75, 77

Espinosa et al. (2003)

Norway: 1, 3, 4, 12, 28, 82

Meisal et al. (2010)

Denmark: 1, 3,12, 28, 89

Luca-Harari et al. (2008)

Germany: 1, 3, 4, 12, 28, 89

Imo¨hl et al. (2010)

Scotland: 1, 4, 12, 28,76, 89

Lindsay et al. (2016)

England: 1, 3, 4, 12, 28, 89

Turner et al. (2016)

Portugal: 1, 3, 4, 6, 12, 28, 89

Fria˜es et al. (2012)

Spain: 1, 3, 4, 6, 12, 75, 89

Tamayo et al. (2014)

Greece: 1, 3, 4, 12, 77, 89

Koutouzi et al. (2015)

Tunisia: 1, 28, 42, 76, 103, 118, st432

Hraoui et al. (2011)

Mali: 18, 25, 42, 55, 58, 65, 109

Tapia et al. (2015)

Kenya: 8, 11, 18, 44, 65, 90, stg866

Seale et al. (2016)

South Africa: 1, 4, 12, 48, 75, 89

Engel et al. (2014)

Brazil: 1, 4, 6, 8, 12, 22, 49, 53, 58, 66, 77, 83, 87, 183

Areˆas et al. (2014) Freschi de Barros et al. (2015) Smeesters et al. (2006) Tartof et al. (2010)

Asia

Oceania

Argentina: 12, 75, 82, 87

Lopardo et al. (2005)

China: 1, 4, 12, 75

Ma et al. (2009)

Japan: 1, 4, 12, 75, 89

Tanaka et al. (2016)

India: 1, 8, 15, 42, 48, 49

Arya et al. (2014)

Turkey: 1, 4, 12, 77, 89

Dundar et al. (2010)

Australia: 1, 3, 4, 12, 22, 28, 44, 75, 81, 92, 113, 197

Boyd et al. (2016) O’Grady et al. (2007) Rogers et al. (2007)

New Zealand: 1, 3, 4, 12, 22, 28, 75, 89

Williamson et al. (2014)

Fiji Island: 1, 12, 22, 28, 75, 89

Steer et al. (2009)

New Caledonia: 1, 25, 76, 95

Baroux et al. (2014)

AUTOIMMUNE FEATURES RHD is the most serious complication of RF and depends on several host factors that mediate a heart tissue driven autoimmune response triggered by a defensive immune response against S. pyogenes. Genetic predisposition is one of the leading factors contributing to the development of autoimmunity. In the last 5 years, using molecular biology tools, several new single-nucleotide polymorphisms (SNPs) of genes

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1258

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

FIGURE 63.2 Acute phase rheumatic lesions (A and B) and cultured intralesional T lymphocytes. (A) Mitral valve surgical fragment obtained from a RHD patient, with verrucae lesions (arrows). (B) Immunohistochemistry of myocardium exhibiting Aschoff bodies, granulomatous structures with mononuclear cells infiltration (circle). Magnification: 200 3 . (C) In vitro proliferation of infiltrating T CD41 isolated from rheumatic lesions. Magnification: 200 3 .

involved with the activation of both innate and adaptive immune responses were associated to the development of RF/RHD (see the “Genetic features” section). The first genetic associations described in the 1980s focused on human leukocytes antigens (HLA) class II alleles coded by HLA-DRB1 and DQB1 genes. The HLA class II molecules are expressed in the surface of antigen-presenting cells (APCs), for example, macrophages, dendritic cells, and B lymphocytes and trigger the activation of the immune system. In the case of RF/RHD, T-cell populations activated upon specific self-antigen stimulation will trigger autoimmune reactions. The production of several inflammatory cytokines will perpetuate the heart tissue damage. These observations are corroborated by the fact that during the acute phase of disease, Aschoff bodies, a granulomatous lesion containing macrophages, Anitschkow cells, multinucleated cells, and polymorphonuclear leukocytes develop in the myocardium and/or endocardium of RHD patients. Inflammatory cytokines such as IL-1, TNFα, and IL-2 have been found, depending on the developmental phase of the Aschoff bodies (Fraser et al., 1997) and as mentioned above, probably initiate the inflammatory process leading to heart tissue rheumatic lesions. More recently, other molecules were described involved with the inflammatory process such as integrins and chemokine and cytokines such as IFNγ, IL-23, and IL-17 that play a role in the recruitment of both T and B lymphocytes leading to the autoimmune reactions observed in rheumatic heart lesions (reviewed by Guilherme et al., 2011b) (Guilherme et al., 2011a). T and B lymphocytes react against self-antigens through molecular mimicry, first in the periphery and later in the heart tissue. The mechanisms of T-cell receptor (TCR) degeneracy and epitope spreading amplify the autoimmune reactions (see the “Pathologic effector mechanisms” section). All these steps are represented in Fig. 63.2.

GENETIC FEATURES RF and RHD occur in 1% 5% of the untreated children with genetic predisposition. The disease is associated with several genes, some of which are related to the innate or adaptive immune response or both (Table 63.2) (Azevedo et al., 2010; Beltrame et al., 2014; Berdeli et al., 2005, 2006; Catarino et al., 2014; Chou et al., 2004; Col-Araz et al., 2013; Du¨zgu¨n et al., 2009; Guilherme and Kalil, 2010; Herna´ndez-Pacheco et al., 2003b; Hirsch et al., 1996; Kamal et al., 2010; Messias Reason et al. 2006, 2009; Ramasawmy et al., 2007, 2008; Sallakci et al., 2005; Settin et al., 2007).

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1259

GENETIC FEATURES

TABLE 63.2 Immune response

Genetic Polymorphism Associated With Development of Rheumatic Fever (RF)/Rheumatic Heart Disease (RHD) Gene

Chromosome localization

Allele/Genotype/Haplotype associated with disease

Clinical picture

Population studied

A (52C, 54G, 57G), O (52T, 54A, 57A)

YA/YA, YA/XA

RHD MS

Brazilian

Messias Reason et al. (2006)

A (52C, 54G, 57G), O (52T, 54A, 57A)

O, O/O

RHD AR

Brazilian

Ramasawmy et al. (2008)

753Gln, Arg753Gln

ARF

Turkish

Berdeli et al. (2005)

RHD

Brazilian

Messias Reason et al. (2006)

Polymorphism

References

2221 X,Y Innate

MBL2

10q11.2-q21

TLR2

4q32

2258A/G (753 Arg/ Gln)

FCN2

9q34

2986G/A, 2602G/A, G/G/A 24G/A

Beltrame et al. (2014)

Adaptive

Both innate and adaptive

MIF

22q11-23

2173G/C

173C/C

RF

Turquish

Col-Araz et al. (2013)

MASP2

1p36.23-31

p.371D, p.377V, p.439R

AG

RHD

Brazilian

Catarino et al. (2014)

FCγRIIA 1q21-q23

494A/G (131H/R)

131R, R/R (high risk), R/H (intermediate risk)

ARF

Turkish

Hirsch et al. (1996)

MHC

6p21.31

DRB1, DRB3, DQB1, DQA1

Several alleles

RF/RHD

Several

Guilherme and Kalil (2010)

CTLA4

2q33.2

149A/G

G/G

RHD

Turkish

Du¨zgu¨n et al. (2009)

TNFα

6p21.3

2308G/A

A

RHD

Mexican

HernandezPacheco et al. (2003b)

A/A, G/G

RHD MVL, MVD

Egyptian

Sallakci et al. (2005)

