NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences Center; 2016-.

Cover of Streptococcus pyogenes

Streptococcus pyogenes : Basic Biology to Clinical Manifestations [Internet].

Show details

Post-Streptococcal Autoimmune Sequelae: Rheumatic Fever and Beyond

, PhD.

Author Information

Created: .

Introduction

Streptococcus pyogenes, the group A streptococcus, and its link to rheumatic fever, rheumatic heart disease, arthritis, and St Vitus dance are reported in the earliest historical accounts of post-streptococcal sequelae that occur anywhere from several weeks to several months after group A streptococcal infection (Stollerman, 2011; Stollerman, 1997; Wannamaker, 1973; Jones, 1944; Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association, 1992; Danjani, et al., 1988). Prior to the discovery of penicillin, hospital wards were filled with cases of children with rheumatic heart disease, which could be associated with polymigrating arthritis, the most common manifestation of rheumatic fever; or with Sydenham chorea, which is also known as St. Vitus dance in the early literature. The Jones criteria, which describe the onset and diagnosis of rheumatic fever, include major manifestations of the heart, brain, joints, and skin. Polymigrating arthritis, carditis associated with a heart murmur, erythema marginatum, a circinate skin rash, subcutaneous nodules, and the neurologic manifestation (Sydenham chorea) are all inflammatory reactions that may occur in acute rheumatic fever (Jones, 1944; Gerber, et al., 2009). Rheumatic fever or other sequelae generally follow group A streptococcal pharyngitis or other mucosal infections, and diagnosis requires elevated anti-streptolysin O and/or anti-DNAse B antibody titers that are increased over normal levels, or a positive throat culture or positive quick strep test for group A streptococci (Gerber, et al., 2009). Streptococcal infection of the throat, skin, or mucosa precedes autoimmune or inflammatory sequelae that are observed in acute rheumatic fever (Steer, Carapetis, Nolan, & Shann, 2002; Cunningham, 2000; Cunningham, 2012).

Post-streptococcal sequelae, such as rheumatic fever (Bisno, Brito, & Collins, 2003; Bisno, 2001; Bisno & Stevens, 1996; Bisno, Pearce, Wall, Moody, & Stollerman, 1970), occur primarily in childhood and adolescence. The primary age group most affected are children between the ages of 5 and 15 years old. Rheumatic fever is a global disease (Steer, Carapetis, Nolan, & Shann, 2002; McDonald, Currie, & Carapetis, 2004; Carapetis, Robins-Browne, Martin, Shelby-James, & Hogg, 1995; Carapetis, Currie, & Good, 1996; Carapetis, Walker, Kilburn, Currie, & MacDonald, 1997), and a resurgence of rheumatic fever in the United States has occurred since approximately 1983 in the intermountain region, specifically in Utah near Salt Lake City and the surrounding area (Kaplan, Johnson, & Cleary, 1989; Veasy, Tani, & Hill, 1994; Veasy, et al., 1987; Veasy, et al., 2004).

Some of the earliest reports of the immunology of rheumatic fever in humans reported that antibodies were bound to heart tissues, including valves and myocardia from rheumatic hearts (Kaplan & Dallenbach, 1961; Kaplan, Bolande, Rakita, & Blair, 1964; Zabriskie & Freimer, 1966), and animal studies suggested that antibodies against group A streptococcus might cross-react with the heart (Kaplan & Svec, 1964; Kaplan & Meyerserian, 1962; Kaplan & Suchy, 1964; Zabriskie, 1967). Heart-reactive antibodies were found in patients with rheumatic fever (Zabriskie, Hsu, & Seegal, 1970), and these antibodies would later be recognized to react with cardiac myosin (Galvin, Hemric, Ward, & Cunningham, 2000; Krisher & Cunningham, 1985). In Sydenham chorea, the neurologic manifestation of rheumatic fever, anti-neuronal antibodies were found in neurons in the basal ganglia of the brain (Husby, van de Rijn, Zabriskie, Abdin, & Williams, 1976). Both rheumatic carditis and Sydenham chorea have been extensively investigated for autoantibodies found in the blood against the heart and brain (Cunningham, 2000; Cunningham, 2012; Kaplan & Dallenbach, 1961; Husby, van de Rijn, Zabriskie, Abdin, & Williams, 1976; Dudding & Ayoub, 1968; Kaplan, Bolande, Rakita, & Blair, 1964). Pathogenic mechanisms of autoimmunity and inflammation, including both humoral and cellular autoimmunity, are continually under investigation in these streptococcal sequelae.

Both of these streptococcal sequelae rheumatic carditis and Sydenham chorea may occur due to molecular mimicry (Galvin, Hemric, Ward, & Cunningham, 2000; Kirvan, Swedo, Heuser, & Cunningham, 2003). Molecular mimicry is part of the normal immune response, including the response of the host to the group A streptococcus. Mimicry is the response against infectious microbes, which cross-react with host antigens and potentially lead to autoimmunity, which may produce inflammation in host tissues and lead to disease pathogenesis in susceptible hosts (Zabriskie & Gibofsky, 1986; Zabriskie, 1985). Mimicry and production of cross-reactive antibodies as well as cross-reactive T cells provide a “survival of the fittest” advantage to the host through immune recognition and immune responses against pathogens, due to the production of antibodies or responsive T cells that recognize both host and microbial antigens. In reference to T cell cross-reactivity, T cell receptor cross-reactivity between similar self and foreign peptides can reduce the size of foreign peptide-specific T cell populations and lead to the emergence of T cell populations that are specific for tissue restricted self-peptides, which can lead to autoimmunity and potentially disease following infection (Nelson, et al., 2015).

The determination of disease in humoral immunity and cross-reactivity is most likely related to the increasing avidity of the antibody, which must cause a cytotoxic reaction or a reaction that leads to inflammation or signaling to produce disease. The avidity of the antibody has also been shown to be important in germinal center reactions, in that antibody feeds back on the germinal center to shut down the production of a high avidity antibody (Zhang, et al., 2013). However, if such antibodies were trapped in immune complexes that were not cleared from the host either normally or quickly, they would prevent the attenuation of a high avidity antibody response, which may damage tissue. It has been known for some time that rheumatic fever is a disease with immune complexes that are probably not cleared normally (Read, Reid, Poon-King, Fischetti, Zabriskie, & Rapaport, 1977; Read, et al., 1986; Read & Zabriskie, 1977; Reddy, et al., 1990), and HLA B5 has been associated with immune complexes in acute rheumatic fever (Yoshinoya & Pope, 1980).

Evidence supports the hypothesis that molecular mimicry between the group A streptococcus and the heart or brain is important in the immune responses in rheumatic fever (Zabriskie & Freimer, 1966; Zabriskie, 1967; Galvin, Hemric, Ward, & Cunningham, 2000; Krisher & Cunningham, 1985; Kirvan, Swedo, Heuser, & Cunningham, 2003; Ellis, et al., 2010). Anti-streptococcal antibodies that are cross-reactive with the heart or brain that could recognize several types of epitopes that have already been defined (Cunningham, 2000; Krisher & Cunningham, 1985; Cunningham, 2003; Cunningham, 2014; Cunningham, Antone, Gulizia, McManus, Fischetti, & Gauntt, 1992). Other mechanisms may involve collagen or anti-collagen antibodies, and have recently been reviewed (Cunningham, 2014; Tandon, Sharma, Chandrasekhar, Kotb, Yacoub, & Narula, 2013). Collagen has not been found to play a direct role in molecular mimicry, but anti-collagen antibodies could be important in attacking collagen in host tissues—especially after a valve is damaged or exposed.

Rheumatic valvular heart disease is the most serious manifestation of rheumatic fever, and has been the focus of decades of research (Cunningham, 2000; Cunningham, 2012; Zabriskie, Hsu, & Seegal, 1970; Zabriskie, 1985; Reddy, et al., 1990; Veasy, 2004). Studies of Sydenham chorea (Kirvan, Swedo, Heuser, & Cunningham, 2003) and its related sequelae, such as pediatric autoimmune neurologic disorder associated with streptococci (PANDAS), have been investigated for anti-neuronal autoantibodies against the brain (Snider & Swedo, 2004; Swedo, 1994; Swedo, et al., 1998; Swedo, et al., 1997; Murphy, et al., 2007; Murphy, Storch, Lewin, Edge, & Goodman, 2012). The first 50 cases of PANDAS were described by Swedo and colleagues in children that presented with tics or obsessive compulsive symptoms and often particularly display small piano-playing choreiform movements of the fingers and toes (Swedo, 2002; Swedo, et al., 1998). A group of youth and young adults with infections, as well as with acute and chronic tic and obsessive compulsive disorders (OCD), has also been investigated (Singer, Gause, Morris, Lopez, & Tourette Syndrome Study Group, 2008). The group of children with OCD/tics who demonstrate small choreiform movements, such as piano-playing movements of the fingers and toes, is immunologically similar to Sydenham chorea and is termed with the acronym PANDAS (Swedo, 1994; Swedo, 2002; Cox, et al., 2013). Acute onset tic and OCD symptoms can also follow other non-streptococcal infections and are considered to be pediatric acute onset neuropsychiatric syndrome, or PANS (Swedo, Leckman, & Rose, 2012). Another clinical research group has called for a broader concept of childhood acute neurologic symptoms, or CANS (Singer, Gilbert, Wolf, Mink, & Kurlan, 2012). The PANDAS subgroup is known to have the small choreiform movements, particularly of the fingers and toes that are usually not present in some of the other groups with acute or chronic tics, and OCD, which would be called PANS. Studies of anti-neuronal autoantibodies in Sydenham chorea and PANDAS with choreiform movements clearly identified a specific group of anti-neuronal antibodies that are present in both Sydenham chorea and PANDAS and identified specific antibody mediated neuronal cell-signaling mechanisms, which may partially lead to disease symptoms (Kirvan, Swedo, Snider, & Cunningham, 2006b; Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Cox, Swedo, & Cunningham, 2007; Brimberg, et al., 2012; Ben-Pazi, Stoner, & Cunningham, 2013). The group of diseases associated with Sydenham chorea and the small choreiform movements generally seem to be related to antibodies against the dopamine receptors D1 and D2. Thus far, anti-D2 receptor antibodies are exclusively seen in Sydenham chorea and PANDAS with the small piano-playing choreiform movements of the fingers and toes (Cox, et al., 2013; Ben-Pazi, Stoner, & Cunningham, 2013). The combination of autoimmunity and behavior is a relatively new concept that links brain, behavior, and neuropsychiatric disorders to streptococcal infections.

Rheumatic Carditis: Anti-Streptococcal Humoral and Cellular Immunity against the Heart

Evidence supports mimicry and cross-reactivity between the group A streptococcal antigens and heart antigens (Zabriskie, 1967; Galvin, Hemric, Ward, & Cunningham, 2000; Kirvan, Swedo, Heuser, & Cunningham, 2003; Kaplan, 1963). Originally, mouse monoclonal antibodies (mAbs) produced against group A streptococci and heart reacted with striations in myocardium or mammalian muscle (Zabriskie, Hsu, & Seegal, 1970), as previously reported for human acute rheumatic fever sera or sera from animals immunized with group A streptococcal antigens (Kaplan, Bolande, Rakita, & Blair, 1964; Zabriskie & Freimer, 1966; Zabriskie, 1967; Zabriskie, Hsu, & Seegal, 1970). Early experiments were performed using human and animal sera that contain thousands of antibodies, and led to complicated studies that were difficult to interpret in order to determine cross-reactivity and molecular mimicry between the host and streptococcus. Mouse and human anti-streptococcal mAbs were developed soon after the discovery of B cell hybridoma production (Galvin, Hemric, Ward, & Cunningham, 2000; Krisher & Cunningham, 1985; Cunningham, Antone, Gulizia, McManus, Fischetti, & Gauntt, 1992; Cunningham & Swerlick, 1986; Shikhman & Cunningham, 1994; Shikhman, Greenspan, & Cunningham, 1994). The anti-streptococcal mAbs reacted with heart cells and identified cardiac myosin as one of the major proteins in heart cells, which was later found to cross-react with the dominant group A carbohydrate epitope, N-acetyl-beta-D-glucosamine (GlcNAc) or streptococcal M protein antigens (Cunningham, 2000; Galvin, Hemric, Ward, & Cunningham, 2000; Krisher & Cunningham, 1985). GlcNAc, the immunodominant epitope of the group A carbohydrate, is composed of a polyrhamnose backbone with side chains of N-acetyl-beta-D-glucosamine (GlcNAc) as the group A carbohydrate specificity that is recognized by many of the human cross-reactive anti-streptococcal antibodies directed against heart cells (Galvin, Hemric, Ward, & Cunningham, 2000). Responses against GlcNAc are strongly linked to antibody responses against cardiac myosin and other alpha helical coiled coil proteins (Shikhman & Cunningham, 1994; Shikhman, Greenspan, & Cunningham, 1994; Shikhman, Greenspan, & Cunningham, 1993; Malkiel, Liao, Cunningham, & Diamond, 2000).

