Poster Presentation Lorne Infection and Immunity 2022

Profiling circulating immunoglobulins and cytokines in Acute Rheumatic Fever Patients (#183)

Natalie Lorenz 1 2 , Reuben McGregor 1 2 , Ciara Ramiah 1 , Julie Bennett 2 3 , Michael Baker 2 3 , Amy Chung 4 , Nicole Moreland 1 2
  1. School of Medical Sciences, University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre for Biodiscovery, Auckland, New Zealand
  3. Department of Public Health, University of Otago, Wellington, New Zealand
  4. Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia

Acute Rheumatic Fever (ARF) is a severe autoinflammatory disease that can develop after a Streptococcus A (StrepA) infection in susceptible children. ARF is a stark example of health inequality in New Zealand, with Māori and Pacific children 20-40 times more likely to experience ARF. Disease pathogenesis remains poorly understood, and this contributes to the lack of specific therapies and treatments.

In a previous systems immunology analysis, we observed that immunoglobulin subclass 3 (IgG3) and complement component 4 (C4) were significantly elevated above the clinical reference ranges in >90% of ARF patients, and that IgG1, IgG3, IgA and C4 were able to distinguish ARF patients from matched healthy controls.1

In this study we have extended these analyses to include circulating cytokines in an expanded cohort comprised of 60 ARF cases and 60 age and ethnically matched controls drawn from recently completed large-scale studies of ARF and StrepA infections in New Zealand.2,3 Circulating concentrations of 20 cytokines, as well as the four previously identified immune features were quantified using bead-based multiplex assays. The results corroborate earlier findings with IgG1, IgG3, IgA and C4 significantly elevated in ARF patients compared to matched healthy and acute StrepA pharyngitis controls. Furthermore, significant elevation of IL-6, IL-7, TNF-a and APRIL were observed in ARF patients, while IP-10 elevation was associated with StrepA pharyngitis. While IL-6 and TNF-a have previously been associated with rheumatic fever and rheumatic heart disease, the identification of lymphocyte growths factors IL-7 and APRIL provides new insight into ARF immunopathogenesis. Correlations and cluster analysis highlight the interplay between immune features in this expanded disease signature, which may help identify targets for immune-modulating drugs or immune-based therapies for ARF in the longer term.

  1. Chung, A. W. et al. Systems immunology reveals a linked IgG3–C4 response in patients with acute rheumatic fever. Immunol Cell Biol 98, 12–21 (2020).
  2. Baker, M. G. et al. Risk Factors for Acute Rheumatic Fever: Literature Review and Protocol for a Case-Control Study in New Zealand. Int J Environ Res Pu 16, 4515 (2019).
  3. Bennett, J. et al. Understanding group A streptococcal pharyngitis and skin infections as causes of rheumatic fever: protocol for a prospective disease incidence study. Bmc Infect Dis 19, 633 (2019).