A

ARF/RHD

Brazilian

Ramasawmy et al. (2007)

A

ARF/RHD

Turkish

Berdeli et al. (2006)

G, G/G

RHD

Mexican

HernandezPacheco et al. (2003b)

A

ARF/RHD

Brazilian

Ramasawmy et al. (2007)

A1/A1

RHD

Egyptian

Settin et al. (2007)

A1, A1/A1

RHD

Brazilian

Azevedo et al. (2010)

2509C/T

T, T/T

RHD

Egyptian

Kamal et al. (2010)

869T/C

C/C

RHD

Egyptian

Chou et al. (2004)

21082G/A

G/G

RHD MVD

Egyptian

Settin et al. (2007)

A/A

RHD MVL

Egyptian

Settin et al. (2007)

2238G/A

IL1RA

TGFβ1

IL-10

2q14.2

19q13.1

1q31-q32

A1, A2, A3, A4

AR, Aortic regurgitation; ARF, acute rheumatic fever; CTLA4, cytotoxic T cell Lymphocyte antigen 4, FCN2, ficolin 2; FCγRIIA, IgG Fc receptor; IL-1RA, IL-1 receptor antagonist; MASP2, mannan-binding lectin serine protease; MASP 2, mannan-binding lectin; MBL, mannan-binding lectin; MHC, major histocompatibility complex; MIF, macrophage inhibitory factor; MS, mitral stenosis; MVD, mitral valve disease; MVL, multivalvular lesions; RHD, rheumatic heart disease; TGFß, transforming growth factor beta; TLR2, toll-like receptor 2; TNFα, tumor necrosis factor alpha.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1260

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

In order to facilitate the comprehension of the role of implicated genes, known up to now, we describe the associated genes/alleles based on their role.

Innate Immune Response MBL2 Gene MBL (mannan-binding lectin) is an acute phase inflammatory protein and functions as a soluble pathogen recognition receptor. It binds to a wide variety of sugars on the surface of pathogens and plays a major role in innate immunity due to its ability to opsonize pathogens, enhancing their phagocytosis and activating the complement cascade via the lectin pathway (Jack et al., 2001). Different variants of the promoter and exon 1 regions of the MBL2 gene, which encodes MBL, have been reported in patients with RF/RHD. Interestingly, the A allele that codes for high production of MBL was associated with the development of mitral stenosis (MS) and most of these patients presented high serum levels of MBL (Messias Reason et al., 2006). In contrast, RHD patients with AR presented the O allele that codes for low production of MBL, and the patients presented low serum levels of MBL (Ramasawmy et al., 2008). TLR-2 Gene Toll-like receptors (TLRs) are sensors of foreign microbial products, which initiate host defense responses in multicellular organisms. A polymorphism of TLR-2 at codon 753 generally leads to the replacement of arginine to glutamine. The genotype 753 Arg/Gln was more frequent in a Turkish ARF cohort when compared to controls (Berdeli et al., 2005). Ficolin Gene Ficolin trigger the innate immune response by either binding collectin cellular receptors or initiating the complement lectin pathway (Beltrame et al., 2014; Messias-Reason et al., 2009). In Brazilian chronic RHD patients, with prolonged time of infection or repeated streptococcal infections, the haplotype G/G/A (-986/-602/-4) was found to be more frequent than in controls and was also correlated with low expression levels of this protein. FcγRIIA Gene The protein plays a role in the clearance of immune complexes by macrophages, neutrophils, and platelets (Hirsch et al., 1996). ARF patients presented histidine (H) in the codon 131, which typically encodes for arginine (A), consequently RF/RHD patients present a protein with low binding capacity to the immune complex, favoring the inflammatory response. Masp2 Gene MBL-associated serine protease (Masp) results from this gene. It is a protease that plays a role during innate immune response process through recognition of the pathogen and complement activation. Three polymorphisms (p.371D, p.377V and p.439R) increase the susceptibility to develop RHD (Catarino et al., 2014). MIF Gene This gene codes for a macrophage inhibitory factor (MIF), expressed in monocytes/macrophages and other type of cells and tissues and has been associated with several inflammatory diseases (Col-Araz et al., 2013). A significant increase in the frequency of MIF-173CC genotype was found in children with RF (Col-Araz et al., 2013).

Adaptive Immune Response The HLA system is located in the short arm of the human chromosome 6 and codes for diverse proteins; it is considered the most polymorphic system, composed by several genes with several alleles. The class I proteins are present in all nucleated cells; however, the class II are expressed only in specialized cells of the immune system (B lymphocytes, activated T lymphocytes, monocytes/macrophages, and dendritic cells). These proteins are involved with antigen recognition and presentation of self and foreign (microbes) antigens.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

GENETIC FEATURES

1261

Major Histocompatibility Complex: DRB1, DRB3, DQB1, DQA1 Genes Several HLA class II alleles were described in association with RF/RHD. Patarroyo et al. (1979) described an alloantigen on the surface of B cells, designated 883, probably related to the HLA class II molecules, which was present in a high frequency in RF patients. Later, a monoclonal antibody (D8/17 MoAb) was produced against B cells from RF patients bearing the 883 alloantigen. Studies performed by Zabriskie et al., (1985) showed an increased frequency of this alloantigen in RF patients. The susceptibility of developing RF/RHD was first associated with the alleles of HLA class II genes (DRB1, DRB3, DQB, and DQA), which are located on human chromosome 6. Briefly, HLA-DR7 was the allele most consistently associated with RF (Guilherme et al., 1991; Gue´dez et al., 1999; Ozkan et al., 1993; Stanevicha et al., 2003; Visentainer et al., 2000; Weidebach et al., 1994). In addition the association of DR7 with different DQB or DQA alleles seems to be related with the development of multiple valvular lesions (MVL) or mitral valve regurgitation in RHD patients (Gue´dez et al., 1999; Stanevicha et al., 2003). HLA-DR53 coded by the DRB3 gene is another HLA class II molecule in linkage disequilibrium with HLA-DR4, DR7, and DR9. This allele was strongly associated with RF/RHD in two studies with Mulatto Brazilian patients (Guilherme et al., 1991; Weidebach et al., 1994), but not in Brazilian Caucasian patients (Visentainer et al., 2000). Although DR53 has not been described in previous studies, DR4 and DR9 were associated with RF in American Caucasian and Arabian patients (Ayoub, 1984; Rajapakse et al., 1987), whereas in Egyptian and Latvian patients, DR7 was associated with the disease (Gue´dez et al., 1999; Stanevicha et al., 2003) (Table 63.1). In Japanese RHD patients, susceptibility to MS seems to be in part controlled by the HLA-DQA gene or by genes in close disequilibrium linkage with HLA-DQA 0104 and DQB1 05031 (Koyanagi et al., 1996). HLA-DQA 0501 DQB 0301 with DRB1 1601 (DR2) were associated with RHD in a Mexican Mestizo population (Herna´ndez-Pacheco et al., 2003a). The molecular mechanism by which MHC class II molecules confers susceptibility to autoimmune diseases is not clear. However, since the role of HLA molecules is to present antigens to the TCR, it is probable that the associated alleles facilitate the presentation of some streptococcal peptides that will later trigger autoimmune reactions mediated by molecular mimicry mechanisms. CTLA4 Gene This gene is an essential inhibitor of T-cell responses. It is a strong candidate susceptibility gene in autoimmunity, and several studies suggest disease-associated polymorphisms (reviewed by Gough et al., 2005).