Inflamed endothelium surrounding the valve allows T cells to enter the valve tissue and proliferate to produce inflammation and a damaged valve. Human mAb 3B6 derived from acute rheumatic carditis reacted with cardiac myosin, as well as with myocardium and valve endothelium (Figure 1), which may explain the reactivity of rheumatic carditis sera with striations in heart muscle as well as reactivity with the valve (Galvin, Hemric, Ward, & Cunningham, 2000). See Figure 1, which shows the reaction of mAb 3B6 with both myocardium striations as well as with the valvular endothelium. The rheumatic carditis derived mAb 3B6 antibody recognized laminin at the laminar basement membrane, as well as specific laminin peptide epitopes, as shown in Figure 2. The antibody cross-reacted with laminin epitopes, as well as with peptide epitopes, in human cardiac myosin (Figure 2), and similar anti-cardiac myosin antibodies were found in the sera of rheumatic heart disease (Galvin, Hemric, Ward, & Cunningham, 2000). Specifically, glycosylated proteins such as laminin or other extracellular matrix proteins glycosylated at the valve surface may also play a role in trapping antibodies at the surface of the valve and activating the endothelium and upregulating VCAM-1. Previous evidence demonstrated that glycosylated proteins and carbohydrate epitopes on the valve did, in fact, cross-react with the group A carbohydrate (Goldstein, Halpern, & Robert, 1967). Most important for the linkage between the group A carbohydrate and valvular heart disease in rheumatic fever, persistence of elevated antibody responses against the group A carbohydrate was correlated to a poor prognosis of valvular heart disease (Dudding & Ayoub, 1968). The evidence strongly links rheumatic valvular heart disease with the group A carbohydrate. Many human mAbs derived from rheumatic fever in humans recognized the group A carbohydrate epitope GlcNAc (Adderson, Shikhman, Ward, & Cunningham, 1998). Antibodies or immune complexes would generally be targeted to the valve surface and can lead to cellular infiltration of the valve.

Figure 1. . Reactivity of rheumatic carditis-derived human IgM monoclonal antibody (mAb) 3.

Figure 1.

Reactivity of rheumatic carditis-derived human IgM monoclonal antibody (mAb) 3.B6 with a normal human valve. Formalin-fixed human mitral valves were treated with human mAb 3.B6 at 10 μg/mL. mAb 3.B6 binding was detected using secondary biotin-conjugated (more...)

Figure 2. . Amino acid sequence alignment of laminin A chain and human cardiac myosin LMM peptide demonstrating sequence homology with epitopes that are recognized by human mAb 3B6 derived from rheumatic heart disease.

Figure 2.

Amino acid sequence alignment of laminin A chain and human cardiac myosin LMM peptide demonstrating sequence homology with epitopes that are recognized by human mAb 3B6 derived from rheumatic heart disease. Amino acid sequence designations of two homologous (more...)

Inflammation is often directly observed at the valve endothelium with upregulation of vascular cell adhesion molecule-1 (VCAM-1), as shown in valves from rheumatic heart disease (Roberts, et al., 2001) (Figure 3). Activation of VCAM-1 on the endothelium is an important first step that leads to valvular injury, edema, and infiltration of T cells that are reactive with the streptococcal M protein, as well as other streptococcal and host proteins. The valve is vulnerable to attack by the immune system following the activation of VCAM-1 on the valve endothelium that promotes subsequent cellular infiltration (Cunningham, 2012; Roberts, Kosanke, Terrence Dunn, Jankelow, Duran, & Cunningham, 2001). A diagram in Figure 4 shows the initial production of cross-reactive antibodies against the group A carbohydrate that attacks the valve endothelium with upregulation of VCAM-1 and subsequent infiltration of T cells from rheumatic carditis, which are specific for the streptococcal M protein and cardiac myosin, as well as other homologous epitopes (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005).

Figure 3. . Vascular cell adhesion molecule-1(VCAM-1) expressed on rheumatic valve.

Figure 3.

Vascular cell adhesion molecule-1(VCAM-1) expressed on rheumatic valve. Tissue stained with anti-human IgG conjugated to alkaline phosphatase and developed using Fast Red. The figure is from Roberts et al. (Roberts, et al., 2001) and is used with permission. (more...)

Figure 4. . Diagram illustrating the B cell and T cell responses against the group A streptococcal antigens and superantigens and the proposed pathogenesis in rheumatic carditis.

Figure 4.

Diagram illustrating the B cell and T cell responses against the group A streptococcal antigens and superantigens and the proposed pathogenesis in rheumatic carditis. Antibodies against the dominant group A carbohydrate epitope N-acetyl-beta-D-glucosamine (more...)

In rheumatic carditis, cross-reactive antibodies may initially cause damage that leads to edema, annular dilation and chordal elongation. This prevents adequate surface coaptation of the valve leaflets (Veasy & Tani, 2005), which by itself does not directly impair myocardial function. Fibrinous vegetations in the rough zone of the anterior leaflet may be observed. After chordal elongation, the scarring of leaflets appears, which is the initial insult that leads to mitral regurgitation, and is then heard as a heart murmur.

Alpha helical coiled-coil protein structures such as the streptococcal M proteins, cardiac myosin, keratin, and laminin are responsible for some of the cross-reactivity between the group A carbohydrate epitope N-acetyl-beta-D glucosamine and the myocardium, skin, or valve (Cunningham, 2000; Shikhman & Cunningham, 1994; Shikhman, Greenspan, & Cunningham, 1994). Some of the cross-reactive antibodies found in rheumatic fever recognize the GlcNAc epitope and react with the myocardium and with valves. Human mAbs, which target the group A carbohydrate epitope GlcNAc, also react with well-defined peptide epitopes taken from alpha-helical coiled-coil proteins, and amino acid substitution experiments show that hydrophobic and aromatic amino acids are important to the interactions between cross-reactive antibody molecules (Shikhman, Greenspan, & Cunningham, 1994). Peptides from alpha-helical coiled-coil molecules have been described that mimic the group A carbohydrate epitope (Shikhman, Greenspan, & Cunningham, 1994).

Analysis of crystallized group A streptococcal M1 protein fragments leads to an explanation of how the alpha-helical coiled-coil structures and epitopes are recognized in alpha-helical proteins as a basis for molecular mimicry and cross-reactivity between streptococcal M proteins and cardiac myosin (McNamara, et al., 2008). Streptococcal M proteins are well known for their alpha-helical coiled-coil cross-reactive properties and cross-reactivity with cardiac myosin (Cunningham, 2000). M1 protein exhibited substantial irregularities and instabilities demonstrating a non-idealized alpha helix (McNamara, et al., 2008) similar to that seen in cardiac myosin and tropomyosin. When the coiled-coil alpha helix was idealized and had much fewer splayed regions that could interact with immune molecules such as antibodies, it had much less cross-reactivity with our cross-reactive mAbs (McNamara, et al., 2008). Mutations in M1 protein encoding an idealized alpha helix, stabilized the alpha-helical structure and diminished cross-reactive properties of the streptococcal M1 protein (McNamara, et al., 2008).

The aggregation of collagen by certain streptococcal serotypes, such as the M3 protein identified as a collagen-binding factor of M3 streptococci (Tandon, et al., 2013; Dinkla, et al., 2003a; Dinkla, et al., 2003b), may lead to autoantibodies against collagen I that are observed in human sera and are produced along with responses against cardiac myosin (Martins, et al., 2008). Immune responses against collagen I may also be due to the release of collagen from damaged valves during rheumatic heart disease (Cunningham, 2012). Antibody responses against collagen I are not cross-reactive, which suggests that the release of collagen from the valve could potentially be a source of exposure of collagen to the human immune system in rheumatic carditis. Streptococcal proteins with similarity to collagen have been reported (Lukomski, et al., 2000; Lukomski, et al., 2001), but apparently, cross-reactivity has not been reported in rheumatic heart disease. The collagen hypothesis as a possibility for the pathogenesis of rheumatic heart disease has been previously reviewed and discussed (Cunningham, 2014; Tandon, Sharma, Chandrasekhar, Kotb, Yacoub, & Narula, 2013). If the valve is damaged and a loss of collagen structure is observed, then collagen is clearly affected (Chopra & Narula, 1991). A loss of collagen structure in the damage to the valve does not preclude immune mediated damage by cross-reactive antibodies and T cells or the exposure of collagen to the immune system after the initial attack, due to cross-reactive immune responses.

There is no cardiac myosin directly in a valve that is attached in papillary muscle that contains cardiac myosin and is affixed to the myocardium (Tandon, et al., 2013; Roberts, et al., 2001). The cross-reactivity of cardiac myosin with a valve is due to the recognition of laminin or related proteins by autoantibodies against group A streptococci and cardiac myosin. Injury to the valve initially is proposed to be by the autoantibody response directed at valve endothelium and laminar basement membrane. Initially, chordae tendinae become edematous and elongated, which leads to abnormal valve leaflet coaptation and closure. Once VCAM-1 is elevated on the activated valve endothelium, lymphocytes and other immune cells extravasate into the valve (Roberts, et al., 2001).

Studies by Chopra et al. have shown that the endomyocardium was primarily infiltrated by T cells and that 56 percent of the specimens demonstrated characteristic Aschoff nodules (Chopra P. , Narula, Kumar, Sachdeva, & Bhatia, 1988) and electron microscopy showed a loss of normal arrangement of endothelial cells and architectural modifications of the valvular collagen (Chopra & Narula, 1991). In studies by Roberts et al., both CD4+ and CD8+ T cells infiltrated the valves in rheumatic fever (Roberts, et al., 2001), but the CD4+ T cell subset predominated over the CD8+ T cell subset in the rheumatic valve (Roberts, et al., 2001)(Figure 5). The granulomatous Th1 reaction is evident and the presence of gamma IFN has been reported in rheumatic valves (Guilherme, et al., 2004). Although less is known about Th17 responses in rheumatic heart disease, Th17 cells are important in group A streptococcal infections and have been identified in nasopharyngeal and tonsillar lymphoid tissues in streptococcal infection animal models (Dileepan, Linehan, Moon, Pepper, & Jenkins, 2011; Pepper, et al., 2010; Carapetis & Steer, 2010). The balance between T regulatory cells and Th17 cells was abnormal, which suggests that Th17 cells were increased in rheumatic heart disease.

Figure 5. . Extravasation of CD4+ lymphocytes (arrows) into valve above Aschoff’s body in the subendocardium of the left atrial appendage.

Figure 5.

Extravasation of CD4+ lymphocytes (arrows) into valve above Aschoff’s body in the subendocardium of the left atrial appendage. A) Tissue stained with anti-CD4+ monoclonal antibody reagent and developed with the alkaline phosphatase and Fast Red (more...)

