Rheumatic fever, autoimmunity, and molecular mimicry: the streptococcal connection

Abstract

The group A streptococcus, Streptococcus pyogenes, and its link to autoimmune sequelae, has acquired a new level of understanding. Studies support the hypothesis that molecular mimicry between the group A streptococcus and heart or brain are important in directing immune responses in rheumatic fever. Rheumatic carditis, Sydenham chorea and a new group of behavioral disorders called pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections are reviewed with consideration of autoantibody and T cell responses and the role of molecular mimicry between the heart, brain and group A streptococcus as well as how immune responses contribute to pathogenic mechanisms in disease. In rheumatic carditis, studies have investigated human monoclonal autoantibodies and T cell clones for their crossreactivity and their mechanisms leading to valve damage in rheumatic heart disease. Although studies of human and animal sera from group A streptococcal diseases or immunization models have been crucial in providing clues to molecular mimicry and its role in the pathogenesis of rheumatic fever, study of human monoclonal autoantibodies have provided important insights into how antibodies against the valve may activate the valve endothelium and lead to T cell infiltration. Passive transfer of anti-streptococcal T cell lines in a rat model of rheumatic carditis illustrates effects of CD4+ T cells on the valve. Although Sydenham chorea has been known as the neurological manifestation of rheumatic fever for decades, the combination of autoimmunity and behavior is a relatively new concept linking brain, behavior and neuropsychiatric disorders with streptococcal infections. In Sydenham chorea, human mAbs and their expression in transgenic mice have linked autoimmunity to central dopamine pathways as well as dopamine receptors and dopaminergic neurons in basal ganglia. Taken together, the studies reviewed provide a basis for understanding streptococcal sequelae and how immune responses against group A streptococci influence autoimmunity and inflammatory responses in the heart and brain.

Keywords: Sydenham chorea; T cells; autoantibodies; autoimmunity; behavior; brain; group A streptococci; rheumatic fever.

Figure 1

Extravasation of CD4+ lymphocytes into valve above Aschoff’s body in the subendocardium of the left atrial appendage. Original magnification 200X Taken from Roberts et al (74).

Figure 2

2A) Induction of valvulitis and cellular infiltration in hematoxylin and-eosin-stained heart valves from Lewis rats immunized with group A streptococcal M5 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-4GLKTENEGLKTENEGLKTE aa residues 40–58; NT-4/5 GLKTEKKEHEAENDKLK aa residues 54–70 Kirvan, et al (86) 2B) Induction of valvulitis, edema and cellular infiltration in hematoxylin and-eosin-stained heart valves from Lewis rats immunized with group A streptococcal M5 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 Kirvan, et al (86). 2C) Verrucous nodule observed on valve after immunization with group A streptococcal rM6 protein. Taken from Quinn et al (85). 2D) Vascular Cell Adhesion Molecule-1 (VCAM-1) expressed on rheumatic valve. Taken from Roberts et al (74).

Figure 3

Human Sydenham chorea 24.3.1 V gene expressed as 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 in vivo. Colocalization of Tg 24.3.1 IgG1a (anti-IgG1a Ab, green Left Panel) and Tyrosine Hydroxylase Antibody (anti-TH Ab, yellow Middle Panel). TH is a marker for dopaminergic neurons. Left panel shows IgG1a (FITC labeled), center panel shows TH Ab (TRITC labeled), and right panel is merged image (FITC-TRITC). Brain sections (basal ganglia) of VH24.3.1 Tg mouse (original magnification 320), showing FITC labeled anti-mouse IgG1a (A), TRITC-labeled anti-TH Ab (B), and merged image (C). Controls treated with secondary antibody are negative. Figure 3 is similar to figure shown in Cox et al (63).