Both Innate and Adaptive Immune Response More recently, with new technologies that have allowed the description of gene variability by SNPs, other associations have been established that could clarify some reactions related with both innate and adaptive immune response leading the autoimmune reactions in RF/RHD. • TNF-α gene, also located in the chromosome 6, between HLA class I and II genes, codes for a proinflammatory cytokine that plays a role during the S. pyogenes infection and later in the inflammatory process in the valves. Polymorphisms at -308G/A and -238G/A were associated with the susceptibility of RHD patients from several countries (Berdeli et al., 2006; Herna´ndez-Pacheco et al., 2003b; Ramasawmy et al., 2007; Sallakci et al., 2005). • IL-10 gene is responsible for the production of IL-10, an antiinflammatory cytokine. The genotype -1082G/A, misrepresented in RHD patients, is apparently associated with the development of MVL and with the severity of RHD (Settin et al., 2007). • TGF-B1 is a gene that controls the proliferation and differentiation of cells. The polymorphism of both the SNPs 869T and -509T alleles were considered possible risk factors for the development of valvular RHD lesions in Egyptian and Taiwan RHD patients (Chou et al., 2004; Kamal et al., 2010). • IL-1Ra gene, for which the most frequent alleles are 1 and 2, encodes the antagonist of IL-1α and IL-1β, which are inflammatory cytokines. Two studies in Brazilian and Egyptian RHD patients with severe carditis showed low frequencies of allele 1, suggesting lack of inflammatory control (Azevedo et al., 2010; Settin et al., 2007).

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1262

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

IN VIVO AND IN VITRO MODELS In Vivo Model of Myocarditis and Valvulitis Humans are unique hosts for S. pyogenes infections. However, several studies have been performed to determine a suitable animal model, and numerous different species (mice, rats, hamsters, rabbits, and primates) have been tested for the development of autoimmune reactions that resemble those observed in RF/RHD patients (Unny and Middlebrooks, 1983), all with little success. In the last decade a model that appears to be useful for the study of RF/RHD has been developed with Lewis rats. These rats have already been used to induce experimental autoimmune myocarditis and to study the pathogenesis of RF/RHD (Li et al., 2004). Immunization of Lewis rats with recombinant M6 protein induced focal myocarditis, myocyte necrosis, and valvular heart lesions in three out of six animals. The disease in these animals included verruca-like nodules and the presence of Anitschkow cells, which are large macrophages (also known as caterpillar cells), in mitral valves. Lymph node cells from these animals showed a proliferative response against cardiac myosin, but not skeletal myosin or actin. A CD41 T-cell line responsive to both the M protein and cardiac myosin was also obtained. Taken together, these results confirmed the cross-reactivity between the M protein and cardiac myosin triggered by molecular mimicry, as observed in humans, possibly causing a break in tolerance and consequently leading to autoimmunity (Quinn et al., 2001). In another study done by the same group, Lewis rats were immunized with a pool of synthetic peptides from the conserved region of the M5 protein. Mononuclear spleen cells from these animals were able to proliferate in response to peptides from both the C-terminal region of M5 protein and the N-terminal region of a heterologous protein (M1) and myosin. These rats developed a focal infiltration of mononuclear cells predominantly in the aortic valve, although no evidence of Aschoff bodies, the hallmark of RF lesions, or Anitschkow cells was observed (Lymbury et al., 2003). Another study immunized Lewis rats with recombinant M5 or synthetic peptides from the B- and C-regions of group A streptococcus (GAS) M5 (Gorton et al., 2009). Sera and T cells from these animals recognized a peptide (M5-B.6) from the B repeat of the N-terminal portion of M5 protein and induced heart lesions (Gorton et al., 2010), confirming the previous results. The immunized rats (five out of seven) developed mononuclear cell infiltration in the myocardial or valvular tissue. Histopathological analysis of valve lesions showed the presence of both CD41 T cells and CD681 macrophages (Gorton et al., 2010), consistent with human studies (Guilherme et al., 1995). Altogether, these studies indicated that the Lewis rats could be a model of autoimmune valvulitis. In the last decade, however, other animal models as mice and guinea pig were also used by several researchers and appear to be also useful as experimental models of RF/RHD as reviewed by Rush et al. (2014).

In Vitro Model of Rheumatic Heart Disease Autoimmune Reactions The major sequels of RF are heart tissue lesions that lead to chronic RHD, which is characterized by permanent valvular lesions. The heart disease starts by pericarditis, followed by myocarditis episodes in which the healing process results in varied degrees of valvular damage (Mota et al., 2009). By isolating infiltrating T lymphocytes from damaged valvular tissue, we could establish the mechanism by which the immune response in the heart leads to autoimmune reactions (Guilherme et al., 1995). Fig. 63.2 shows a damaged mitral valve in which verrucae lesions are observed, indicative of an acute RF episode. Furthermore, the presence of Aschoff bodies in the myocardium tissue allowed for histological diagnosis of an active episode of rheumatic disease. In vitro tissue culture of small pieces of the surgical fragment allowed to the isolation of infiltrating T cells. The in vitro analysis of these tissue-infiltrating T cells showed their ability to recognize several streptococcalM protein peptides and self-antigens by molecular mimicry mechanisms. We identified some mitral valve derived proteins such as vimentin, PDIA3 (protein disulfide isomerase ER-60 precursor) and HSPA5 (78 kDa glucose-regulated protein precursor) that were recognized by both peripheral and intralesional T-cell clones (Fae´ et al., 2008). The identification of heart-M protein cross-reactive T cell clones directly from rheumatic valvular lesions established their involvement in the pathogenesis of the disease.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

