Presence of Bound Immunoglobulins and Complement in the Myocardium in Acute Rheumatic Fever

Kaplan, Melvin H.; Bolande, Robert P.; Rakita, Louis; Blair, John E.

doi:10.1056/nejm196409242711301

Cited by 159 publications

(77 citation statements)

References 14 publications

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“…The pathogenesis of RHD is autoimmune in nature, with both Abs and T cells playing important roles (15)(16)(17)(18). Various studies have identified the surface M protein of GAS as one such likely target (19)(20)(21)(22), inducing Abs and T cells capable of cross-reacting with cardiac myosin and tropomyosin (23)(24)(25)(26).…”

Section: S Treptococcus Pyogenes (Group a Streptococcus [Gas]mentioning

confidence: 99%

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

Pandey

Mortensen

Calcutt

et al. 2016

The Journal of Immunology

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Cluster of virulence responder/sensor (CovR/S) mutant group A streptococci (GAS) are serious human pathogens of multiple M protein strains that upregulate expression of virulence factors, including the IL-8 protease Streptococcus pyogenes cell envelope proteinase (SpyCEP), thus blunting neutrophil-mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. We previously showed that a combination vaccine incorporating J8-DT (conserved peptide vaccine from the M protein) and a recombinant SpyCEP fragment protects against CovR/S mutants. To enhance the vaccine’s safety profile, we identified a minimal epitope (S2) that was the target for anti-SpyCEP Abs that could protect IL-8 from SpyCEP-mediated proteolysis. Abs from healthy humans and from mice experimentally infected with GAS also recognized S2, albeit at low titers. Native SpyCEP may be poorly immunogenic (cryptic or subdominant), and it would be to the organism’s advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2) that protect IL-8 from proteolysis and other Abs (anti-J8) that cause strain-independent killing in the presence of neutrophils. We show that either component alone is ineffectual in preventing skin infection and bacteremia due to CovR/S mutants but that the combination induces complete protection. This protection correlated with a significant influx of neutrophils to the infection site. The data strongly suggest that the lack of natural immunity to hypervirulent GAS strains in humans could be rectified by this combination vaccine.

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Section: S Treptococcus Pyogenes (Group a Streptococcus [Gas]mentioning

confidence: 99%

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

Pandey

Mortensen

Calcutt

et al. 2016

The Journal of Immunology

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“…The presence of antibodies and complement elements in heart and valvular tissue of patients with RF (22,23,25) as well as the presence of antiheart antibodies and antimyosin antibodies in the sera of patients with RF (5,39) led to the suggestion that rheumatic carditis could be immune mediated. It has also been shown that cross-reactive human and murine monoclonal antibodies recognized N-acetylglucosamine (GlcNAc) of GAS (30,31).…”

mentioning

confidence: 99%

Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology

Ramasawmy

Spina

Faé

et al. 2008

Clin Vaccine Immunol

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N-Acetylglucosamine (GlcNAc) is the major immunoepitope of group A streptococcal cell wall carbohydrates. Antistreptococcal antibodies cross-reactive with anti-GlcNAc and laminin are present in sera of patients with rheumatic fever. The cross-reactivity of these antibodies with human heart valvular endothelium and the underlying basement membrane has been suggested to be a possible cause of immune-mediated valve lesion. Mannose-binding lectin (MBL) encoded by the MBL2 gene, a soluble pathogen recognition receptor, has high affinity for GlcNAc. We postulated that mutations in exon 1 of the MBL2 gene associated with a deficient serum level of MBL may contribute to chronic severe aortic regurgitation (AR) of rheumatic etiology. We studied 90 patients with severe chronic AR of rheumatic etiology and 281 healthy controls (HC) for the variants of the MBL2 gene at codons 52, 54, and 57 by using a PCR-restriction fragment length polymorphism-based method. We observed a significant difference in the prevalence of defective MBL2 alleles between patients with chronic severe AR and HC. Sixteen percent of patients with chronic severe AR were homozygotes or compound heterozygotes for defective MBL alleles in contrast to 5% for HC (P ‫؍‬ 0.0022; odds ratio, 3.5 [95% confidence interval, 1.6 to 7.7]). No association was detected with the variant of the MASP2 gene. Our study suggests that MBL deficiency may contribute to the development of chronic severe AR of rheumatic etiology.Rheumatic fever (RF), which results from a nonsuppurative sequela of pharyngitis caused by group A streptococcus (GAS) in untreated genetically susceptible hosts, displays a wide spectrum of clinical manifestations including carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum (3). Arthritis occurs in 60 to 65% of patients while carditis, the most serious manifestation and one which often leads to valvular scarring, is observed in 30 to 45% of patients with RF.

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“…25 In rheumatic carditis, infection plays a major role as well as anti-myosin antibody 46,47 that has been shown to be cytotoxic for heart cells in culture and to recognize cell surface crossreactive antigen laminin on the valve and myocyte cell surface. 29,30 In rheumatic carditis, antibodies deposit in myocardium as well as valvular endothelium 30,48,49 and T cells infiltrate the valve. 50 There have been a number of studies that have demonstrated anti-cardiac myosin or anti-heart antibodies in acute and chronic myocarditis [51][52][53][54] and soluble interleukin-2 levels were correlated with disease severity and cardiac autoantibodies.…”

mentioning

confidence: 99%

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

Cunningham

2001

The American Journal of Pathology

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Presence of Bound Immunoglobulins and Complement in the Myocardium in Acute Rheumatic Fever

Cited by 159 publications

References 14 publications

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci

Association of Mannose-Binding Lectin Gene Polymorphism but Not of Mannose-Binding Serine Protease 2 with Chronic Severe Aortic Regurgitation of Rheumatic Etiology

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

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