The valve endocardium is the site of CD4+ T cell infiltration into the valve (Roberts, et al., 2001) (Figure 5). As Figure 2 shows, subendocardial infiltration is present and is shown near the papillary muscle attachment of the valve into the myocardium. Studies of T lymphocytes from both humans and Lewis rats (Lymbury, et al., 2003; Quinn, Kosanke, Fischetti, Factor, & Cunningham, 2001; Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014) suggest a strong cross-reactivity between cardiac myosin and streptococcal M protein by the T lymphocytes isolated and cloned from blood (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005) or heart valve (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005; Guilherme, et al., 2004; Faé, Kalil, Toubert, & Guilherme, 2004; Faé, et al., 2006; Guilherme, Weidebach, Kiss, Snitcowsky, & Kalil, 1991; Guilherme, et al., 2000). Guilherme et al. reported that T cells cloned from peripheral blood in human rheumatic heart disease reflect similar specificities as T cells cloned from heart valves in rheumatic carditis (Guilherme, et al., 2001). Immunization with streptococcal recombinant M6 protein and the pepsin fragment of M protein (PepM5), as well as immunization with peptides from the A, B, and C repeat regions of the streptococcal M5 protein molecule, induced valvular heart disease in the Lewis rat model of valvulitis (Lymbury, et al., 2003; Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014; Gorton, Blyth, Gorton, Govan, & Ketheesan, 2010; Gorton, Govan, Olive, & Ketheesan, 2009).

More detailed studies of T cell lines produced from Lewis rats immunized with streptococcal PepM5 protein induced valvulitis, and were strongly stimulated by specific M5 peptides (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Passive transfer of the M5 protein specific T cell lines transferred valvulitis as shown by infiltration of CD4+ T cells and upregulation of VCAM-1 on the valve endothelium (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). It was notable that the passive transfer of a potentially pathogenic T cell line led to upregulation of the VCAM-1, while a control T cell line did not, and therefore did not infiltrate the valve. M protein-specific T cells may be important mediators of valvulitis in the Lewis rat model of rheumatic carditis (Quinn, Kosanke, Fischetti, Factor, & Cunningham, 2001). Mononuclear cells were infiltrated at the valve surface and inner valve in Lewis rats that were immunized with the group A streptococcal M5 serotype amino acid sequence residues 1–76 in the A repeat region (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Figure 6A shows infiltrated edematous valves from Lewis rats immunized with a peptide from a group A streptococcal M5 serotype, amino acid sequences in residues 59–115 found in the A repeat region of the M5 protein (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Edema of the valve structure at the chordae tendinae leads to loss of valve coaptation, regurgitation, and disease of the valve. Figure 6B illustrates a verrucous-type lesion, and Figure 6C shows an example of the cellular infiltration in a valve from Lewis rat immunized with recombinant M6 protein where 50% of the rats developed rheumatic valvulitis (3/6 rats studied) (Shikhman & Cunningham, 1994). In rheumatic heart disease, verrucae are seen in tissue sections of the valve (Stollerman, 2011; Stollerman, 1997; Wannamaker, 1973; Jones, 1944; Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association, 1992; Danjani, et al., 1988). VCAM-1 was observed on activated endothelium in the Lewis rat after administration of pathogenic T cell lines that targeted the valve and led directly to upregulation of VCAM-1 at the valve surface, which allowed for penetration of the T cell lines after their passive transfer (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). VCAM-1 appeared on the Lewis rat valve (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014) (not shown), similar to that seen in human rheumatic valves, as shown in Figure 3.

Figure 6. . A) Induction of valvulitis, edema and cellular infiltration (arrows) in hematoxylin and-eosin-stained heart valves from Lewis rats immunized with group A streptococcal M5 peptides as a group including peptides NT1-NT4/5 [AVTRGTINDPQRAKEALD amino acid (aa) residues 1–18; NT-2 KEALDKYELENHDLKTKN aa residues 14–31; NT-3 LKTKNEGLKTENEGLKTE aa residues 27–44;NT-4 GLKTENEGLKTENEGLKTE aa residues 40–58; NT-4/5 GLKTEKKEHEAENDKLK aa residues 54–70.

Figure 6.

A) Induction of valvulitis, edema and cellular infiltration (arrows) in hematoxylin and-eosin-stained heart valves from Lewis rats immunized with group A streptococcal M5 peptides as a group including peptides NT1-NT4/5 [AVTRGTINDPQRAKEALD amino acid (more...)

Lewis rat T cells that recognize the M5 protein T cell peptide epitope DKLKQQRDTLSTQKETLE (NT5/6 ~ M5 peptide amino acid sequence from the A repeat region of M5 protein serotype of Streptococcus pyogenes) were reported to target the valve in the T cell passive transfer studies in the Lewis rat (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Most importantly, in studies of human rheumatic valves by Guilherme and colleagues, cloned T cells from the valves also recognized the DKLKQQRDTLSTQKETLE peptide sequence (Guilherme, et al., 2004; Faé, et al., 2006). Other T cell lines in the Lewis rat that recognized other epitopes were not pathogenic, and did not target the valve (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Guilherme et al. have shown the importance of the cytokines, such as gamma IFN production, in the valve, which would be associated with the CD4+ cellular infiltrate (Guilherme, et al., 2004). Heart-infiltrating T cell clones from humans recognized both streptococcal and heart proteins in studies of human T cell clones isolated from rheumatic valves (Guilherme, et al., 2000; Guilherme, et al., 1995; Guilherme & Kalil, 2004).

The Lewis rat model suggests that the more pathogenic T cell clones releasing cytokines that affect the valve may actually lead to the activation of the VCAM-1 on the valve endothelium, which promotes the infiltration of particular clones (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014). Antibodies or immune complexes that bind the valve surface affect the surface endothelium, and lead to activation of the endothelium/endocardium on the valve and upregulation of VCAM-1. Antibodies against the valve, including those human mAbs derived from human rheumatic carditis, react with streptococcal group A carbohydrate and glycosylated proteins or cross-reactive sequences in alpha helical matrix proteins in the laminar basement membrane, such as laminin (Galvin, Hemric, Ward, & Cunningham, 2000). Once the valve endothelium is activated and collagen is exposed, the valve may continually be damaged by antibodies against laminin, as well as antibodies against collagen and other immunogenic valvular proteins (Martins, et al., 2008) (Figure 7). Anti-collagen antibodies can bind to M proteins or other collagen-binding proteins on the group A streptococcus and induce an immune response against the valve (Cunningham, 2014; Tandon, Sharma, Chandrasekhar, Kotb, Yacoub, & Narula, 2013). Initial damage of the valve chordae tendinae lead to annular dilation and chordal elongation, which prevents adequate surface coaptation of the valve leaflets (Veasy & Tani, 2005). Elevated troponin levels are not seen in rheumatic carditis, as the main damage is at and within the valve rather than in the myocardium.

Figure 7. . Multistep hypothesis of development of rheumatic carditis and heart disease.

Figure 7.

Multistep hypothesis of development of rheumatic carditis and heart disease. Diagram illustrates the process of initial mimicry that leads to granuloma formation, gamma interferon production and fibrosis/scarring in the valve. After the initial process (more...)

Although cardiac myosin is not present in the valve, it serves as a biomarker of streptococcal cross-reactivity against the heart and is cross-reactive with other alpha-helical proteins in the valve, such as laminin and vimentin (Galvin, Hemric, Ward, & Cunningham, 2000; Goldstein, Halpern, & Robert, 1967; Galvin, Hemric, Kosanke, Factor, Quinn, & Cunningham, 2002; Guilizia, Cunningham, & McManus, 1992). Amino acid sequence homology between cardiac myosin and alpha-helical coiled coil proteins in the valve may be partially responsible for cross-reactivity with the valve (Gulizia, Cunningham, & McManus, 1991). Mimicry between the streptococcus and heart may result in initial damage to the valve, while more chronic disease could be related to the release of collagen I and other valvular proteins from damaged valves (Martins, et al., 2008). Cross-reactive anti-cardiac myosin antibodies may lead to initial valve inflammation at the endothelium, leading to edema, cellular infiltration, and fibrinous vegetations in the rough zone of the anterior leaflet. Scarring of the leaflets appears after chordal elongation, which is the initial cause of mitral regurgitation.

Repetitive streptococcal infections in children may lead to increased scar formation in the valve, and are responsible for recurrent rheumatic heart disease. Once the valve is infiltrated by T cells, scarring occurs, where neovascularization leaves the valve susceptible to subsequent attack. Elevated antibodies against the group A carbohydrate have long been associated with a poor prognosis and poor recovery from of rheumatic carditis until the diseased valve is replaced (Dudding & Ayoub, 1968).

In rheumatic carditis, disease activity is associated with immune responses against specific peptide epitopes of the human cardiac myosin heavy chain (Ellis, et al., 2010). Disease progression and monitoring effective treatment can potentially be followed by responses against human cardiac myosin peptides in the S2 hinge region of human cardiac myosin (Gorton, et al., 2011). The reactivity against cardiac myosin epitopes in rheumatic carditis were similar in children from different global regions, such as the US, India, and Hawaii. The underlying basis for the recognition of similar cardiac myosin epitopes in rheumatic carditis suggests that antigen-specific B cells are allowed to proliferate in susceptible individuals and pathogenic B cells are not eliminated by clonal deletion, receptor editing, or anergy. T cell clones were found in human rheumatic carditis that demonstrated strong avidity to cardiac myosin. Cardiac-myosin–specific T cells would normally be deleted or rendered anergic by normal tolerance mechanisms, but may be stimulated by streptococcal M proteins during infections. The T cell clones with the highest avidity for cardiac myosin, as compared to other host proteins, were isolated from rheumatic carditis (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005) and were strongly stimulated by peptides of streptococcal M protein and cardiac myosin. T cells isolated from human rheumatic valves were similar to those found in peripheral blood, and also proliferated to peptides of streptococcal M protein and cardiac myosin (Faé, et al., 2006).

Guilherme has proposed several other antigens in the valve that are of importance, such as vimentin, which are recognized by T cells cloned from valves (Guilherme, Köhler, Postol, & Kalil, 2011). Vimentin in human valve tissues was previously reported to be recognized by the mouse cross-reactive anti-streptococcal mAbs (Gulizia, Cunningham, & McManus, 1991), and the mouse mAbs were also reactive with DNA, similar to antibodies in systemic lupus erythematosus (Cunningham & Swerlick, 1986). Studies of anti-idiotypic antibodies developed against the anti-cardiac myosin idiotype My1 in rheumatic fever demonstrated the presence of the rheumatic fever idiotype My1 in rheumatic fever and acute glomerulonephritis, and also in systemic lupus erythematosus and Sjogrens syndrome (McCormack, Crossley, Ayoub, Harley, & Cunningham, 1993).

Human antibody responses against human cardiac myosin have identified peptide epitopes in acute rheumatic carditis (Ellis, et al., 2010). Immune responses to cardiac myosin were similar among a small sample of worldwide populations, in which immunoglobulin G targeted the S2 subfragment hinge region within S2 peptides that contained human cardiac myosin heavy chain amino acid residues 842–992 and 1164–1272. The human cardiac myosin S2 fragment epitopes were also found to be similar among populations with rheumatic carditis worldwide, regardless of the infecting group A streptococcal M protein serotype. Homologous epitopes shared among different rheumatogenic streptococcal M protein serotypes could prime the immune system against the heart during repeated streptococcal infections, and eventually lead to breaking tolerance, epitope spreading, and initiating rheumatic heart disease in susceptible individuals.

Susceptibility to ARF and RHD may result from variations in host genes, which may be potential risk factors for disease. Thus, identifying genetic associations may be important in understanding the immune responses which can be misdirected toward heart, joints, or the brain, and that lead to carditis, arthritis, or Sydenham’s chorea. In some studies of ARF, familial associations were found to be inherited with limited penetrance and concordance among dizygotic twins, which suggests an inherited susceptibility, but not classical Mendelian genetics (Bryant, Robins-Browne, Carapetis, & Curtis, 2009). Genetic associations and polymorphisms have been found in several immune related genes, as described herein. It is likely that ARF is immunologically related to systemic lupus erythematosus and Sjogren’s syndrome, since the My1 idiotype, identified in rheumatic fever, was present only on antibodies in these two diseases, but not in others, such as rheumatoid arthritis or IgA nephropathy (McCormack, Crossley, Ayoub, Harley, & Cunningham, 1993).