PATHOLOGIC EFFECTOR MECHANISMS

1263

PATHOLOGIC EFFECTOR MECHANISMS The term of “molecular mimicry” was introduced in 1964 by Damian to define the mechanism by which selfantigens are recognized after an infection by cross-reactivity (Damian, 1964). Pathogen and self-antigens can be recognized by T lymphocytes and antibodies through molecular mimicry by four different mechanisms. They can recognize (1) identical amino acid sequences, (2) homologous but nonidentical sequences, (3) common or similar amino acid sequences of different molecules (proteins, carbohydrates), and (4) structural similarities between the microbe or environmental agent and its host (Peterson and Fujimani, 2007). RF/RHD is the most convincing example of molecular mimicry in human pathological autoimmunity, in light of the cross-reactions between streptococcal antigens and human tissue proteins, mainly heart tissue proteins that follow throat infection by S. pyogenes in susceptible individuals. The inflammatory process that follows a S. pyogenes throat infection in individuals with genetic predisposition leads to intense cytokine production by monocytes and macrophages that trigger the activation of B and T lymphocytes. Several heart-reactive antibodies, first described from 1945 (reviewed by Cunningham, 2000 and Guilherme et al., 2011b) (Guilherme et al., 2011a), also play a role in the development of the disease. Streptococcal and heart tissue cross-reactive antibodies activate the heart tissue valvular endothelial cells increasing the expression of adhesion molecules such as VCAM1, which facilitates cellular infiltration by neutrophils, monocytes, B and T cells (Ye˘gin et al., 1997). The “rolling” of leukocytes through vessels is triggered by chemokines expressed by activated endothelial cells that induce the expression of integrins, selectins, and subsequent transendothelial migration. Recently, we identified increased expression of intercellular adhesion molecule (ICAM), another adhesion molecule, a few chemokines (CCL-1, CCL-3, and CCL9) (Fae´ et al., 2013) as well as some integrins (P- and E-selectins and) in the myocardium and valvular tissue of RHD patients. All of these molecules are involved with the inflammatory process and T and B lymphocytes infiltration leading to rheumatic valvular tissue damage. CD41 infiltrating T cells are predominant in the heart rheumatic lesions (Kemeny et al., 1989; Raizada et al., 1983), and the first evidence of the molecular mimicry between streptococcus and heart tissue was obtained through an analysis of these heart tissue infiltrating T cells. Three immunodominant regions of the M5 protein (residues 1-25, 81-103, and 163-177), heart tissue proteins (myocardium and valve-derived proteins, as well as vimentin), and synthetic peptides of the beta chain of cardiac myosin-light meromyosin region (LMM) were recognized by cross-reactivity by intralesional T-cell clones (Ellis et al., 2005; Fae´ et al., 2006; Guilherme et al., 1995, 2001). Peripheral T-cell clones also recognized human-purified myosin, tropomyosin, laminin, and cardiac myosin-derived peptides from LMM and S2 regions (Guilherme et al., 1995). Employing a proteomics approach, we characterized a number of mitral valve proteins identified by molecular weight and isoelectric point (pI). Four valve-derived proteins with molecular masses ranging between 52 and 79 kDa and different pI cross-reacted with the M5 immunodominant peptides and were recognized in proliferation assays by intralesional T-cell clones from patients with severe RHD. Vimentin was one of the identified proteins, a result that reinforces the role of this protein as a putative autoantigen involved in the rheumatic lesions. Novel heart tissue proteins were also identified, including disulfide isomerase ER-60 precursor (PDIA3) protein and a 78-kDa glucose-regulated protein precursor (HSPA5). The role of PDIA3 in RHD pathogenesis and other autoimmune diseases is not clear (Table 63.3) (Fae´ et al., 2008). A mass spectrometry analysis allowed the identification of several valve proteins that suffered expression alterations probably due to the autoimmune process. Briefly, we identified abundant expression of two isoforms of vimentin (45 and 42 kDa) with reduced expression of the full size of protein (54 kDa). Vitronectin was other altered protein that presented increased expression and reduced collagen VI expression (Martins et al., 2014). Immunohistochemical analysis of their distribution in valve tissue lesions was also analyzed, and a disorganized distribution of these proteins in RHD valves was found and correlates with clinical manifestations such as valve regurgitation or stenosis. Confocal microscopy analysis revealed a diverse pattern of distribution of collagen VI and lumican into RHD and myxomatous degeneration (MXD) valves (Martins et al., 2014). The analysis of the TCRs of autoreactive T lymphocytes that infiltrate both myocardium and valves allowed us to evaluate the Vβ chains usage of TCR and the degree of clonality of heart tissue infiltrating T cells (Guilherme et al., 2000). In the heart tissue (myocardium and valves) of both chronic and acute RHD patients, several expanded T-cell populations with an oligoclonal profile were found. Such oligoclonal expansions were identified by TCRs analyses (Guilherme et al., 2000). The finding of oligoclonal T-cell populations is in contrast with the peripheral blood scenario, which contains polyclonal TCR-BV families. The fact that a high number of

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1264

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

TABLE 63.3 Mitral Valve Proteins Identified by 2-D Gel Electrophoresis and Mass Spectrometry Analysis Recognized by Peripheral and Intralesional T Cells Protein

Accession number

Coverage (%)

Masses matched/total

MW/pI

Vimentin

P08670

34

20/23

53.0/5.4 53.7/5.1

Vimentin

P08670

49

23/87

51.0/5.9

PDIA3 Protein disulfide isomerase ER-60 precursor

P30101

45

19/92

56.0/6.7 56.0/6.0

HSPA5 78 kD glucose-regulated protein precursor

P11021

43

27/69

68.0/5.9

MW, molecular weight; pI, isoelectrical point; coverage (%), percentage of matched peptides identification in terms of amino acid residues. Adapted from Fae´, K.C., Diefenbach da Silva, D., Bilate, A.M., Tanaka, A.C., Pomerantzeff, P.M., Kiss, M.H., et al., 2008. PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients. J. Autoimmun., 31(2), 136 141.

T-cell oligoclonal expansions could be found in the valvular tissue indicates that specific and cross-reactive T cells migrate to the valves and proliferate upon specific cytokine stimulation at the site of the lesions (Guilherme et al., 2000). Cytokines are important secondary signals following an infection because they trigger effective immune responses in most individuals and probably deleterious responses in patients with autoimmune diseases. Three subsets of T helper cytokines are currently described. Antigen-activated CD41 T cells polarize to the Th1, Th2, or Th17 subsets, depending on the cytokine secreted. Th1 is involved with the cellular immune response and produces IL-2, IFNγ, and TNFα. Th2 cells mediate humoral and allergic immune responses and produce IL-4, IL-5, and IL-13. Another lineage of CD41 T cells, namely Th17 cells, produces a set of cytokines identified as IL-17, TGFβ, IL-6, and IL-23, and this subset of cells is involved with inflammatory reactions and in association with several autoimmune diseases (Volin and Shahrara, 2011). In RHD, in both myocardium and valvular tissue, we found large numbers of infiltrating mononuclear cells secreting the inflammatory cytokines IFNγ and TNFα. However, mononuclear cells secreting IL-10 and IL-4, which are regulatory cytokines, were also found in the myocardium tissue; nonetheless, in the valvular tissue, only a few cells secrete IL-4, suggesting that low numbers of IL-4-producing cells may contribute to the progression of valvular RHD lesions (Guilherme et al., 2004). Increased numbers of Th17 cells in peripheral blood were found in a cohort of RHD patients from Turkey, in which high levels of IL-17A cytokine in the sera were observed (Bas et al., 2014). We also identified large numbers of IL-17- and IL-23-producing cells in both myocardium and valvular endothelium of RHD, confirming that Th17 cells also play an important role in the inflammatory process in RHD heart lesions.

AUTOANTIBODIES AS POTENTIAL IMMUNOLOGIC MARKERS Several streptococcal and human cross-reactive antibodies have been found in the sera of RF patients and immunized rabbits and mice over the last 60 years and have been recently reviewed (Carapetis et al., 2016). N-Acetyl-β-D-glucosamine that is present in both the streptococcal cell wall and heart valvular tissue is one of the major targets of the humoral response in RF/RHD, and antibodies against this polysaccharide displayed crossreactivity with laminin, an extracellular matrix alpha-helical coiled-coil protein that surrounds heart cells and is also present in the valves (Cunningham, 2000; Cunningham et al., 1989). Cardiac myosin is the most important protein in the myocardium and by using affinity purified antimyosin antibody, Cunningham’s group identified a five-amino acid residue (Gln-Lys-Ser-Lys-Gln) epitope of the N-terminal M5 and M6 proteins as being cross-reactive with cardiac myosin (Cunningham et al., 1989). The permanent rheumatic lesions that damage the valves and antibodies against vimentin, an abundant protein in the valvular tissue, probably play a role in the valvular lesions (Cunningham, 2000). In agreement with this observation the permanent rheumatic lesions that damage the valves and antibodies against vimentin, an

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

REFERENCES

1265

abundant protein in the valvular tissue, probably play a role in the valvular lesions (Cunningham, 2000). In agreement with this observation, as mentioned before, two isoforms of vimentin (45 and 42 kDa) were recently identified by proteomics approach in damaged valves probably due to the autoimmune process (Martins et al., 2014). In conclusion, antibodies against N-acetyl-β-D-glucosamine, some epitopes of cardiac myosin, vimentin, collagen, and vitronectin can be considered the immunological markers of the disease.

