Post-infectious group A streptococcal autoimmune syndromes and the heart

Martin, William J.; Steer, Andrew C.; Smeesters, Pierre; Keeble, Joanne; Inouye, Michael; Carapetis, Jonathan R.; Wicks, Ian P.

doi:10.1016/j.autrev.2015.04.005

Cited by 96 publications

(64 citation statements)

References 271 publications

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“…In rheumatic heart disease, epitope shifting may indicate the release of more self-proteins later in the immune response against cardiac myosin such as in the S2-8 non-responders. As discussed by Martin et al [27], these pathogenic mechanisms may play a role in other streptococcal diseases including pediatric autoimmune syndromes associated with streptococcal infections but more importantly related to anti-phospholipid syndromes that includes Libman-Sacks endocarditis [27, 28]. …”

Section: Discussionmentioning

confidence: 99%

Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever

Garcia

Yamaga

Shafer

et al. 2016

Pediatric Infectious Disease Journal

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Background Acute rheumatic fever (ARF) is an autoimmune disorder associated with Streptococcus pyogenes infection. A prevailing hypothesis to account for this disease is that epitopes of self-antigens, such as cardiac myosin react to antibodies against S. pyogenes. The goal of our study was to confirm disease epitopes of cardiac myosin, identify immunodominant epitopes and to monitor the epitope response pattern in acute and convalescent rheumatic fever. Methods Enzyme-linked immunosorbant assays were used to determine epitopes immunodominant in acute disease and to track the immune response longitudinally to document any changes in the epitope pattern in convalescent sera. Multiplex fluorescence immunoassay was used to correlate anti-streptolysin O and anti-human cardiac myosin antibodies. Results Disease specific epitopes in rheumatic fever were identified as S2-1, 4 and 8. Epitopes S2-1, 4, 8, and 9 were found to be immunodominant in acute sera and S2-1, 8, 9, 29 and 30 in the convalescent sera. Frequency analysis showed that 50% of the ARF subjects responded to S2-8. S2-8 responders tended to maintain their epitope pattern throughout the convalescent period, while the S2-8 non-responders tended to spread their responses to other epitopes later in the immune response. There was a significant correlation between anti-cardiac myosin and ASO titers. In addition, S2-8 responders showed elevated ASO titers compared with S2-8 non-responders. Conclusion Our studies confirm the existence of S2-1, 4 and 8 as disease specific epitopes. We provide evidence that cardiac myosin S2-8 responders remain epitope stable in convalescence, while S2-8 non-responders shift to neoepitopes. Multiplex data indicated a correlation between elevated anti-streptolysin O and anti-human cardiac myosin antibody titers. Mapping of cardiac myosin epitopes recognized in rheumatic fever sera may identify immunophenotypes of rheumatic fever.

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Section: Discussionmentioning

confidence: 99%

Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever

Garcia

Yamaga

Shafer

et al. 2016

Pediatric Infectious Disease Journal

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“…Moreover, even in highly endemic settings where childhood GAS infections are ubiquitous, only a minority of the population develop ARF or RHD during their lifetime (up to 5–6%), and this may indicate that the disease develops only in those who are genetically predisposed7. Despite this, efforts to delineate host genetic susceptibility have so far been limited to a number of small candidate gene studies—many focused on the HLA locus—the results of which have been inconsistent and largely inconclusive8.…”

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confidence: 99%

Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania

et al. 2017

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The indigenous populations of the South Pacific experience a high burden of rheumatic heart disease (RHD). Here we report a genome-wide association study (GWAS) of RHD susceptibility in 2,852 individuals recruited in eight Oceanian countries. Stratifying by ancestry, we analysed genotyped and imputed variants in Melanesians (607 cases and 1,229 controls) before follow-up of suggestive loci in three further ancestral groups: Polynesians, South Asians and Mixed or other populations (totalling 399 cases and 617 controls). We identify a novel susceptibility signal in the immunoglobulin heavy chain (IGH) locus centring on a haplotype of nonsynonymous variants in the IGHV4-61 gene segment corresponding to the IGHV4-61*02 allele. We show each copy of IGHV4-61*02 is associated with a 1.4-fold increase in the risk of RHD (odds ratio 1.43, 95% confidence intervals 1.27–1.61, P=4.1 × 10−9). These findings provide new insight into the role of germline variation in the IGH locus in disease susceptibility.

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“…Additionally, GAS exposure may trigger serious postinfection sequelae, including acute rheumatic fever or acute poststreptococcal glomerulonephritis (14). The remarkable diversity of GAS diseases can be traced to the ability of the pathogen to express a large repertoire of virulence factors, including adhesins, proteases, immunoprotective proteins, and superantigens (15,16).…”

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confidence: 99%

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

et al. 2017

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Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease. This is true for the group A Streptococcus (GAS), a pathogen that causes both invasive (e.g., necrotizing fasciitis) and noninvasive (e.g., pharyngitis) diseases. The control of virulence (CovRS) two-component system has a major role in regulating GAS virulence factor expression. The regulator of cov (RocA) protein, which is a predicted kinase, functions in an undetermined manner through CovRS to alter gene expression and reduce invasive disease virulence. Here, we show that the ectopic expression of a truncated RocA derivative, harboring the membrane-spanning domains but not the dimerization or HATPase domain, is sufficient to complement a rocA mutant strain. Coupled with a previous bioinformatic study, the data are consistent with RocA being a pseudokinase. RocA reduces the ability of serotype M1 GAS isolates to express capsule and to evade killing in human blood, phenotypes that are not observed for M3 or M18 GAS due to isolates of these serotypes naturally harboring mutant rocA alleles. In addition, we found that varying the RocA concentration attenuates the regulatory activity of Mg 2ϩ and the antimicrobial peptide LL-37, which positively and negatively regulate CovS function, respectively. Thus, we propose that RocA is an accessory protein to the CovRS system that influences the ability of GAS to modulate gene expression in response to host factors. A model of how RocA interacts with CovRS, and of the regulatory consequences of such activity, is presented.

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Post-infectious group A streptococcal autoimmune syndromes and the heart

Cited by 96 publications

References 271 publications

Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever

Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever

Association between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania

RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus

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