In ARF and RHD, susceptibility to disease may be linked to HLA predisposition, as is the case for many autoimmune-related diseases. In rheumatic heart disease, the DR-7 haplotype has been associated with mitral valve disease in a large Latvian population (>1200 children), along with several other haplotypes that conferred risk or protection (Stanevicha, et al., 2003), and HLA haplotype DR-7 has been linked to rheumatic heart disease in the Brazilian population (Guilherme, Weidebach, Kiss, Snitcowsky, & Kalil, 1991; Guilherme, Kalil, & Cunningham, 2006) as well as in the Egyptian and Turkish populations (Guilherme, Köhler, Postol, & Kalil, 2011). Other genes such as polymorphisms in cytokine genes, which have been associated with rheumatic fever and rheumatic heart disease, and a more detailed discussion of HLA haplotypes has been performed by Guilherme et al. (Guilherme, Köhler, Postol, & Kalil, 2011). Genes that were associated with rheumatic fever included a TLR 2 polymorphism. Berdeli et al. reported that the common TLR-2 Arg to Gln polymorphism at position 753 was significantly (p<0.0001) associated with acute rheumatic fever in Caucasian Turkish population compared to controls. It is interesting that our recent study in humans reported the tendency of human cardiac myosin or its fragments to bind to human TLR 2, which stimulated monocytes to produce proinflammatory cytokines (Zhang, Cox, Alvarez, & Cunningham, 2009). Human cardiac myosin epitopes may link innate and adaptive immunity, which leads to chronic inflammation in the heart (Zhang, Cox, Alvarez, & Cunningham, 2009).

Additional genes linked to rheumatic fever include the mannose-binding lectin gene O allele, which was associated with aortic regurgitation in rheumatic heart disease. The mannose binding lectin allele encodes for a lower production of the protein and is associated with increased risk of rheumatic fever and rheumatic heart disease (Guilherme, Köhler, Postol, & Kalil, 2011; Ramasawmy, et al., 2008). Mannose-binding lectin is important in clearance of bacteria and is associated with the complement system (Guilherme, Köhler, Postol, & Kalil, 2011). The FcRγIIA receptor gene may express a polymorphism, which causes differences in binding of IgG2 in humans. Turkish children with a high risk of developing rheumatic fever possessed the 131R/R genotype of FcRγIIA, and the 131H/R allele of the FcRγIIA was associated with an intermediate risk (Berdeli, Celik, Ozyürek, & Aydin, 2004). Failure to clear immune complexes from the blood may potentially lead to the continued development of high-affinity antibodies (Zhang, et al., 2013) that would attack the heart, brain, or other tissue sites in rheumatic fever. HLA B5 has been associated with immune complexes in acute rheumatic fever (Yoshinoya & Pope, 1980). These genetic associations are important to note as they are involved in inflammatory and immune responses against the streptococcus, and potentially predispose those who possess them to rheumatic heart disease.

Although host susceptibility may be a result of host genetic predisposition, the environmental influence exerted by S. pyogenes on host-streptococcal interactions is important in the development of rheumatic fever and RHD. Although the role of specific streptococcal strain variations in acute rheumatic fever may not be well characterized in epidemics of rheumatic fever, there have been reports of a relationship between rheumatic-fever–associated strains that were isolated from the great acute rheumatic fever epidemics of the World War II era where the S. pyogenes were rich in M protein, heavily encapsulated by hyaluronic acid, and highly virulent in mice (Stollerman, 2001). These highly mucoid strains primarily infected the throat rather than the skin and were also seen with the rheumatic fever outbreak in Utah in the United States (Veasy, et al., 2004). In the past, certain M protein serotypes were associated with rheumatic fever outbreaks, such as the well-known M5 protein serotype (Bisno, 1995; Bisno, Pearce, Wall, Moody, & Stollerman, 1970). S. pyogenes strains isolated in more tropical climates do not have the characteristics of these earlier strains isolated in North America. The epidemiology suggests a greater diversity of S. pyogenes strains, and skin-associated strains may dominate in ARF in the more tropical regions (Bryant, Robins-Browne, Carapetis, & Curtis, 2009). Both skin and throat strains are evident in rheumatic fever in the tropics, and there is increasing evidence of skin-associated strains linked to cases of rheumatic fever (Bryant, Robins-Browne, Carapetis, & Curtis, 2009).

The host-streptococcal interaction may have evolved from years of penicillin therapy and prophylaxis, which might lead to rheumatic fever outbreaks which do not have the same characteristic “rheumatogenic” strains that have been reported in previous outbreaks in the United States over the past 50 years (Bisno, 1995). Children in the great rheumatic fever epidemics who did not survive also did not transfer the most severe genetic predisposition to rheumatic fever to another generation. Changes in both the streptococcus and host over the past 100 years may have attenuated the host and the streptococcus such that we may not see severe ARF outbreaks, similar to those reported in the preantibiotic era.

Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococci (PANDAS): Anti-Streptococcal Humoral Immunity against the Brain

Sydenham chorea is well established as the primary neurologic manifestation of acute rheumatic fever (Taranta & Stollerman, 1956). The symptoms of Sydenham chorea include involuntary movements and neuropsychiatric behaviors that predate the involuntary movements. Initially in Sydenham chorea, IgG was observed to be associated with neurons in caudate and putamen regions of the basal ganglia (Husby, van de Rijn, Zabriskie, Abdin, & Williams, 1976). In later studies, human mAbs were derived from Sydenham chorea (Kirvan, Swedo, Heuser, & Cunningham, 2003) and were shown to cross-react with the group A streptococcal carbohydrate epitope N-acetyl-beta-D-glucosamine (GlcNAc) and brain antigens lysoganglioside (Kirvan, Swedo, Heuser, & Cunningham, 2003) and tubulin (Kirvan, Cox, Swedo, & Cunningham, 2007), which are both enriched in the brain. Evidence for the autoantibody cross-reactivity between streptococci and brain is shown by the reaction of the chorea-derived human mAbs with group A streptococcal wall-membranes, as well as the group A carbohydrate epitope GlcNAc and the brain (Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Cox, Swedo, & Cunningham, 2007; Kirvan, Swedo, Kurahara, & Cunningham, 2006a). IgG antibodies in sera or cerebrospinal fluid or the chorea-derived mAbs from Sydenham chorea reacted with human neuronal cells (SKNSH cell line) at the cell membrane and also activated the calcium calmodulin-dependent protein kinase II (CaMKII) (Kirvan, Swedo, Heuser, & Cunningham, 2003) in human neuronal cells. The activation of CaMKII led to increased dopamine release from the human neuronal cell line, as shown in experiments using tritiated dopamine (Kirvan, Swedo, Kurahara, & Cunningham, 2006a). In addition, intrathecal transfer of the chorea-derived mAb 24.3.1 into brains of Lewis rats induced elevated tyrosine hydroxylase activity in dopaminergic neurons (Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Swedo, Kurahara, & Cunningham, 2006a). CaMKII activation and signaling activity by Sydenham chorea sera was abrogated by removal of IgG from the sera (Kirvan, Swedo, Heuser, & Cunningham, 2003; Brimberg, et al., 2012), and plasmaphoresis led to improvement of symptoms (Perlmutter, et al., 1999; Garvey, Snider, Leitman, Werden, & Swedo, 2005). Antibody-mediated neuronal cell CaMKII activation and signaling by IgG antibodies in serum or cerebrospinal fluid from Sydenham chorea was also associated with symptoms (Kirvan, Swedo, Heuser, & Cunningham, 2003; Ben-Pazi, Stoner, & Cunningham, 2013). Antibody-mediated neuronal cell signaling in Sydenham chorea is a novel pathogenic mechanism, which may lead to symptoms of involuntary movements with associated neuropsychiatric behaviors in acute rheumatic fever (Kirvan, Swedo, Heuser, & Cunningham, 2003). Sydenham chorea may serve as a model for other movement and neuropsychiatric disorders, such as pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections, or PANDAS (Swedo, et al., 1998).

To investigate the in vivo targets of the human mAbs derived from Sydenham chorea, the antibody V genes of Sydenham chorea mAb 24.3.1 (Cox, et al., 2013) were expressed in transgenic (Tg) mice. The Tg mice demonstrated chorea antibody V gene expression in serum, and upon breaking the blood brain barrier, the human-mouse chimeric IgG antibody targeted dopaminergic tyrosine hydroxylase positive neurons in the basal ganglia (Cox, et al., 2013) as shown in merged Figure 8. mAb 24.3.1 derived from Sydenham chorea was shown to react with and signal the human dopamine D2 receptor (Cox, et al., 2013). Evidence suggested that chorea-derived human mAb reacted with the dopamine receptor D2. mAb 24.3.1 reacted with a flag-tagged dopamine D2 receptor and functionally signaled the human D2 receptor that was expressed in transfected cell lines. The data show that the human mAb and human Sydenham chorea sera IgG targeted the dopamine D2 receptor (Cox, et al., 2013). Symptoms measured by the USCRS Sydenham chorea rating scale were correlated to the ratio of anti-D1R/D2R antibodies (Ben-Pazi, Stoner, & Cunningham, 2013). Cox et al. further described that anti-D1 receptor and anti-D2 receptor antibodies (IgG) were significantly elevated in serum from Sydenham chorea, as well as from PANDAS (Cox, et al., 2013).

Figure 8. . Human Sydenham chorea 24.

Figure 8.

Human Sydenham chorea 24.3.1 V gene expressed as a human V gene-mouse IgG1a constant region in Transgenic(Tg) mice targets dopaminergic neurons. Chimeric Tg24.3.1 VH IgG1a Ab expressed in Tg mouse sera penetrated dopaminergic neurons in Tg mouse brain (more...)

For years, little attention was given to neuropsychiatric obsessive-compulsive symptoms, which can predate chorea as the primary neurologic manifestation of acute rheumatic fever (Ben-Pazi, Stoner, & Cunningham, 2013). Small choreiform piano-playing movements of the fingers and toes were reported in the first 50 cases of PANDAS reported by Swedo et al. (Swedo, et al., 1998). PANDAS, which has similarities to Sydenham chorea (including a similar immunologic profile of anti-neuronal antibodies), is characterized by the abrupt onset of tics and obsessive-compulsive disorder (OCD). The fine choreiform movements in PANDAS are not as obvious as the choreoathetoid involuntary movements seen in Sydenham chorea (Garvey, Snider, Leitman, Werden, & Swedo, 2005; Garvey & Swedo, 1997). The fine choreiform movements may go unnoticed in PANDAS, and cause a child to have poor handwriting skills (which are generally associated with learning and behavioral regression), enuresis, separation anxiety and night-time fears; anorexia may appear in approximately 17 percent of cases (Swedo, et al., 1998). PANDAS symptoms and pathogenesis, which is also covered in great detail in a separate chapter in this book, may be observed in other types of infections and are not always associated with group A streptococcal infections. In the presence of other infections or in the absence of streptococcal infection, the disease is referred to as pediatric acute onset neuropsychiatric syndrome, or PANS (Swedo, Leckman, & Rose, 2012). The clinical evaluation consensus of PANDAS and PANS has recently been published (Chang, et al., 2015). More chronic types of tics and OCD may or may not be associated with streptococcal infections, and may be associated with Mycoplasma infections, influenza, or Lyme disease, but few studies have methodically considered the infections that may exacerbate PANS. More chronic tics and OCD do not appear to display the small choreiform piano-playing movements of the fingers and toes, and are not similar to Sydenham chorea in their anti-neuronal antibody patterns of antibodies against the dopamine D2 receptor. Chronic forms of tics and OCD do not appear to have the IgG antibodies against the D2 receptor (Cox, et al., 2015; Singer, et al., 2015). The PANDAS cases that have the small choreiform piano-playing movements of the fingers and toes appear to share antibodies against both D1 and D2 receptors, and may also have elevated antibodies against tubulin and lysoganglioside (Kirvan, Cox, Swedo, & Cunningham, 2007; Cox, et al., 2013; Brimberg, et al., 2012; Ben-Pazi, Stoner, & Cunningham, 2013). Studies suggest that more chronic forms of tics and OCD appeared to have anti-neuronal antibodies that were significantly elevated against only the dopamine D1 receptor and/or antibodies against lysoganglioside (Cox, et al., 2015; Singer, et al., 2015). Most cases of PANDAS and/or PANS notably appeared to have elevated serum CamKII activation and signaling of a human neuronal cell line (SKNSH), regardless of the presence of one or both of the anti-D2 or anti-D1 receptor antibodies (Cox, et al., 2015).