CONCLUDING REMARKS—FUTURE PROSPECTS RF/RHD is the most convincing example of molecular mimicry in which the response against S. pyogenes triggers autoimmune reactions with human tissues. RF/RHD lesions result from a complex network of several genes that control both innate and adaptive immune responses after a S. pyogenes throat infection. An inflammatory process permeates the development of heart lesions, in which adhesion molecules and specific chemokines facilitate the valvular-tissue infiltration by B and T cells. CD41 T lymphocytes are the prime effectors of heart lesions. Several self-antigens such as vimentin, collagen VI, vitronectin, myosin proteins, and other human targets proteins are recognized by molecular mimicry mechanism between streptococcal immunodominant peptides, particularly in individuals with genetic predisposition. The production of inflammatory cytokines (IFNγ, TNFα, IL-17, and IL-23), and low numbers of IL-4-producing cells, a regulatory cytokine, lead to local inflammation. All these information create a new scenario for the development of RHD, opening new possibilities for immunotherapy. Molecular knowledge of the autoimmune reactions mediated by antibodies and peripheral and intralesional T cells will certainly assist in the choice of streptococcal protective epitopes for the construction of an effective and safe vaccine. Anti-GAS vaccine candidates based on the M protein and other alternative streptococcal antigens, including A-CHO, C5a peptidase (SCPA), cysteine protease (Spe), binding proteins, streptococcus pili, and other antigens are under investigation as reviewed by Steer and Carapetis (2009). Briefly, a recombinant N-terminal protein candidate vaccine including the 30 most prevalent S. pyogenes serotypes in the US strains was constructed and has entered into phase I clinical trials (Dale et al., 2011). J8 is a candidate vaccine that incorporates a minimal C-terminal protective epitope and induced protective antibodies in mouse models (Batzloff et al., 2003). StreptInCor, composed of 55 amino acid residues is a vaccine epitope based on the selection of a large panel of human sera and peripheral blood cells. This epitope can undergo processing by APCs (monocytes and/or macrophages) and generates a universal, robust, and safe immune response (Guilherme et al., 2009, 2011b). Experimental assays using several animal models showed that the candidate vaccine induced high titers of opsonic, neutralizing, and protective antibodies (De Amicis et al., 2014; Postol et al., 2013). The immunogenicity and safety of the StreptInCor vaccine epitope was also evaluated for a period of 1 year in a model of HLA class II transgenic mice. Specific and nonautoreactive antibodies were produced without autoimmune or pathological reactions in the heart or other organs (Guerino et al., 2011). In conclusion, of a vaccine to protect against S. pyogenes without triggering autoimmune reactions remains a challenge. The knowledge of the mechanisms that lead to RF and/or RHD allows and favors the construction of a safe and efficacious anti-S. pyogenes vaccine.

References Areˆas, G.P., Schuab, R.B., Neves, F.P., Barros, R.R., 2014. Antimicrobial susceptibility patterns, emm type distribution and genetic diversity of Streptococcus pyogenes recovered in Brazil. Mem. Inst. Oswaldo Cruz 109 (7), 935 939. Arya, D.K., Sharma, A., Mehta, G., Dua, M., Johri, A.K., 2014. Molecular epidemiology and virulence characteristics of prevalent group A streptococci recovered from patients in northern India. J. Infect. Dev. Ctries. 8 (3), 271 281. Ayoub, E.M., 1984. The search for host determinants of susceptibility to rheumatic fever: the missing link. T. Duckett Jones Memorial Lecture. Circulation 69 (1), 197 201. Azevedo, P.M., Bauer, R., Caparbo, V. e F., Silva, C.A., Bonfa´, E., Pereira, R.M., 2010. Interleukin-1 receptor antagonist gene (IL1RN) polymorphism possibly associated to severity of rheumatic carditis in a Brazilian cohort. Cytokine 49 (1), 109 113. Barbosa, P.J.B., Mu¨ller, R.E., 2009. Diretrizes Brasileiras para o Diagno´stico, Tratamento e Prevena˜o da Febre Reuma´tica. Arquivo Brasileiro de Cardiologia, 1 18. Baroux, N., D’Ortenzio, E., Ame´de´o, N., Baker, C., Ali Alsuwayyid, B., Dupont-Rouzeyrol, M., et al., 2014. The emm-cluster typing system for Group A Streptococcus identifies epidemiologic similarities across the Pacific region. Clin. Infect. Dis. 59 (7), e84 92. Bas, H.D., Baser, K., Yavuz, E., Bolayir, H.A., Yaman, B., Unlu, S., et al., 2014. A shift in the balance of regulatory T and T helper 17 cells in rheumatic heart disease. J. Invest. Med. 62 (1), 78 83.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1266

