Poster Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

A Systematic Analysis of Immunoglobulin and Complement Pathways in Patients with Acute Rheumatic Fever (#175)

Amy W Chung 1 , Paulina Hanson-Manful 2 , Susan Tritscheller 2 , Jeremy M Raynes 2 , Deborah A Williamson 1 , Nicole Moreland 2 , Rheumatic Fever Risk Factor Study Group
  1. The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  2. University of Auckland, Auckland, NZ, New Zealand

Acute rheumatic fever (ARF) is an auto-inflammatory sequela that can develop after a Group A Streptococcus infection. Carditis, the most severe ARF manifestation, can lead to permanent heart valve damage and rheumatic heart disease. While immunoglobulin and complement were first observed in the myocardium and mitral valves of children who had died from cardiac failure following ARF over 50 years ago (Kaplan 1964), contemporary investigations of complement pathways in ARF have been lacking. The aim of this study was to determine how complement drives inflammation in ARF. The concentration of 17 complement factors spanning the classical, lectin and alternative pathways, together with six immunoglobulin isotypes and subclasses were measured in participant serum using bead-based immunoassays (BDTM Cytometric Bead Array and Luminex xMAPR). An integrative statistical approach was utilised to analyze relationships among immunoglobulin and complement in ARF patients stratified by concentration of C‑reactive protein (CRP).

Patients with high CRP had significantly elevated levels of several complement factors and immunoglobulin types compared with patients with low CRP and healthy controls. Key features contributing to ARF inflammation were identified by multidimensional analysis combining feature selection (the least absolute shrinkage and selection operator; LASSO) and partial least-squares discriminant analysis (PLSDA). Just 5 of the 23 analytes accounted for 71% of the variance between high and low CRP patients. Notably, patients in the high CRP group exhibited linked IgG3/C4 responses. This, together with an absence of any lectin pathway features, suggests a dominant role for the classical complement pathway in the immunopathogenesis of ARF.