Animal models of Sydenham chorea and PANDAS have been successful in showing that immunization with group A streptococcal antigens or passive transfer of purified anti-streptococcal IgG antibodies in both a mouse model (Yaddanapudi, et al., 2010; Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004) and a Lewis rat model (Brimberg, et al., 2012; Lotan, et al., 2014) are associated with behavioral changes. To be more specific, immunization of a mouse model (Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004) with a streptococcal antigen led to antibody deposits in several brain regions, including deep cerebellar nuclei (DCN), globus pallidus, and the thalamus, and led to a display of behavioral alterations, such as increased rearing behavior and obsessive responses (Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004). Evidence suggested that immune responses against group A streptococci were associated with motoric and behavioral disturbances, and also suggested that anti-streptococcal anti-neuronal antibodies that are potentially cross-reactive with brain components may lead to movement and obsessive behaviors following streptococcal infections (Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004). Passive transfer of purified IgG anti-streptococcal antibodies from the immunized mice into naïve recipients led to behavior changes and antibody deposits in brain tissues (Yaddanapudi, et al., 2010).

Studies in the Lewis rat model (Brimberg, et al., 2012) demonstrated that exposure to group A streptococcal antigens led to the inability of the rats to hold a food pellet for a normal length of time, and immunized rats could not traverse a narrow beam as well as control rats (Brimberg, et al., 2012). Group A streptococcal immunized rats demonstrated compulsive grooming behavior, as compared to normal rats, after spray treatment with a water mist (Brimberg, et al., 2012). Deposits of IgG were found in the striatum, thalamus, and frontal cortex of group A streptococcal immunized rats. Study of the cortex and basal ganglia revealed alterations in dopamine and glutamate levels, which is consistent with the pathophysiology of Sydenham chorea and its related neuropsychiatric disorder. Anti-streptococcal sera from rats immunized with S. pyogenes antigen activated CaMKII in SKNSH human neuronal cells (Brimberg, et al., 2012), in a manner similar to sera from Sydenham chorea (Kirvan, Swedo, Heuser, & Cunningham, 2003; Kirvan, Swedo, Snider, & Cunningham, 2006b). Antibody removal with anti-igG beads removed the signaling activity of the sera (Brimberg, et al., 2012), which further demonstrated its association with IgG antibodies. The fact that plasmaphoresis improves the symptoms in Sydenham chorea and in PANDAS is consistent with the hypothesis that antibodies are mediating the symptoms of disease (Perlmutter, et al., 1999; Perlmutter, et al., 1998).

To summarize, the antineuronal antibodies found in Sydenham chorea, PANDAS and PANS, anti-lysoganglioside (Kirvan, Swedo, Snider, & Cunningham, 2006b), anti-tubulin (Kirvan, Cox, Swedo, & Cunningham, 2007), anti-dopamine D2 receptor (Cox, et al., 2013; Brimberg, et al., 2012; Ben-Pazi, Stoner, & Cunningham, 2013), and anti-dopamine D1 receptor (Ben-Pazi, Stoner, & Cunningham, 2013) antibodies have all been reported and studied. The anti-dopamine D2 receptor/anti-dopamine D1 receptor antibody ratio was correlated with the UFMG-Sydenham-Chorea-Rating-Scale (USCRS) of neuropsychiatric symptoms (Ben-Pazi, Stoner, & Cunningham, 2013). Most importantly, the functional signaling activity of the anti-neuronal antibodies was observed when human chorea derived mAbs or sera from Sydenham chorea or PANDAS was reacted with dopamine D2 receptor-expressing transfected cell lines (Cox, et al., 2013). Further evidence that Sydenham chorea is antibody-mediated includes the study of human Sydenham chorea-derived mAbs, which activated CaMKII signaling in human neuronal cells (Cox, et al., 2013). The signaling activity in the human neuronal cell line also led to the overproduction of dopamine (Kirvan, Swedo, Kurahara, & Cunningham, 2006a), which would affect central dopamine pathways.

A model diagram of the potential immunological and physiological mechanism of Sydenham chorea, the major neurologic manifestation of rheumatic fever, is shown in Figure 9 (Cunningham, 2012). In theory, this mechanism may also apply to PANDAS and PANS. The effects of antineuronal antibodies on the brain may include: 1) the binding of antibody to the D1 and D2 dopamine receptors with subsequent signaling of the receptors, which are often found as heterodimers with each other or with other G protein coupled receptors in the membrane; 2) the potential effects of binding to lysoganglioside in the membranes of neurons; and 3) the release of excess dopamine, which can affect receptor density and potentially sensitivity, as well as the possible effects of the excess dopamine and CaMKII signaling on other receptors expressed in the membranes of the neurons and their projections. Excess dopamine released from the SKNSH cell line was observed when treated with a human mAb 24.3.1 or acute Sydenham chorea sera (Kirvan, Swedo, Kurahara, & Cunningham, 2006a). As described above, evidence in animal models and humans strongly suggests that antibodies mediate inflammatory consequences in Sydenham chorea, PANDAS, and PANS (Perlmutter, et al., 1999). It is highly possible that other brain antigens are targeted by autoantibodies in PANDAS/PANS or other related autoimmune neuropsychiatric and mental disorders that may affect memory, learning, and behavior (Yaddanapudi, et al., 2010; Hoffman, Hornig, Yaddanapudi, Jabado, & Lipkin, 2004; Huerta, Kowal, DeGiorgio, Volpe, & Diamond, 2006; Kowal, et al., 2004; DeGiorgio, et al., 2001).

Figure 9. . Simplified illustration of a potential pathogenic mechanism in Sydenham chorea.

Figure 9.

Simplified illustration of a potential pathogenic mechanism in Sydenham chorea. An antineuronal antibody (IgG) may bind to receptors on neuronal cells and trigger the signaling cascade of CaMKII, tyrosine hydroxylase and dopamine release which may potentially (more...)

Summary and Perspective

Molecular mimicry between the group A streptococcus, heart, and brain is supported by evidence from studies of human mAbs, human T cell clones, and serum IgG antibodies derived from streptococcal sequelae and rheumatic fever (Galvin, Hemric, Ward, & Cunningham, 2000; Kirvan, Swedo, Heuser, & Cunningham, 2003). Human mAbs derived from rheumatic carditis and Sydenham chorea have supported the hypothesis that antibodies against the group A streptococcal carbohydrate epitope GlcNAc recognize cross-reactive structures in the heart and brain, which can lead to rheumatic carditis/rheumatic heart disease and Sydenham chorea, respectively (Galvin, Hemric, Ward, & Cunningham, 2000; Kirvan, Swedo, Heuser, & Cunningham, 2003). The rheumatic valve has been linked to humoral immune responses that attack the endocardium and allow activated T cells cross-reactive with cardiac myosin and streptococcal M protein epitopes to enter through activated VCAM-1+ endothelium at the valve surface (Roberts, et al., 2001). Although a Th1 response was observed by Guilherme et al. in the valve (Guilherme, et al., 2004), Th17 cells have also been recognized to have the potential for importance in the pathogenesis of rheumatic heart disease, where the balance between Th17 and T regulatory lymphocyte subsets was altered in disease that favored the Th17 subset. (Bas, et al., 2014). As early as 1989, Bhatia et al. reported changes in the lymphocyte subsets (Bhatia, et al., 1989). Changes in the subsets may lead to a Th17 predominance in disease with excess antibody production, including the cross-reactive antibodies, as well as the formation of immune complexes. Th17 cells have been established in responses against group A streptococci (Dileepan, Linehan, Moon, Pepper, & Jenkins, 2011; Wang, et al., 2010) and extracellular pathogens. Antibody-mediated neuronal cell signaling may be an important mechanism of antibody pathogenesis in Sydenham chorea, as well as in diseases such as PANDAS and PANS.

The emerging theme in mimicry suggests that cross-reactive autoantibodies target intracellular antigens, but to be pathogenic, antibodies must also target the surface antigens of neuronal cells or valve endothelial cells by targeting extracellular matrix proteins on the heart valve, such as laminin (Galvin, Hemric, Ward, & Cunningham, 2000), or binding to receptors such as the dopamine receptors which signal neurons (Cox, et al., 2013) or by other inflammatory effects caused by immune complexes of cross-reactive antibodies (Nelson, et al., 2015; Zhang, et al., 2002).

The avidity of the cross-reactive antibodies is important in dictating antibody-mediated cell signaling in the brain (Kirvan, Swedo, Heuser, & Cunningham, 2003), or complement-mediated cytotoxicity on heart cells (Cunningham, et al., 1992; Mertens, Galvin, Adderson, & Cunningham, 2000). For example, see Figure 10, where cross-reactive mouse anti-streptococcal/anti-myosin mouse mAbs were compared for their binding avidity. The two mAbs that were cytotoxic for heart cells (mAb36.2.2 and mAb54.2.8) were found to have the highest avidity for cardiac myosin as shown in Figure 10 (mAbs 36.2.2 and 54.2.8 as shown farthest to the left in Figure 10). Antibodies can be cross-reactive without rendering disease consequences in the host, if their avidity is not strong enough to dictate functional signaling, cytotoxicity of a host cell, or deposit in tissues. Most of the mAbs shown in Figure 10 are cross-reactive, but are without consequences (no cytotoxicity of heart cells) and may not be associated with disease (Mertens, Galvin, Adderson, & Cunningham, 2000), but the two most avid mAbs were cytotoxic for heart cells in culture (Cunningham, et al., 1992).

Figure 10. . Comparison of binding avidity of antistreptococcal antibodies reactive to human cardiac myosin in the enzyme-linked immunosorbent assay.

Figure 10.

Comparison of binding avidity of antistreptococcal antibodies reactive to human cardiac myosin in the enzyme-linked immunosorbent assay. Highest avidity mAbs (36.2.2 and 54.2.8) were cytotoxic for rat primary heart cells (ATCC) in culture in the presence (more...)

The presence of cross-reactive T cells in the host repertoire has been related to the recognition of antigen in the thymus where T cells that are too reactive with self antigens are deleted. Recent studies by Jenkins and colleagues suggest that cross-reactive T cells that recognize self and foreign epitopes with lower affinity are not deleted and remain in the T cell repertoire of the host, which predisposes the host to autoimmune disease after exposure to microbial antigens (Nelson, et al., 2015). Figure 11 shows the cross-reactivity of a T cell clone G4s from rheumatic carditis, which recognized M protein more avidly than cardiac myosin (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005). The recognition of the streptococcal antigen more avidly than the host antigen is expected—but T cell clones which bind host antigen more avidly will become activated and produce the cytokines that lead to autoimmune consequences and disease in the host, as described above for the T cell clones passively transferred into Lewis rats (Kirvan, Galvin, Hilt, Kosanke, & Cunningham, 2014).

Figure 11. . Dose response of cross-reactive T cell clone G4s.

Figure 11.