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

Batzloff, M.R., Hayman, W.A., Davies, M.R., Zeng, M., Pruksakorn, S., Brandt, E.R., et al., 2003. Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specific antibodies to protection. J. Infect. Dis. 187 (10), 1598 1608. Beltrame, M.H., Catarino, S.J., Goeldner, I., Boldt, A.B., de Messias-Reason, I.J., 2014. The lectin pathway of complement and rheumatic heart disease. Front. Pediatr. 2, 148. Berdeli, A., Celik, H.A., Ozyu¨rek, R., Dogrusoz, B., Aydin, H.H., 2005. TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children. J. Mol. Med. (Berl.) 83 (7), 535 541. Berdeli, A., Tabel, Y., Celik, H.A., Ozyu¨rek, R., Dogrusoz, B., Aydin, H.H., 2006. Lack of association between TNFalpha gene polymorphism at position -308 and risk of acute rheumatic fever in Turkish patients. Scand. J. Rheumatol. 35 (1), 44 47. Boyd, R., Patel, M., Currie, B.J., Holt, D.C., Harris, T., Krause, V., 2016. High burden of invasive group A streptococcal disease in the Northern Territory of Australia. Epidemiol. Infect. 144 (5), 1018 1027. Carapetis, J.R., Steer, A.C., Mulholland, E.K., Weber, M., 2005. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5 (11), 685 694. Carapetis, J.R., Beaton, A., Cunningham, M.W., Guilherme, L., Karthikeyan, G., Mayosi, B.M., et al., 2016. Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Primers 2, 15084. Catarino, S.J., Boldt, A.B., Beltrame, M.H., Nisihara, R.M., Schafranski, M.D., de Messias-Reason, I.J., 2014. Association of MASP2 polymorphisms and protein levels with rheumatic fever and rheumatic heart disease. Hum. Immunol. 75 (12), 1197 1202. Chou, H.T., Chen, C.H., Tsai, C.H., Tsai, F.J., 2004. Association between transforming growth factor-beta1 gene C-509T and T869C polymorphisms and rheumatic heart disease. Am. Heart J. 148 (1), 181 186. Col-Araz, N., Pehlivan, S., Baspinar, O., Sever, T., Oguzkan-Balci, S., Balat, A., 2013. Association of macrophage migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms in acute rheumatic fever. Cardiol. Young 23 (4), 486 490. Cunningham, M.W., 2000. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13 (3), 470 511. Cunningham, M.W., McCormack, J.M., Fenderson, P.G., Ho, M.K., Beachey, E.H., Dale, J.B., 1989. Human and murine antibodies cross-reactive with streptococcal M protein and myosin recognize the sequence GLN-LYS-SER-LYS-GLN in M protein. J. Immunol. 143 (8), 2677 2683. Dajani, A., Ayoub, E., Bierman, F., Bisno, A., Denny, F., Durack, D., et al., 1992. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 update. JAMA 268 (15), 2069 2073. Dale, J.B., Penfound, T.A., Chiang, E.Y., Walton, W.J., 2011. New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci. Vaccine 29 (46), 8175 8178. Damian, R., 1964. Molecular mimicry. Antigen sharing by parasite and host and its consequences. Am. Nat. 98 (900), 21. De Amicis, K.M., Freschi de Barros, S., Alencar, R.E., Posto´l, E., Martins, C.O., Arcuri, H.A., et al., 2014. Analysis of the coverage capacity of the StreptInCor candidate vaccine against Streptococcus pyogenes. Vaccine 32 (32), 4104 4110. Dundar, D., Sayan, M., Tamer, G.S., 2010. Macrolide and tetracycline resistance and emm type distribution of Streptococcus pyogenes isolates recovered from Turkish patients. Microb. Drug Resist. 16 (4), 279 284. ˘ Du¨zgu¨n, N., Duman, T., Haydardedeoglu, F.E., Tutkak, H., 2009. Cytotoxic T lymphocyte-associated antigen-4 polymorphism in patients with rheumatic heart disease. Tissue Antigens 74 (6), 539 542. Ellis, N.M., Li, Y., Hildebrand, W., Fischetti, V.A., Cunningham, M.W., 2005. T cell mimicry and epitope specificity of cross-reactive T cell clones from rheumatic heart disease. J. Immunol. 175 (8), 5448 5456. Engel, M.E., Muhamed, B., Whitelaw, A.C., Musvosvi, M., Mayosi, B.M., Dale, J.B., 2014. Group A streptococcal emm type prevalence among symptomatic children in Cape Town and potential vaccine coverage. Pediatr. Infect. Dis. J. 33 (2), 208 210. Espinosa, L.E., Li, Z., Gomez Barreto, D., Calderon Jaimes, E., Rodriguez, R.S., Sakota, V., et al., 2003. M protein gene type distribution among group A streptococcal clinical isolates recovered in Mexico City, Mexico, from 1991 to 2000, and Durango, Mexico, from 1998 to 1999: overlap with type distribution within the United States. J. Clin. Microbiol. 41 (1), 373 378. Fae´, K.C., da Silva, D.D., Oshiro, S.E., Tanaka, A.C., Pomerantzeff, P.M., Douay, C., et al., 2006. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J. Immunol. 176 (9), 5662 5670. Fae´, K.C., Diefenbach da Silva, D., Bilate, A.M., Tanaka, A.C., Pomerantzeff, P.M., Kiss, M.H., et al., 2008. PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients. J. Autoimmun. 31 (2), 136 141. Fae´, K.C., Palacios, S.A., Nogueira, L.G., Oshiro, S.E., Demarchi, L.M., Bilate, A.M., et al., 2013. CXCL9/Mig mediates T cells recruitment to valvular tissue lesions of chronic rheumatic heart disease patients. Inflammation 36 (4), 800 811. Fraser, W.J., Haffejee, Z., Jankelow, D., Wadee, A., Cooper, K., 1997. Rheumatic Aschoff nodules revisited. II: Cytokine expression corroborates recently proposed sequential stages. Histopathology 31 (5), 460 464. Freschi de Barros, S., De Amicis, K.M., Alencar, R., Smeesters, P.R., Trunkel, A., Posto´l, E., et al., 2015. Streptococcus pyogenes strains in Sao Paulo, Brazil: molecular characterization as a basis for StreptInCor coverage capacity analysis. BMC Infect. Dis. 15, 308. Fria˜es, A., Pinto, F.R., Silva-Costa, C., Ramirez, M., Melo-Cristino, J., 2012. The Portuguese Group for the Study of Streptococcal Infections. Group A streptococci clones associated with invasive infections and pharyngitis in Portugal present differences in emm types, superantigen gene content and antimicrobial resistance. BMC Microbiol 12, 280. Gorton, D., Govan, B., Olive, C., Ketheesan, N., 2009. B- and T-cell responses in group a streptococcus M-protein- or peptide-induced experimental carditis. Infect. Immun. 77 (5), 2177 2183. Gorton, D., Blyth, S., Gorton, J.G., Govan, B., Ketheesan, N., 2010. An alternative technique for the induction of autoimmune valvulitis in a rat model of rheumatic heart disease. J. Immunol. Methods 355 (1 2), 80 85. Gough, S.C., Walker, L.S., Sansom, D.M., 2005. CTLA4 gene polymorphism and autoimmunity. Immunol. Rev. 204, 102 115. Gue´dez, Y., Kotby, A., El-Demellawy, M., Galal, A., Thomson, G., Zaher, S., et al., 1999. HLA class II associations with rheumatic heart disease are more evident and consistent among clinically homogeneous patients. Circulation 99 (21), 2784 2790. Guerino, M.T., Postol, E., Demarchi, L.M., Martins, C.O., Mundel, L.R., Kalil, J., et al., 2011. HLA class II transgenic mice develop a safe and long lasting immune response against StreptInCor, an anti-group A streptococcus vaccine candidate. Vaccine 29 (46), 8250 8256.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

