An acute rheumatic fever immune signature comprising inflammatory markers, IgG3, and <i>Streptococcus pyogenes</i>-specific antibodies

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Summary

Understanding the immune profile of acute rheumatic fever (ARF), a serious post-infectious sequelae of Streptococcal pyogenes (group A Streptococcus [GAS]), could inform disease pathogenesis and management. Circulating cytokines, immunoglobulins, and complement were analyzed in participants with first-episode ARF, swab-positive GAS pharyngitis and matched healthy controls. A striking elevation of total IgG3 was observed in ARF (90% > clinical reference range for normal). ARF was also associated with an inflammatory triad with significant correlations between interleukin-6, C-reactive protein, and complement C4 absent in controls. Quantification of GAS-specific antibody responses revealed that subclass polarization was remarkably consistent across the disease spectrum; conserved protein antigens polarized to IgG1, while M-protein responses polarized to IgG3 in all groups. However, the magnitude of responses was significantly higher in ARF. Taken together, these findings emphasize the association of exaggerated GAS antibody responses, IgG3, and inflammatory cytokines in ARF and suggest IgG3 testing could beneficially augment clinical diagnosis.

Graphical abstract

Highlights

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Total IgG3 is significantly elevated in acute rheumatic fever when compared to controls
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Acute rheumatic fever displays an inflammatory triad comprising IL-6, CRP, and C4
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Antibody responses polarize to IgG3 for M-protein and IgG1 for conserved GAS antigens
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GAS-specific antibody responses are exaggerated in acute rheumatic fever

Abstract

Immunology; Immune response; Microbiology; Cell biology

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mixOmics: An R package for ‘omics feature selection and multiple data integration

Florian Rohart, Benoît Gautier, Amrit Singh … (2017)

The advent of high throughput technologies has led to a wealth of publicly available ‘omics data coming from different sources, such as transcriptomics, proteomics, metabolomics. Combining such large-scale biological data sets can lead to the discovery of important biological insights, provided that relevant information can be extracted in a holistic manner. Current statistical approaches have been focusing on identifying small subsets of molecules (a ‘molecular signature’) to explain or predict biological conditions, but mainly for a single type of ‘omics. In addition, commonly used methods are univariate and consider each biological feature independently. We introduce mixOmics, an R package dedicated to the multivariate analysis of biological data sets with a specific focus on data exploration, dimension reduction and visualisation. By adopting a systems biology approach, the toolkit provides a wide range of methods that statistically integrate several data sets at once to probe relationships between heterogeneous ‘omics data sets. Our recent methods extend Projection to Latent Structure (PLS) models for discriminant analysis, for data integration across multiple ‘omics data or across independent studies, and for the identification of molecular signatures. We illustrate our latest mixOmics integrative frameworks for the multivariate analyses of ‘omics data available from the package.

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Disease manifestations and pathogenic mechanisms of group a Streptococcus.

Mark Walker, Timothy C Barnett, Jason McArthur … (2014)

Streptococcus pyogenes, also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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Acute rheumatic fever and rheumatic heart disease

Jonathan Carapetis, Andrea Beaton, Madeleine W. Cunningham … (2016)

Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances - including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life - give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.

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Author and article information

Contributors

Nicole J. Moreland

Journal

Journal ID (nlm-ta): iScience

Journal ID (iso-abbrev): iScience

Title: iScience

Publisher: Elsevier

ISSN (Electronic): 2589-0042

Publication date PMC-release: 20 July 2024

Publication date Collection: 16 August 2024

Publication date (Electronic): 20 July 2024

Volume: 27

Issue: 8

Electronic Location Identifier: 110558

Affiliations

[1 ]School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand

[2 ]Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand

[3 ]Department of Public Health, University of Otago, Wellington, New Zealand

[4 ]Independent Advisor, Wellington, New Zealand

[5 ]Starship Children’s Hospital, Health New Zealand – Te Whatu Ora, Auckland, New Zealand

[6 ]Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia

Author notes

[∗ ]Corresponding author n.moreland@ 123456auckland.ac.nz

[7]

These authors contributed equally

[8]

Lead contact

Article

Publisher Item ID: S2589-0042(24)01783-8 Publisher ID: 110558

DOI: 10.1016/j.isci.2024.110558

PMC ID: 11342286

PubMed ID: 39184444

SO-VID: c8d1b827-19c5-4d6a-9b72-bf56c61982cd

License:

This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

History

Date received : 24 April 2024

Date revision received : 11 July 2024

Date accepted : 17 July 2024

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