Dose response of cross-reactive T cell clone G4s. A cross- reactive Ag dose-dependent IFN-gamma response curve is shown for 1000 cells/ well G4s cells at 24 h after stimulation with rM6 protein, human cardiac myosin, laminin, and tropomyosin. The response (more...)

Acute rheumatic fever and its related autoimmune sequelae associated with group A streptococcal infections is complicated by several risk factors that contribute to disease, including repeated streptococcal infections, a host’s genetic susceptibility (such as HLA haplotype), and environmental aspects, which can include the interaction of host and streptococcus determining the outcome and disease. The same three risk factors are important in autoimmune diseases. The study of molecular mimicry in rheumatic fever has revealed interesting and plausible mechanisms and host-microbe relationships for both B and T cell responses in disease. Pathogenic mechanisms have been suggested and supported by disease-derived human mAbs (Galvin J. E., Hemric, Ward, & Cunningham, 2000; Kirvan, Swedo, Heuser, & Cunningham, 2003; Shikhman & Cunningham, 1994), human T cell clones (Ellis, Li, Hildebrand, Fischetti, & Cunningham, 2005), animal models of both rheumatic valvulitis (Quinn, Kosanke, Fischetti, Factor, & Cunningham, 2001) and Sydenham chorea (Brimberg, et al., 2012; Lotan, et al., 2014), and translation of the disease models back to the human to apply the findings directly to rheumatic fever and streptococcal sequelae.