REFERENCES

1267

Guilherme, L., Kalil, J., 2010. Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J. Clin. Immunol. 30 (1), 17 23. Guilherme, L., Weidebach, W., Kiss, M.H., Snitcowsky, R., Kalil, J., 1991. Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population. Circulation 83 (6), 1995 1998. Guilherme, L., Cunha-Neto, E., Coelho, V., Snitcowsky, R., Pomerantzeff, P.M., Assis, R.V., et al., 1995. Human heart-infiltrating T-cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins. Circulation 92 (3), 415 420. Guilherme, L., Dulphy, N., Douay, C., Coelho, V., Cunha-Neto, E., Oshiro, S.E., et al., 2000. Molecular evidence for antigen-driven immune responses in cardiac lesions of rheumatic heart disease patients. Int. Immunol. 12 (7), 1063 1074. Guilherme, L., Oshiro, S.E., Fae´, K.C., Cunha-Neto, E., Renesto, G., Goldberg, A.C., et al., 2001. T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect. Immun. 69 (9), 5345 5351. Guilherme, L., Cury, P., Demarchi, L.M., Coelho, V., Abel, L., Lopez, A.P., et al., 2004. Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions. Am. J. Pathol. 165 (5), 1583 1591. Guilherme, L., Postol, E., Freschi de Barros, S., Higa, F., Alencar, R., Lastre, M., et al., 2009. A vaccine against S. pyogenes: design and experimental immune response. Methods 49 (4), 316 321. Guilherme, L., Ko¨hler, K.F., Kalil, J., 2011a. Rheumatic heart disease: mediation by complex immune events. Adv. Clin. Chem. 53, 31 50. Guilherme, L., Alba, M.P., Ferreira, F.M., Oshiro, S.E., Higa, F., Patarroyo, M.E., et al., 2011b. Anti-group A streptococcal vaccine epitope: structure, stability, and its ability to interact with HLA class II molecules. J. Biol. Chem. 286 (9), 6989 6998. Herna´ndez-Pacheco, G., Aguilar-Garcı´a, J., Flores-Domı´nguez, C., Rodrı´guez-Pe´rez, J.M., Pe´rez-Herna´ndez, N., Alvarez-Leon, E., et al., 2003a. MHC class II alleles in Mexican patients with rheumatic heart disease. Int. J. Cardiol. 92 (1), 49 54. Herna´ndez-Pacheco, G., Flores-Domı´nguez, C., Rodrı´guez-Pe´rez, J.M., Pe´rez-Herna´ndez, N., Fragoso, J.M., Saul, A., et al., 2003b. Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with rheumatic heart disease. J. Autoimmun. 21 (1), 59 63. Hirsch, E., Irikura, V.M., Paul, S.M., Hirsh, D., 1996. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc. Natl. Acad. Sci. U.S.A. 93 (20), 11008 11013. Hraoui, M., Boutiba-Ben Boubaker, I., Doloy, A., Ben Redjeb, S., Bouvet, A., 2011. Molecular mechanisms of tetracycline and macrolide resistance and emm characterization of Streptococcus pyogenes isolates in Tunisia. Microb. Drug Resist. 17 (3), 377 382. Imo¨hl, M., Reinert, R.R., Ocklenburg, C., van der Linden, M., 2010. Epidemiology of invasive Streptococcus pyogenes disease in Germany during 2003 2007. FEMS Immunol. Med. Microbiol. 58 (3), 389 396. Jack, D.L., Klein, N.J., Turner, M.W., 2001. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol. Rev. 180, 86 99. Kamal, H., Hussein, G., Hassoba, H., Mosaad, N., Gad, A., Ismail, M., 2010. Transforming growth factor-beta1 gene C-509T and T869C polymorphisms as possible risk factors in rheumatic heart disease in Egypt. Acta Cardiol. 65 (2), 177 183. Kemeny, E., Grieve, T., Marcus, R., Sareli, P., Zabriskie, J.B., 1989. Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin. Immunol. Immunopathol. 52 (2), 225 237. Koutouzi, F., Tsakris, A., Chatzichristou, P., Koutouzis, E., Daikos, G.L., Kirikou, E., et al., 2015. Streptococcus pyogenes emm types and clusters during a 7-year period (2007 to 2013) in pharyngeal and nonpharyngeal pediatric isolates. J. Clin. Microbiol. 53 (7), 2015 2021. Koyanagi, T., Koga, Y., Nishi, H., Toshima, H., Sasazuki, T., Imaizumi, T., et al., 1996. DNA typing of HLA class II genes in Japanese patients with rheumatic heart disease. J. Mol. Cell Cardiol. 28 (6), 1349 1353. Li, Y., Heuser, J.S., Kosanke, S.D., Hemric, M., Cunningham, M.W., 2004. Cryptic epitope identified in rat and human cardiac myosin S2 region induces myocarditis in the Lewis rat. J. Immunol. 172 (5), 3225 3234. Lindsay, D.S., Brown, A.W., Scott, K.J., Denham, B., Thom, L., Rundell, G., et al., 2016. Circulating emm types of Streptococcus pyogenes in Scotland: 2011 2015. J. Med. Microbiol. 65 (10), 1229 1231. Lopardo, H.A., Vidal, P., Sparo, M., Jeric, P., Centron, D., Facklam, R.R., et al., 2005. Six-month multicenter study on invasive infections due to Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis in Argentina. J. Clin. Microbiol. 43 (2), 802 807. Luca-Harari, B., Ekelund, K., van der Linden, M., Staum-Kaltoft, M., Hammerum, A.M., Jasir, A., 2008. Clinical and epidemiological aspects of invasive Streptococcus pyogenes infections in Denmark during 2003 and 2004. J. Clin. Microbiol. 46 (1), 79 86. Lymbury, R.S., Olive, C., Powell, K.A., Good, M.F., Hirst, R.G., LaBrooy, J.T., et al., 2003. Induction of autoimmune valvulitis in Lewis rats following immunization with peptides from the conserved region of group A streptococcal M protein. J. Autoimmun. 20 (3), 211 217. Ma, Y., Yang, Y., Huang, M., Wang, Y., Chen, Y., Deng, L., et al., 2009. Characterization of emm types and superantigens of Streptococcus pyogenes isolates from children during two sampling periods. Epidemiol. Infect. 137 (10), 1414 1419. Martins, C. e O., Santos, K.S., Ferreira, F.M., Teixeira, P.C., Pomerantzeff, P.M., Branda˜o, C.M., et al., 2014. Distinct mitral valve proteomic profiles in rheumatic heart disease and myxomatous degeneration. Clin. Med. Insights Cardiol. 8, 79 86. Meisal, R., Andreasson, I.K., Høiby, E.A., Aaberge, I.S., Michaelsen, T.E., Caugant, D.A., 2010. Streptococcus pyogenes isolates causing severe infections in Norway in 2006 to 2007: emm types, multilocus sequence types, and superantigen profiles. J. Clin. Microbiol. 48 (3), 842 851. Messias Reason, I.J., Schafranski, M.D., Jensenius, J.C., Steffensen, R., 2006. The association between mannose-binding lectin gene polymorphism and rheumatic heart disease. Hum. Immunol. 67 (12), 991 998. Messias-Reason, I.J., Schafranski, M.D., Kremsner, P.G., Kun, J.F., 2009. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157 (3), 395 399. Mota, C., Aiello, D., Anderson, R., 2009. Chronic rheumatic heart disease. In: Anderson, R., Baker, E., Penny, D. (Eds.), Pediatric Cardiology, third ed. Churchill Livingstone/Elsevier, Philadelphia, PA, pp. 1091 1133. O’Brien, K.L., Beall, B., Barrett, N.L., Cieslak, P.R., Reingold, A., Farley, M.M., et al., 2002. Epidemiology of invasive group a streptococcus disease in the United States, 1995 1999. Clin. Infect. Dis. 35 (3), 268 276. O’Grady, K.A., Kelpie, L., Andrews, R.M., Curtis, N., Nolan, T.M., Selvaraj, G., et al., 2007. The epidemiology of invasive group A streptococcal disease in Victoria, Australia. Med. J. Aust. 186 (11), 565 569. Ozkan, M., Carin, M., So¨nmez, G., Senocak, M., Ozdemir, M., Yakut, C., 1993. HLA antigens in Turkish race with rheumatic heart disease [see comment]. Circulation 87 (6), 1974 1978.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES

