An acute rheumatic fever immune signature comprising inflammatory markers, IgG3, and Streptococcus pyogenes-specific antibodies
Natalie Lorenz,
Reuben McGregor,
Alana L. Whitcombe,
Prachi Sharma,
Ciara Ramiah,
Francis Middleton,
Michael G. Baker,
William J. Martin,
Nigel J. Wilson,
Amy W. Chung,
Nicole J. Moreland
Affiliations
Natalie Lorenz
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand
Reuben McGregor
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand
Alana L. Whitcombe
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand
Prachi Sharma
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
Ciara Ramiah
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
Francis Middleton
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand
Michael G. Baker
Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand; Department of Public Health, University of Otago, Wellington, New Zealand
William J. Martin
Independent Advisor, Wellington, New Zealand
Nigel J. Wilson
Starship Children’s Hospital, Health New Zealand – Te Whatu Ora, Auckland, New Zealand
Amy W. Chung
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
Nicole J. Moreland
School of Medical Science, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Biodiscovery, The University of Auckland, Auckland, New Zealand; Corresponding author
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.