References

  • Adderson E. E., Shikhman A. R., Ward K. E., Cunningham M. W. Molecular analysis of polyreactive monoclonal antibodies from rheumatic carditis: human anti-N-acetyl- glucosamine/anti-myosin antibody V region genes. Journal of immunology. The Journal of Immunology. 1998;161(4):2020–2031. [PubMed: 9712075]
  • Bas H. D., Baser K., Yavuz E., Bolayir H. A., Yaman B., Unlu S., et al. A shift in the balance of regulatory T and T helper 17 cells in rheumatic heart disease. Journal of Investigative Medicine. 2014;62(1):78–83. [PubMed: 24158043]
  • Ben-Pazi H., Stoner J. A., Cunningham M. W. Dopamine Receptor Autoantibodies Correlate with Symptoms in Sydenham's Chorea. PLoS One. 2013;8(9):e73516. [PMC free article: PMC3779221] [PubMed: 24073196]
  • Berdeli A., Celik H. A., Ozyürek R., Aydin H. H. Involvement of immunoglobulin FcgammaRIIA and FcgammaRIIIB polymorphisms in susceptibility to rheumatic fever. Clinical Biochemistry. 2004;37(10):925–929. [PubMed: 15369725]
  • Bhatia R., Narula J., Reddy K. S., Koicha M., Malaviya A. N., Pothineni R. B., et al. Lymphocyte subsets in acute rheumatic fever and rheumatic heart disease. Clinical Cardiology. 1989;12(1):34–38. [PubMed: 2912606]
  • Bisno, A. L. (1995). Non-Suppurative Poststreptococcal Sequelae: Rheumatic Fever and Glomerulonephritis. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (pp. 1799-1810). New York: Churchill Livingstone.
  • Bisno A. L. Acute pharyngitis. The New England Journal of Medicine. 2001;344(3):205–211. [PubMed: 11172144]
  • Bisno A. L., Stevens D. L. Streptococcal infections of skin and soft tissues. The New England Journal of Medicine. 1996;334:240–245. [PubMed: 8532002]
  • Bisno A. L., Brito M. O., Collins C. M. Molecular basis of group A streptococcal virulence. The Lancet Infectious Diseases. 2003;3(4):191–200. [PubMed: 12679262]
  • Bisno A. L., Pearce I. A., Wall H. P., Moody M. D., Stollerman G. H. Contrasting epidemiology of acute rheumatic fever and acute glomerulonephritis: nature of the antecedent streptococcal infection. The New England Journal of Medicine. 1970;283:561–565. [PubMed: 4915873]
  • Brimberg L., Benhar I., Mascaro-Blanco A., Alvarez K., Lotan D., Winter C., et al. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012;37(9):2076–2087. [PMC free article: PMC3398718] [PubMed: 22534626]
  • Bryant P. A., Robins-Browne R., Carapetis J. R., Curtis N. Some of the people, some of the time: susceptibility to acute rheumatic fever. Circulation. 2009;119(5):742–753. [PubMed: 19204317]
  • Carapetis J. R., Currie B. J., Good M. F. Towards understanding the pathogenesis of rheumatic fever. Scandiavian Journal of Rheumatology. 1996;25(3):127–131. [PubMed: 8668953]
  • Carapetis J. R., Walker A. R., Kilburn C. J., Currie B. J., MacDonald K. T. Ten-year follow up of a cohort with rheumatic heart disease (RHD). Australian and New Zealand Journal of Medicine. 1997;27(6):691–697. [PubMed: 9483238]
  • Carapetis J., Steer A. C. Prevention of rheumatic fever. Pediatric Infectious Disease Journal. 2010;29(1):91–92. [PubMed: 20035211]
  • Carapetis J., Robins-Browne R., Martin D., Shelby-James T., Hogg G. Increasing severity of invasive group A streptococcal disease in Australia: clinical and molecular epidemiologicalfeatures and identification of a new virulent M-nontypeable clone. Clinical Infectious Diseases. 1995;21(5):1220–1227. [PubMed: 8589146]
  • Chang K., Frankovich J., Cooperstock M., Cunningham M. W., Latimer M. E., Murphy T. K., et al. Clinical evaluation of youth with pediatric acute onset neuropsychiatric syndrome(PANS): Recommendations from the 2013 PANS consensus conference. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):3–13. [PMC free article: PMC4340805] [PubMed: 25325534]
  • Chopra P., Narula J. P. Scanning electron microscope features of rheumatic vegetations in acute rheumatic carditis. International Journal of Cardiology. 1991;30(1):109–112. [PubMed: 1991659]
  • Chopra P., Narula J., Kumar A. S., Sachdeva S., Bhatia M. L. Immunohistochemical characterisation of Aschoff nodules and endomyocardial inflammatory infiltrates in left atrial appendages from patients with chronic rheumatic heart disease. International Journal of Cardiology. 1988;20(1):99–105. [PubMed: 3042638]
  • Cox C. J., Sharma M., Leckman J. F., Zuccolo J., Zuccolo A., Kovoor A., et al. Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine d2 receptor: implications in human disease. The Journal of Immunology. 2013;191(11):5524–5541. [PMC free article: PMC3848617] [PubMed: 24184556]
  • Cox C. J., Zuccolo A. J., Edwards E. V., Mascaro-Blanco A., Alvarez K., Stoner J., et al. Antineuronal antibodies in a heterogeneous group of youth and young adults with tics and obsessive compulsive disorder. Journal of Child and Adolescent Psychopharmacology. 2015;25(1):76–85. [PMC free article: PMC4340634] [PubMed: 25658702]
  • Cunningham M. W. Pathogenesis of Group A Streptococcal Infections. Clinical Microbiology Reviews. 2000;13(3):470–511. [PMC free article: PMC88944] [PubMed: 10885988]
  • Cunningham M. W. Autoimmunity and molecular mimicry in the pathogenesis of post-streptococcal heart disease. Frontiers in Bioscience. 2003;8:s533–s543. [PubMed: 12700052]
  • Cunningham, M. W. (2006). Molecular mimicry, autoimmunity and infection in the pathogenesis of rheumatic fever. In K. S. Sriprakash (Ed.), Proceedings of the XVIth Lancefield International Symposium on Streptococci and Streptococcal Diseases, held in Palm Cove, Australia between 25 and 29 September, 2005 / International Congress, No. 1289 (Book 1289 (pp. 14-19). Amsterdam: Elsevier.
  • Cunningham M. W. Streptococcus and rheumatic fever. Current Opinion in Rheumatology. 2012;24(4):408–416. [PMC free article: PMC3645882] [PubMed: 22617826]
  • Cunningham M. W. Rheumatic fever revisited. Nature Reviews Cardiology. 2014;11:123. [PMC free article: PMC5967633] [PubMed: 24419260]
  • Cunningham M. W., Swerlick R. A. Polyspecificity of antistreptococcal murine monoclonal antibodies and their implications in autoimmunity. The Journal of Experimental Medicine. 1986;164(4):998–1012. [PMC free article: PMC2188424] [PubMed: 3531385]
  • Cunningham M. W., Antone S. M., Gulizia J. M., McManus B. M., Fischetti V. A., Gauntt C. J. Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(4):1320–1324. [PMC free article: PMC48441] [PubMed: 1311095]
  • Danjani A. S., Bisno A. L., Chung K. J., Durack D. T., Gerber M. A., Kaplan E. L., et al. Prevention of rheumatic fever: A statement for health professionals by the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Circulation. 1988;78(4):1082–1086. [PubMed: 3139324]
  • DeGiorgio L. A., Konstantinov K. N., Lee S. C., Hardin J. A., Volpe B. T., Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with theNR2 glutamate receptor in systemic lupus erythematosus. Nature Medicine. 2001;7(11):1189–1193. [PubMed: 11689882]
  • Dileepan T., Linehan J. L., Moon J. J., Pepper M., Jenkins M. K. Robust antigen specific Th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection. PLoS Pathogens. 2011;7(9):e1002252. [PMC free article: PMC3178561] [PubMed: 21966268]
  • Dinkla K., Rohde M., Jansen W. T., Carapetis J. R., Chhatwal G. S., Talay S. R. Streptococcus pyogenes recruits collagen via surface-bound fibronectin: a novel colonization and immune evasion mechanism. Molecular Microbiology. 2003a;47(3):861–869. [PubMed: 12535082]
  • Dinkla K., Rohde M., Jansen W. T., Kaplan E. L., Chhatwal G. S., Talay S. R. Rheumatic fever-associated Streptococcus pyogenes isolates aggregate collagen. The Journal of Clinical Investigation. 2003b;111(12):1905–1912. [PMC free article: PMC161421] [PubMed: 12813026]
  • Dudding B. A., Ayoub E. M. Persistence of streptococcal group A antibody in patients with rheumatic valvular disease. The Journal of Experimental Medicine. 1968;128(5):1081–1098. [PMC free article: PMC2138567] [PubMed: 5682941]
  • Ellis N. M., Kurahara D. K., Vohra H., Mascaro-Blanco A., Erdem G., Adderson E. E., et al. Priming the immune system for heart disease: a perspective on group A streptococci. The Journal of Infectious Diseases. 2010;202(7):1059–1067. [PubMed: 20795820]
  • Ellis N. M., Li Y., Hildebrand W., Fischetti V. A., Cunningham M. W. T cell mimicry and epitope specificity of crossreactive T cell clones from rheumatic heart disease. The Journal of Immunology. 2005;175(8):5448–5456. [PubMed: 16210652]
  • Faé K. C., da Silva D. D., Oshiro S. E., Tanaka A. C., Pomerantzeff P. M., Douay C., et al. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. The Journal of Immunology. 2006;176(9):5662–5670. [PubMed: 16622036]
  • Faé K., Kalil J., Toubert A., Guilherme L. Heart infiltrating T cell clones from a rheumatic heart disease patient display a common TCR usage and a degenerate antigen recognition pattern. Molecular Immunology. 2004;40(14-15):1129–1135. [PubMed: 15036919]
  • Galvin J. E., Hemric M. E., Kosanke S. D., Factor S. M., Quinn A., Cunningham M. W. Induction of myocarditis and valvulitis in Lewis rats by different epitopes of cardiac myosin and its implications in rheumatic carditis. The American Journal of Pathology. 2002;160(1):297–306. [PMC free article: PMC1867128] [PubMed: 11786423]
  • Galvin J. E., Hemric M. E., Ward K., Cunningham M. W. Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. The Journal of Clinical Investigation. 2000;106(2):217–224. [PMC free article: PMC314302] [PubMed: 10903337]
  • Garvey M. A., Swedo S. E. Sydenham's chorea. Clinical and therapeutic update. Advances in Experimental Medicine and Biology. 1997;418:115–120. [PubMed: 9331612]
  • Garvey M. A., Snider L. A., Leitman S. F., Werden R., Swedo S. E. Treatment of Sydenham's chorea with intravenous immunoglobulin, plasma exchange, or prednisone. Journal of Child Neurology. 2005;20(5):424–429. [PubMed: 15968928]
  • Gerber M. A., Baltimore R. S., Eaton C. B., Gewitz M., Rowley A. H., Shulman S. T., et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease. Circulation. 2009;119(11):1541–1551. [PubMed: 19246689]
  • Goldstein I., Halpern B., Robert L. Immunological relationship between streptococcus A polysaccharide and the structural glycoproteins of heart valve. Nature. 1967;213:44–47.
  • Gorton D. E., Govan B. L., Ketheesan N., Sive A. A., Norton R. E., Currie B. J., et al. Cardiac myosin epitopes for monitoring progression of rheumatic fever. The Pediatric Infectious Disease Journal. 2011;30(11):1015–1016. [PMC free article: PMC3358003] [PubMed: 21997667]
  • Gorton D., Blyth S., Gorton J. G., Govan B., Ketheesan N. An alternative technique for the induction of autoimmune valvulitis in a rat model of rheumatic heart disease. Journal of Immunological Methods. 2010;355(1-2):80–85. [PubMed: 20206182]
  • Gorton D., Govan B., Olive C., Ketheesan N. B- and T-Cell Responses in Group A Streptococcus M-Protein- or Peptide-Induced Experimental Carditis. Infection and Immunity. 2009;77(5):2177–2183. [PMC free article: PMC2681745] [PubMed: 19273562]
  • Guilherme, L., & Kalil, J. (2004). Rheumatic Fever: How streptococcal throat infection triggers an autoimmune disease. In Y. Shoenfeld, N. Agmon-Levin, & N. R. Rose (Eds.), Infection and Autoimmunity (pp. 321-331). Amsterdam: Elsevier.
  • Guilherme L., Cunha-Neto E., Coelho V., Snitcowsky R., Pomerantzeff P. M., Assis R. V., et al. Human Heart–Infiltrating T-Cell Clones From Rheumatic Heart Disease Patients Recognize Both Streptococcal and Cardiac Proteins. Circulation. 1995;92:415–420. [PubMed: 7634457]
  • Guilherme L., Cury P., Demarchi L. M., Coelho V., Abel L., Lopez A. P., et al. Rheumatic heart disease: proinflammatory cytokines play a role in the progression and maintenance of valvular lesions. The American Journal of Pathology. 2004;165(5):1583–1591. [PMC free article: PMC1618676] [PubMed: 15509528]
  • Guilherme L., Dulphy N., Douay C., Coelho V., Cunha-Neto E., Oshiro S. E., et al. Molecular evidence for antigen-driven immune responses in cardiac lesions of rheumatic heart disease patients. International Immunology. 2000;12(7):1063–1074. [PubMed: 10882418]
  • Guilherme L., Kalil J., Cunningham M. W. Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease. Autoimmunity. 2006;39(1):31–39. [PubMed: 16455580]
  • Guilherme L., Köhler K. F., Postol E., Kalil J. Genes, autoimmunity, and pathogenesis of rheumatic heart disease. Annals of Pediatric Cardiology. 2011;4(1):13–21. [PMC free article: PMC3104525] [PubMed: 21677799]
  • Guilherme, L., Oshiro, S. E., Faé, 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. 69(9), 5345-5351. [PMC free article: PMC98644] [PubMed: 11500404]
  • Guilherme L., Weidebach W., Kiss M. H., Snitcowsky R., Kalil J. Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population. Circulation. 1991;83(6):1995–1998. [PubMed: 2040052]
  • Guilizia, J. M., Cunningham, M. W., & McManus, B. M. (1992). Anti-streptococcal monoclonal antibodies recognize multiple epitopes in human heart valves: cardiac myosin, vimentin, and elastin as potential valvular autoantigens. In G. Orefici (Ed.), New perspectives on streptococci and streptococcal infections Proceedings of the XI Lancefield International Symposium. 22 (pp. 267-269). New York: VCH Pub.
  • Gulizia J. M., Cunningham M. W., McManus B. M. Immunoreactivity of anti-streptococcal monoclonal antibodies to human heart valves. Evidence for multiple cross-reactive epitopes. The American Journal of Pathology. 1991;138(2):285–301. [PMC free article: PMC1886198] [PubMed: 1704188]
  • Hoffman K. L., Hornig M., Yaddanapudi K., Jabado O., Lipkin W. I. A murine model for neuropsychiatric disorders associated with group A beta-hemolytic streptococcal infection. The Journal of Neuroscience. 2004;24(7):1780–1791. [PMC free article: PMC6730451] [PubMed: 14973249]
  • Huerta P. T., Kowal C., DeGiorgio L. A., Volpe B. T., Diamond B. Immunity and behavior: antibodies alter emotion. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(3):678–683. [PMC free article: PMC1334673] [PubMed: 16407105]
  • Husby G., van de Rijn I., Zabriskie J. B., Abdin Z. H., Williams R. C. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. The Journal of Experimental Medicine. 1976;144(4):1094–1110. [PMC free article: PMC2190435] [PubMed: 789810]
  • Jones T. D. The diagnosis of rheumatic fever. JAMA. 1944;126(8):481–484.
  • Kaplan E. L., Johnson D. R., Cleary P. P. Group A streptococcal serotypes isolated from patients and sibling contacts during the resurgence of rheumatic fever in the United States in the mid-1980s. The Journal of Infectious Diseases. 1989;159(1):101–103. [PubMed: 2642516]
  • Kaplan M. H. Immunologic relation of streptococcal and tissue antigens. I. Properties of an antigen in certain strains of group A streptococci exhibiting an immunologic cross reaction with human heart tissue. The Journal of Immunology. 1963;90:595–606. [PubMed: 14082021]
  • Kaplan M. H., Dallenbach F. D. Immunologic studies of heart tissue. II. Occurrence of bound gamma-globulin in auricular appendages from rheumatic hearts. Relationship to certain histopathologic features of rheumatic heart disease. The Journal of Experimental Medicine. 1961;113:1–16. [PMC free article: PMC2137344] [PubMed: 13751306]
  • Kaplan M. H., Meyerserian M. An immunological cross reaction between group A streptoccal cells and human heart tissue. Lancet. 1962;1(7232):706–710. [PubMed: 14453769]
  • Kaplan M. H., Suchy M. L. Immunologic relation of streptococcal and tissue antigens. II. Cross reactions of antisera to mammalian heart tissue with a cell wall constituent of certain strains of group A streptococci. The Journal of Experimental Medicine. 1964;119(4):643–650. [PMC free article: PMC2137843] [PubMed: 14151104]