1268

63. RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE

Patarroyo, M.E., Winchester, R.J., Vejerano, A., Gibofsky, A., Chalem, F., Zabriskie, J.B., et al., 1979. Association of a B-cell alloantigen with susceptibility to rheumatic fever. Nature 278 (5700), 173 174. Peterson, L., Fujimani, R., 2007. Molecular mimicry. In: Shoenfeld, Y., Gershwin, M., Meroni, P. (Eds.), Autoantibodies. Elsevier, Burlington, NJ, pp. 13 19. Postol, E., Alencar, R., Higa, F.T., Freschi de Barros, S., Demarchi, L.M., Kalil, J., et al., 2013. StreptInCor: a candidate vaccine epitope against S. pyogenes infections induces protection in outbred mice. PLoS One 8 (4), e60969. Quinn, A., Kosanke, S., Fischetti, V.A., Factor, S.M., Cunningham, M.W., 2001. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infect. Immun. 69 (6), 4072 4078. Raizada, V., Williams, R.C., Chopra, P., Gopinath, N., Prakash, K., Sharma, K.B., et al., 1983. Tissue distribution of lymphocytes in rheumatic heart valves as defined by monoclonal anti-T cell antibodies. Am. J. Med. 74 (1), 90 96. Rajapakse, C.N., Halim, K., Al-Orainey, I., Al-Nozha, M., Al-Aska, A.K., 1987. A genetic marker for rheumatic heart disease. Br. Heart J. 58 (6), 659 662. Ramasawmy, R., Fae´, K.C., Spina, G., Victora, G.D., Tanaka, A.C., Pala´cios, S.A., et al., 2007. Association of polymorphisms within the promoter region of the tumor necrosis factor-alpha with clinical outcomes of rheumatic fever. Mol. Immunol. 44 (8), 1873 1878. Ramasawmy, R., Spina, G.S., Fae, K.C., Pereira, A.C., Nisihara, R., Messias Reason, I.J., et al., 2008. Association of mannose-binding lectin gene polymorphism but not of mannose-binding serine protease 2 with chronic severe aortic regurgitation of rheumatic etiology. Clin. Vaccine Immunol. 15 (6), 932 936. Rogers, S., Commons, R., Danchin, M.H., Selvaraj, G., Kelpie, L., Curtis, N., et al., 2007. Strain prevalence, rather than innate virulence potential, is the major factor responsible for an increase in serious group A streptococcus infections. J. Infect. Dis. 195 (11), 1625 1633. Rush, C.M., Govan, B.L., Sikder, S., Williams, N.L., Ketheesan, N., 2014. Animal models to investigate the pathogenesis of rheumatic heart disease. Front. Pediatr. 2, 116. Sallakci, N., Akcurin, G., Ko¨ksoy, S., Kardelen, F., Uguz, A., Coskun, M., et al., 2005. TNF-alpha G-308A polymorphism is associated with rheumatic fever and correlates with increased TNF-alpha production. J. Autoimmun. 25 (2), 150 154. Seale, A.C., Davies, M.R., Anampiu, K., Morpeth, S.C., Nyongesa, S., Mwarumba, S., et al., 2016. Invasive group A Streptococcus infection among children, rural Kenya. Emerg Infect. Dis. 22 (2), 224 232. Settin, A., Abdel-Hady, H., El-Baz, R., Saber, I., 2007. Gene polymorphisms of TNF-alpha(-308), IL-10(-1082), IL-6(-174), and IL-1Ra(VNTR) related to susceptibility and severity of rheumatic heart disease. Pediatr. Cardiol. 28 (5), 363 371. Shea, P.R., Ewbank, A.L., Gonzalez-Lugo, J.H., Martagon-Rosado, A.J., Martinez-Gutierrez, J.C., Rehman, H.A., et al., 2011. Group A Streptococcus emm gene types in pharyngeal isolates, Ontario, Canada, 2002 2010. Emerg Infect. Dis. 17 (11), 2010 2017. Shulman, S.T., Tanz, R.R., Dale, J.B., Beall, B., Kabat, W., Kabat, K., et al., 2009. Seven-year surveillance of North American pediatric group a streptococcal pharyngitis isolates. Clin. Infect. Dis. 49 (1), 78 84. Smeesters, P.R., Vergison, A., Campos, D., de Aguiar, E., Miendje Deyi, V.Y., Van Melderen, L., 2006. Differences between Belgian and Brazilian group A Streptococcus epidemiologic landscape. PLoS One 1, e10. Smeesters, P.R., McMillan, D.J., Sriprakash, K.S., 2010. The streptococcal M protein: a highly versatile molecule. Trends Microbiol. 18 (6), 275 282. Stanevicha, V., Eglite, J., Sochnevs, A., Gardovska, D., Zavadska, D., Shantere, R., 2003. HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia. Arthritis Res. Ther. 5 (6), R340 346. Steer, A.C., Carapetis, J.R., 2009. Prevention and treatment of rheumatic heart disease in the developing world. Nat. Rev. Cardiol. 6 (11), 689 698. Steer, A.C., Kado, J., Wilson, N., Tuiketei, T., Batzloff, M., Waqatakirewa, L., et al., 2009a. High prevalence of rheumatic heart disease by clinical and echocardiographic screening among children in Fiji. J. Heart Valve Dis. 18 (3), 327 335. discussion 336. Steer, A.C., Law, I., Matatolu, L., Beall, B.W., Carapetis, J.R., 2009b. Global emm type distribution of group A streptococci: systematic review and implications for vaccine development. Lancet Infect. Dis. 9 (10), 611 616. Tamayo, E., Montes, M., Garcı´a-Arenzana, J.M., Pe´rez-Trallero, E., 2014. Streptococcus pyogenes emm-types in northern Spain; population dynamics over a 7-year period. J. Infect. 68 (1), 50 57. Tanaka, Y., Gotoh, K., Teramachi, M., Ishimoto, K., Tsumura, N., Shindou, S., et al., 2016. Molecular epidemiology, antimicrobial susceptibility, and characterization of macrolide-resistant Streptococcus pyogenes in Japan. J. Infect. Chemother. 22, 727 732. Tapia, M.D., Sow, S.O., Tamboura, B., Keita, M.M., Berthe, A., Samake, M., et al., 2015. Streptococcal pharyngitis in schoolchildren in Bamako, Mali. Pediatr. Infect. Dis. J. 34 (5), 463 468. Tartof, S.Y., Reis, J.N., Andrade, A.N., Ramos, R.T., Reis, M.G., Riley, L.W., 2010. Factors associated with Group A Streptococcus emm type diversification in a large urban setting in Brazil: a cross-sectional study. BMC Infect. Dis. 10, 327. Turner, C.E., Pyzio, M., Song, B., Lamagni, T., Meltzer, M., Chow, J.Y., et al., 2016. Scarlet fever upsurge in England and molecular-genetic analysis in north-west London, 2014. Emerg Infect. Dis. 22 (6), 1075 1078. Unny, S.K., Middlebrooks, B.L., 1983. Streptococcal rheumatic carditis. Microbiol Rev 47 (1), 97 120. Visentainer, J.E., Pereira, F.C., Dalalio, M.M., Tsuneto, L.T., Donadio, P.R., Moliterno, R.A., 2000. Association of HLA-DR7 with rheumatic fever in the Brazilian population. J. Rheumatol. 27 (6), 1518 1520. Volin, M.V., Shahrara, S., 2011. Role of TH-17 cells in rheumatic and other autoimmune diseases. Rheumatology (Sunnyvale) 1 (104). Weidebach, W., Goldberg, A.C., Chiarella, J.M., Guilherme, L., Snitcowsky, R., Pileggi, F., et al., 1994. HLA class II antigens in rheumatic fever. Analysis of the DR locus by restriction fragment-length polymorphism and oligotyping. Hum. Immunol. 40 (4), 253 258. Williamson, D.A., Moreland, N.J., Carter, P., Upton, A., Morgan, J., Proft, T., et al., 2014. Molecular epidemiology of group A streptococcus from pharyngeal isolates in Auckland, New Zealand, 2013. N. Z. Med. J. 127 (1388), 55 60. ˘ ˘ H., 1997. Cytokines in acute rheumatic fever. Eur. J. Pediatr. 156 (1), 25 29. Yegin, O., Co¸skun, M., Ertug, Zabriskie, J.B., Lavenchy, D., Williams, R.C., Fu, S.M., Yeadon, C.A., Fotino, M., et al., 1985. Rheumatic fever-associated B cell alloantigens as identified by monoclonal antibodies. Arthritis Rheum. 28 (9), 1047 1051.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES