Introduction

A complete and comprehensive understanding of the pathogenesis of acute rheumatic fever (ARF) has eluded scientists for decades. ARF is a multiorgan inflammatory disorder affecting the heart (carditis), joints (arthritis and arthralgia), brain (Sydneham’s chorea), skin (erythema marginatum), and subcutaneous tissue (subcutaneous nodules). Rheumatic heart disease (RHD) is characterized by typical heart valve lesions, classified clinically as regurgitation and stenosis, and histopathologically by the presence of pathognomonic granulomatous Aschoff bodies.

It is well established that ARF follows infection with group A Streptococcus (GAS), otherwise known as Streptococcus pyogenes, through an inflammatory process in susceptible individuals, and that RHD occurs as a result of a severe initial or multiple episodes of ARF. Researchers have attempted to unravel the inflammatory basis of the pathogenesis of ARF, focusing on humoral and cellular immune responses with molecular mimicry as the central mediator of cross-reactivity with GAS. Molecular mimicry is where a foreign antigen shares sequence or structural similarities with self-antigens. Many questions remain, including whether skin infection can trigger ARF, whether groups C and G streptococci might also lead to the disease, and whether there is a genetic basis to susceptibility to ARF.

In this chapter, we outline the current understanding of the pathogenesis of ARF. We begin with a broad overview and describe the mediators of autoimmune response, and then delve more deeply into molecular mimicry, pathogenesis of carditis and RHD, the role of T cells in RHD, pathogenesis of Sydenham’s chorea, and finally genetic susceptibility.

Overview of the Pathogenesis of Acute Rheumatic Fever

Pharyngeal infection with GAS leads to activation of cells of the innate immune system. Neutrophils, macrophages, and dendritic cells phagocytose the bacteria, and then present antigens to T cells, in turn leading to activation of humoral and cellular immune responses. The immune response becomes cross-reactive with human tissues in susceptible individuals—this is the driving mechanism of ARF. The B- and T-cell response leads to antibody production and CD4+ T-cell activation. These cross-reactive antibodies and T cells are generated through the process of molecular mimicry whereby antigenic epitopes are shared between host and bacteria. This autoimmune process is believed to be the basis of all of the clinical manifestations of ARF: carditis is caused by both cross-reactive antibodies and T cells, arthritis by immune complex deposition, chorea by antibody binding to neuronal cells and the skin, and subcutaneous manifestations by a delayed hypersensitivity reaction ( Fig. 2.1 ).

Generation of a cross-reactive immune response in acute rheumatic fever (ARF). Following GAS adhesion to and invasion of the pharyngeal epithelium, GAS antigens activate both B and T cells. Molecular mimicry between GAS group A carbohydrate and serotype-specific M protein and the host heart, brain, or joint tissues can lead to an autoimmune response, which causes the major manifestations of ARF. BCR, B-cell receptor; TCR, T-cell receptor.

Reproduced with permission from Carapetis JR et al.

Mediators of Autoimmune Reactions

Although immunity against GAS is intended to eliminate the bacterium from our bodies, in some instances, the immune response against GAS turns into an autoimmune response. Autoimmune T and B lymphocyte responses target antigens both of GAS and the human heart, brain, skin, and articular joint tissues. Heart-tissue cross-reactive antibodies may bind to the valvular endothelial tissue generating inflammation and consequently upregulation of the vascular cell adhesion molecule-1 (VCAM-1).

Cytokines and chemokines are involved initially in the response against GAS as well as throughout the entire inflammatory process of clearance of the streptococcus and development of sequelae in the heart of ARF and chronic RHD patients. Chemokines are important mediators of cellular migration. In an in vitro assay, autoreactive T cells were shown to migrate into the inflamed heart tissue mainly toward a CXCL9/Mig gradient suggesting that these specific chemokines mediated both CD4 ⁺ and CD8 ⁺ T-cell recruitment into valvular heart tissue. A cascade of soluble mediators consisting of cytokines such as IL-1, IL-2, IL-17, IFNγ, and TNF-α culminates in an inflammatory response that leads to tissue injury primarily in valves, leading to valvulitis with mild-to-severe functional consequences, and somewhat in the adjoining myocardium.

Molecular Mimicry

Molecular mimicry is immune cross-recognition of conformational protein or carbohydrate structures and/or amino acid sequences with similarities between microbes and human tissues. It is believed to be an important part of the pathogenesis of ARF including the development of autoimmunity and inflammation in the heart and brain.