  • Kaplan M. H., Svec K. H. Immunologic relation of streptococcal and tissue antigens. III. Presence in human sera of stretpcoccal antibody cross reactive with heart tissue. Association with streptococcal infection, rheumatic fever, and glomerulonephritis. The Journal of Experimental Medicine. 1964;119:651–666. [PMC free article: PMC2137853] [PubMed: 14151105]
  • Kaplan M. H., Bolande R., Rakita L., Blair J. Presence of bound immunoglobulins and complement in the myocardium in acute rheumatic fever. Association with cardiac failure. The New England Journal of Medicine. 1964;271:637–645. [PubMed: 14170842]
  • Kirvan C. A., Cox C. J., Swedo S. E., Cunningham M. W. Tubulin is a neuronal target of autoantibodies in Sydenham's chorea. The Journal of Immunology. 2007;178(11):7412–7421. [PubMed: 17513792]
  • Kirvan C. A., Galvin J. E., Hilt S., Kosanke S., Cunningham M. W. Identification of streptococcal m-protein cardiopathogenic epitopes in experimental autoimmune valvulitis. Journal of Cardiovascular Translational Research. 2014;7(2):172–181. [PMC free article: PMC3943786] [PubMed: 24346820]
  • Kirvan C. A., Swedo S. E., Heuser J. S., Cunningham M. W. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nature Medicine. 2003;9(7):914–920. [PubMed: 12819778]
  • Kirvan C. A., Swedo S. E., Kurahara D., Cunningham M. W. Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham's chorea. Autoimmunity. 2006a;39(1):21–29. [PubMed: 16455579]
  • Kirvan C. A., Swedo S. E., Snider L. A., Cunningham M. W. Antibody-mediated neuronal cell signaling in behavior and movement disorders. Journal of Neuroimmunology. 2006b;179(1-2):173–179. [PubMed: 16875742]
  • Kowal C., DeGiorgio L. A., Nakaoka T., Hetherington H., Huerta P. T., Diamond B., et al. Cognition and immunity: antibody impairs memory. Immunity. 2004;21(2):179–188. [PubMed: 15308099]
  • Krisher K., Cunningham M. W. Myosin: a link between streptococci and heart. Science. 1985;227(4685):413–415. [PubMed: 2578225]
  • Lotan D., Benhar I., Alvarez K., Mascaro-Blanco A., Brimberg L., Frenkel D., et al. Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain, Behavior, and Immunity. 2014;38:249–262. [PMC free article: PMC4000697] [PubMed: 24561489]
  • Lukomski S., Nakashima K., Abdi I., Cipriano V. J., Ireland R. M., Reid S. D., et al. Identification and characterization of the scl gene encoding a group A Streptococcus extracellular protein virulence factor with similarity to human collagen. Infection and Immunity. 2000;68(12):6542–6553. [PMC free article: PMC97748] [PubMed: 11083763]
  • Lukomski S., Nakashima K., Abdi I., Cipriano V. J., Shelvin B. J., Graviss E. A., et al. Identification and characterization of a second extracellular collagen-like protein made by group A Streptococcus: control of production at the level of translation. Infection and Immunity. 2001;69(3):1729–1738. [PMC free article: PMC98079] [PubMed: 11179350]
  • Lymbury R. S., Olive C., Powell K. A., Good M. F., Hirst R. G., LaBrooy J. T., et al. Induction of autoimmune valvulitis in Lewis rats following immunization with peptides from the conserved region of group A streptococcal M protein. Journal of Autoimmunity. 2003;20(3):211–217. [PubMed: 12753806]
  • Malkiel S., Liao L., Cunningham M. W., Diamond B. T-cell-dependent antibody response to the dominant epitope of streptococcal polysaccharide, N-acetyl-glucosamine, is cross-reactive with cardiac myosin. Infection and Immunity. 2000;68(10):5803–5808. [PMC free article: PMC101540] [PubMed: 10992488]
  • Martins T. B., Hoffman J. L., Augustine N. H., Phansalkar A. R., Fischetti V. A., Zabriskie J. B., et al. Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever. International Immunology. 2008;20(3):445–452. [PubMed: 18245783]
  • McCormack J. M., Crossley C. A., Ayoub E. M., Harley J. B., Cunningham M. W. Poststreptococcal anti-myosin antibody idiotype associated with systemic lupus erythematosus and Sjögren's syndrome. The Journal of Infectious Diseases. 1993;168(4):915–921. [PubMed: 8376838]
  • McDonald M., Currie B. J., Carapetis J. R. Acute rheumatic fever: a chink in the chain that links the heart to the throat? The Lancet Infectious Diseases. 2004;4(4):240–245. [PubMed: 15050943]
  • McNamara C., Zinkernagel A. S., Macheboeuf P., Cunningham M. W., Nizet V., Ghosh P. Coiled-coil irregularities and instabilities in group A streptococcus M1 are required for virulence. Science. 2008;319(5868):1405–1408. [PMC free article: PMC2288698] [PubMed: 18323455]
  • Mertens N. M., Galvin J. E., Adderson E. E., Cunningham M. W. Molecular analysis of cross-reactive anti-myosin/anti-streptococcal mouse monoclonal antibodies. Molecular Immunology. 2000;37(15):901–913. [PubMed: 11282394]
  • Murphy T. K., Snider L. A., Mutch P. J., Harden E., Zaytoun A., Edge P. J., et al. Relationship of movements and behaviors to Group A Streptococcus infections in elementary school children. Biological Psychiatry. 2007;61(3):279–284. [PubMed: 17126304]
  • Murphy T. K., Storch E. A., Lewin A. B., Edge P. J., Goodman W. K. Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The Journal of Pediatrics. 2012;160(2):314–319. [PMC free article: PMC3227761] [PubMed: 21868033]
  • Nelson R. W., Beisang D., Tubo N. J., Dileepan T., Wiesner D. L., Nielsen K., et al. T cell receptor cross-reactivity between similar foreing and self peptides influences naive cell population size and autoimmunity. Immunity. 2015;42(1):95–107. [PMC free article: PMC4355167] [PubMed: 25601203]
  • Pepper M., Linehan J. L., Pagán A. J., Zell T., Dileepan T., Cleary P. P., et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nature Immunology. 2010;11(1):83–89. [PMC free article: PMC2795784] [PubMed: 19935657]
  • Perlmutter S. J., Garvey M. A., Castellanos X., Mittleman B. B., Giedd J., Rapoport J. L., et al. A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The American Journal of Psychiatry. 1998;155(11):1592–1598. [PubMed: 9812123]
  • Perlmutter S. J., Leitman S. F., Garvey M. A., Hamburger S., Feldman E., Leonard H. L. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. 1999;354(9185):1153–1158. [PubMed: 10513708]
  • Quinn A., Kosanke S., Fischetti V. A., Factor S. M., Cunningham M. W. Induction of autoimmune valvular heart disease by recombinant streptococcal M protein. Infection and Immunity. 2001;69(6):4072–4078. [PMC free article: PMC98471] [PubMed: 11349078]
  • Ramasawmy R., Spina G. S., Fae K. C., Pereira A. C., Nisihara R., Reason I. J., et al. Association of mannose binding lectin gene polymorphism but not of mannose binding serine protease 2 with chronic severe aortic regurgitation of rheumatic etiology. Clinical and Vaccine Immunology. 2008;15(6):932–936. [PMC free article: PMC2446618] [PubMed: 18400978]
  • Read, S. E., & Zabriskie, J. B. (1977). Immunological concepts in rheumatic fever pathogenesis. In P. A. Miescher, & H. J. Muller-Eberhard (Eds.), Textbook of Immunopathology: v. 2 (p. 471). New York: Grune and Stratton.
  • Read S. E., Reid H. F., Fischetti V. A., Poon-King T., Ramkissoon R., McDowell M., et al. Serial studies on the cellular immune response to streptococcal antigens in acute and convalescent rheumatic fever patients in Trinidad. Journal of Clinical Immunology. 1986;6(6):433–441. [PubMed: 3536986]
  • Read S. E., Reid H., Poon-King T., Fischetti V. A., Zabriskie J. B., Rapaport F. T. HLA and predisposition to the nonsuppurative sequelae of group A streptococcal infections. Transplantation Proceedings. 1977;9(1):543–546. [PubMed: 325790]
  • Reddy K. S., Narula J., Bhatia R., Shailendri K., Koicha M., Taneja V., et al. Immunologic and immunogenetic studies in rheumatic fever and rheumatic heart disease. Indian Journal of Pediatrics. 1990;57(5):693–700. [PubMed: 2094670]
  • Roberts S., Kosanke S., Terrence Dunn S., Jankelow D., Duran C. M., Cunningham M. W. Immune mechanisms in rheumatic carditis: Focus on valvular endothelium. The Journal of Infectious Diseases. 2001;183(3):507–511. [PubMed: 11133385]
  • Shikhman A. R., Cunningham M. W. Immunological mimicry between N-acetyl-beta-D-glucosamine and cytokeratin peptides. Evidence for a microbially driven anti-keratin antibody response. The Journal of Immunology. 1994;152(9):4375–4387. [PubMed: 7512592]
  • Shikhman A. R., Greenspan N. S., Cunningham M. W. A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-D-glucosamine. The Journal of Immunology. 1993;151(7):3902–3913. [PubMed: 7690820]
  • Shikhman A. R., Greenspan N. S., Cunningham M. W. Cytokeratin peptide SFGSGFGGGY mimics N-acetyl-beta-D-glucosamine in reaction with antibodies and lectins, and induces in vivo anti-carbohydrate antibody response. The Journal of Immunology. 1994;153(12):5593–5606. [PubMed: 7527445]
  • Singer H. S., Gause C., Morris C., Lopez P., Tourette Syndrome Study Group. Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Pediatrics. 2008;121(6):1198–1205. [PubMed: 18519490]
  • Singer H. S., Gilbert D. L., Wolf D. S., Mink J. W., Kurlan R. Moving from PANDAS to CANS. The Journal of Pediatrics. 2012;160(5):725–731. [PubMed: 22197466]
  • Singer H. S., Mascaro-Blanco A., Alvarez K., Morris-Berry C., Kawikova I., Ben-Pazi H., et al. Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection. PLoS One. 2015;10(3):e0120499. [PMC free article: PMC4368605] [PubMed: 25793715]
  • Snider L. A., Swedo S. E. PANDAS: current status and directions for research. Molecular Psychiatry. 2004;9(10):900–907. [PubMed: 15241433]
  • Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. (1992). Guidelines for the diagnosis of rheumatic fever (Jones criteria, 1992 update). JAMA, 268, 2069-2073. [PubMed: 1404745]
  • Stanevicha V., Eglite J., Sochnevs A., Gardovska D., Zavadska D., Shantere R. HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia. Arthritis Research & Therapy. 2003;5(6):R340–R346. [PMC free article: PMC333411] [PubMed: 14680508]
  • Steer A. C., Carapetis J. R., Nolan T. M., Shann F. Systematic review of rheumatic heart disease prevalence in children in developing countries: the role of environmental factors. Journal of Paediatrics and Child Health. 2002;38(3):229–234. [PubMed: 12047688]
  • Stollerman G. H. Rheumatic fever. Lancet. 1997;349(9056):935–942. [PubMed: 9093263]
  • Stollerman G. H. Rheumatic fever in the 21st century. Clinical Infectious Diseases. 2001;33(6):806–814. [PubMed: 11512086]
  • Stollerman, G. H. (2011). Rheumatic and heritable connective tissue diseases of the cardiovascular system. In E. Braunwald, Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine (pp. 1706-1734). Philadelphia: W. B. Saunders Co. Ltd.
  • Swedo S. E. Sydenham's chorea: A model for childhood autoimmune neuropsychiatric disorders. JAMA. 1994;272(22):1788–1791. [PubMed: 7661914]
  • Swedo S. E. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Molecular Psychiatry. 2002;7 Suppl 2:S24–S25. [PubMed: 12142939]
  • Swedo S. E., Leckman J. F., Rose N. R. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatrics & Therapeutics. 2012;2:113.
  • Swedo S. E., Leonard H. L., Garvey M., Mittleman B., Allen A. J., Perlmutter S., et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. The American Journal of Psychiatry. 1998;155(2):264–271. [PubMed: 9464208]
  • Swedo S. E., Leonard H. L., Mittleman B. B., Allen A. J., Rapoport J. L., Dow S. P., et al. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. The American Journal of Psychiatry. 1997;154(1):110–112. [PubMed: 8988969]
  • Tandon R., Sharma M., Chandrasekhar Y., Kotb M., Yacoub M. H., Narula J. Revisiting the pathogenesis of rheumatic fever and carditis. Nature Reviews Cardiology. 2013;10(3):171–177. [PubMed: 23319102]
  • Taranta A., Stollerman G. H. The relationship of Sydenham's chorea to infection with group A streptococci. The American Journal of Medicine. 1956;20(2):170–175. [PubMed: 13282936]
  • Veasy L. G. Rheumatic fever. The Lancet Infectious Diseases. 2004;4(11):661. [PubMed: 15522676]
  • Veasy L. G., Tani L. Y. A new look at acute rheumatic mitral regurgitation. Cardiology in the Young. 2005;15(6):568–577. [PubMed: 16297248]
  • Veasy L. G., Tani L. Y., Hill H. R. Persistence of acute rheumatic fever in the intermountain area of the United States. The Journal of Pediatrics. 1994;124(1):9–16. [PubMed: 7802743]
  • Veasy L. G., Tani L. Y., Daly J. A., Korgenski K., Miner L., Bale J., et al. Temporal association of the appearance of mucoid strains of Streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah. Pediatrics. 2004;113(3 Pt 1):e168–e172. [PubMed: 14993572]
  • Veasy L. G., Wiedmeier S. E., Orsmond G. S., Ruttenberg H. D., Boucek M. M., Roth S. J., et al. Resurgence of acute rheumatic fever in the intermountain area of the United States. The New England Journal of Medicine. 1987;316(8):421–427. [PubMed: 3807984]
  • Wang B., Dileepan T., Briscoe S., Hyland K. A., Kang J., Khoruts A., et al. Induction of TGF-beta1 and TGF-beta1-dependent predominant Th17 differentiation by group A streptococcal infection. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(13):5937–5942. [PMC free article: PMC2851870] [PubMed: 20231435]
  • Wannamaker L. W. The chain that links the throat to the heart. Circulation. 1973;48(1):9–18. [PubMed: 4592577]
  • Yaddanapudi K., Hornig M., Serge R., De Miranda J., Baghban A., Villar G., et al. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Molecular Psychiatry. 2010;15(7):712–726. [PubMed: 19668249]
  • Yoshinoya S., Pope R. M. Detection of immune complexes in acute rheumatic fever and their relationship to HLA-B5. The Journal of Clinical Investigation. 1980;65(1):136–145. [PMC free article: PMC371348] [PubMed: 6765956]
  • Zabriskie J. B. Mimetic relationships between group A streptococci and mammalian tissues. Advances in Immunology. 1967;7:147–188. [PubMed: 4868522]
  • Zabriskie J. B. Rheumatic fever: the interplay between host, genetics and microbe. Circulation. 1985;71:1077–1086. [PubMed: 3995703]
  • Zabriskie J. B., Freimer E. H. An immunological relationship between the group A streptococcus and mammalian muscle. The Journal of Experimental Medicine. 1966;124(4):661–678. [PMC free article: PMC2138256] [PubMed: 5922288]
  • Zabriskie J. B., Gibofsky A. Genetic control of the susceptibility to infection with pathogenic bacteria. Current Topics in Microbiology and Immunology. 1986;124:1–20. [PubMed: 3519099]
  • Zabriskie J. B., Hsu K. C., Seegal B. C. Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance. Clinical & Experimental Immunology. 1970;7(2):147–159. [PMC free article: PMC1712832] [PubMed: 4920603]
  • Zhang H., Leckman J. F., Pauls D. L., Tsai C. P., Kidd K. K., Campos M. R., et al. Genomewide scan of hoarding in sib pairs in which both sibs have Gilles de la Tourette syndrome. American Journal of Human Genetics. 2002;70(4):896–904. [PMC free article: PMC379118] [PubMed: 11840360]
  • Zhang P., Cox C. J., Alvarez K. M., Cunningham M. W. Cutting edge: cardiac myosin activates innate immune responses through TLRs. The Journal of Immunology. 2009;183(1):27–31. [PMC free article: PMC2720835] [PubMed: 19535635]
  • Zhang Y., Meyer-Hermann M., George L. A., Figge M. T., Khan M., Goodall M., et al. Germinal center B cells govern their own fate via antibody feedback. The Journal of Experimental Medicine. 2013;210(3):457–464. [PMC free article: PMC3600904] [PubMed: 23420879]
© The University of Oklahoma Health Sciences Center.

Except where otherwise noted, this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC-BY-NC-ND 4.0). To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK333434PMID: 26866235

Views

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...