The development of autoimmune responses against the heart and the brain are thought to be primarily in response to the group A carbohydrate epitope N-acetyl-β- d -glucosamine (GlcNAc), the dominant epitope of the group A carbohydrate. In one study, individuals with a diagnosis of RHD who made strong responses against the group A carbohydrate had a poor prognosis compared to those who did not have elevated anticarbohydrate antibodies. Valvular carbohydrate epitopes are important in targeting an immune response against the valve. Studies of human and mouse antistreptococcal/antimyosin monoclonal antibodies (mAbs) that reacted strongly with N-acetyl-glucosamine have demonstrated cytotoxicity for human cardiomyocytes or endothelium and the antibodies also reacted with valvular endothelium in tissue sections of human valves. Cytotoxic mAbs recognized α-helical laminin as part of the extracellular matrix in the basement membrane underlying the valvular endothelium. These data suggested that human antibody cross-reactivity with valve tissues is established through antimyosin/anti-N-acetyl-glucosamine/antilaminin reactivity.

Carditis and Rheumatic Heart Disease

Rheumatic carditis is characterized by regurgitant lesions of the mitral and aortic valves (otherwise known as rheumatic valvulitis – see Chapter 3 ). Fig. 2.2 shows a diagram of the proposed pathogenesis of disease in the valve. Antibodies, potentially directed against the group A carbohydrate, react with valve endothelium to initiate inflammation at the valve surface and promote T-cell infiltration of the valve in RHD. Cross-reactive T cells responsive to streptococcal M proteins and homologous α-helical protein antigens such as myosin, laminin, tropomyosin, or vimentin become activated and extravasate through activated endothelium into the valve where they differentiate into CD4+ TH1 cells producing γ IFN.

Diagram of proposed pathogenesis of rheumatic heart disease as described in the text. Antistreptococal antibodies directed against the group A streptococcus and the heart target the valve endothelium containing laminin. The antiheart antibodies are proposed to lead to upregulation of VCAM-1 on the valve surface, which then attracts T cells that enter the valve and lead to valve damage and continued heart disease with every streptococcal infection. T cells recognize the streptococcal M protein and α-helical proteins in the valve including laminin and vimentin. VCAM-1 , vascular cell adhesion molecule-1. (Reproduced with permission from Cunningham MW )

Initial damage in RHD may originate at the chordae tendinae, where damage to the endothelium of these very delicate valve structures may begin the process of injury, edema, fibrosis, and scarring. T cells infiltrate and congregate at the basement membrane of the valve with upregulation of VCAM-1, which allows the valve to be infiltrated by the T cells and leads to explosive valve injury with repeated streptococcal infections. Cross-reactive T cells penetrate the valve endothelium into an originally avascular valve. T cells in peripheral blood of patients and the valve have been shown to be cross-reactive with M protein and cardiac proteins including cardiac myosin epitopes, and they are both CD4+ and CD8+ phenotypes, but the CD4+ phenotype and Th1 cells dominate. The development of scarring and fibrosis in the valve is part of the pathogenesis caused by γ-interferon (IFN) production and IL-17A. As the scarring promotes neovascularization and development of a blood supply into normally avascular valve tissue, T cells can subsequently enter the valve through blood vessels developed in the scar. In summary, cardiac valves with their thin avascular structure become inflamed and vascularized in acute rheumatic valvulitis. The healing process evolves after rheumatic valvulitis with a combination of neovascularization and tissue fibrosis.

Cardiac myosin is a major antigen in the myocardium that cross-reacts with antibodies and T cells produced in response to GAS infection. Using affinity-purified antimyosin antibodies from ARF patients, the cross-reactive streptococcal epitope has been further defined: a five-amino acid residue (Gln-Lys-Ser-Lys-Gln) of the N-terminal M5 and M6 proteins. Later, several other cardiac myosin epitopes, identified as peptide sequences in light meromyosin (LMM), were also described as targets of both peripheral and heart-tissue infiltrating T-cell clones that demonstrated specific cross-reactivity between streptococcal M5 protein and cardiac myosin epitopes. A high proportion (63.2%) of intralesional T-cell clones that recognized LMM peptides was observed, indicating that streptococcal-primed peripheral T-cell clones migrated to the heart and were maintained by their cross-reactivity with cardiac myosin in adjacent valve tissues or with other valve proteins such as vimentin and laminin. Peptides in the S2 fragment of cardiac myosin are recognized by autoantibodies in rheumatic carditis.

T-cell reactivity toward cardiac myosin epitopes in ARF and RHD patients may also trigger broader recognition of valvular proteins with structural or functional similarities, such as vimentin, laminin and others. RHD with more chronic disease displays more fibrosis, but the avascular valve becomes neovascularized to provide more blood vessels to the scar tissue in the valve, and with every streptococcal infection disease can explode in the valve leading to dysfunction and the need for valve replacement.

Increased but disorganized expression of vimentin, along with reduced expression of collagen VI, involved with repair and tissue integrity and a target for adhesion by GAS through collagen-binding proteins, was recently observed in ARF and RHD valvular tissue. Noncross-reactive antibodies develop against collagen in RHD, and may contribute to the pathogenesis of disease. Once mimicry damages the valve, collagen is exposed to the immune system and antibodies develop against collagen.

Cardiac myosin has an α-helical structure very similar to the streptococcal M protein. Studies have shown that the structure of the M protein has regions of splayed helical amino acid sequence where the α-helix is disrupted due to irregularities in the amino acid periodicity required for the coiled-coil structure. Antimyosin antibody only cross-reacts with the splayed regions of the α-helical coiled-coil streptococcal M protein structure, not if the splayed regions are closed and the structure is designed as a perfect helix. Studies were undertaken to crystallize a portion of the streptococcal M1 protein to evaluate its virulence properties when portions of the amino acid sequence were mutated to eliminate the splayed α-helical regions, and also to investigate regions and structures responsible for eliciting or reacting with cross-reactive antibodies that participate in molecular mimicry. The structural study revealed irregularities and instabilities in the coiled coil of the M1 fragment crystal. Similar structural instabilities and irregularities occur in myosin and tropomyosin that had previously been demonstrated to cross-react with the streptococcal M proteins. Using mutation of specific amino acids, the study showed enhanced stability of the coiled-coil diminished the virulence properties of the M1 protein and reduced cross-reactivity of the M protein with cross-reactive autoantibodies that reacted with both cardiac myosin and GAS M proteins. Thus, the stabilization of the α-helix to remove the splayed helical regions of the M protein led to a reduction of virulence and loss of cross-reactivity with heart reactive antibodies ( Table 2.1 ).

T Cells and Rheumatic Heart Disease

T-cell clones isolated from mitral valves, papillary muscle, and the left atrium of patients with RHD have been shown to be responsive to several peptides of streptococcal M5 protein and proteins from heart tissue extracts. In BALB/c mice immunized with human cardiac myosin, myosin-cross-reactive T-cell epitopes from the A, B repeat regions of the M5 protein were identified. Thus, the regions of M protein that can induce heart cross-reactivity, cause disease in the heart, or be identified by T cells from lesions of rheumatic carditis and RHD have been investigated in rodents and humans. Six dominant myosin cross-reactive T-cell epitopes were recognized by T cells when reacted with the M5 molecule ( Table 2.2 ) . Listed in Table 2.2 include (1) the dominant Balb/c mouse T-cell epitopes or amino acid sequences of GAS M5 protein that react with T cells taken from BALB/c mice that have been immunized with the streptococcal M5 protein ; (2) the amino acid sequences of the GAS M5 protein that are recognized by T-cell clones from rheumatic heart valves ; and (3) amino acid sequences of the streptococcal M5 protein that have been previously reported to stimulate human T cells from ARF patients. An important correlation/finding seen in Table 2.2 is that M5 peptides NT4/NT5 (GLKTENEGLKTENEGLKTE and KKEHEAENDKLKQQRDTL) and B1B2/B2 (VKDKIAKEQENKETIGTL and TIGTLKKILDETVKDKIA), which were dominant cross-reactive T-cell epitopes in the M5 immunized BALB/c mouse, contain sequences similar to those M protein sequences recognized by T cells from rheumatic valves. Peptides NT4 and NT5 produced inflammatory infiltrates in the myocardium of rodents immunized with those peptides. Amino acid sequences in the N-terminal portion of M5 protein that share homology with cardiac myosin may break immune tolerance and promote T cell-mediated inflammatory heart disease. The correlation of similar or the same peptide sequences as observed in animal models as well as in T cells derived from human rheumatic heart valves suggests that these may be the peptides that lead to disease in humans. Certain HLA haplotypes may also predispose and enhance the recognition of these sequences and epitopes by T cells and increase susceptibility to RHD.

Table 2.2

Myosin or Heart Cross-reactive T-Cell Epitopes of Streptococcal M5 Protein.

Taken from Cunningham MW , with permission from ASM press.

Peptide	Sequence	Origin of T-Cell Clone or Response
1–25	TVTRGTISDPQRAKEALDKYELENH a	ARF/Valve
81–96	DKLKQQRDTLSTQKETLEREVQN a	ARF/Valve
163–177	ETIGTLKKILDETVK a	ARF/Valve
337–356	LRRDLDASREAKKQVEKAL	Normal/PBL
347–366	AKKQVEKALEEANSKLAALE	Mice /Normal PBL
397–416	LKEQLAKQAEELAKLRAGKA	ARF/PBL
NT4 40–58	GLKTENEGLKTENEGLKTE	BALB/c/Lymph node b
NT5 59–76	KKEHEAENDKLKQQRDTL	BALB/c/Lymph node b
B1B2 137–154	VKDKIAKEQENKETIGTL	BALB/c/Lymph node b
B2 150–167	TIGTLKKILDETVKDKIA	BALB/c/Lymph node b
C2A 254–271	EASRKGLRRDLDASREAK	BALB/c/Lymph node b
C3 293–308	KGLRRDLDASREAKKQ	BALB/c/Lymph node b

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