Serological Evidence of Immune Priming by Group A Streptococci in Patients with Acute Rheumatic Fever.

Jeremy M Raynes,Jacelyn M Loh,Hannah R C Frost,John D Steemson,Nicole J Moreland,P R Dunbar,Deborah A Williamson,Polly E Atatoa Carr,Edward N Baker,Anita Bell,Paul G Young,Thomas Proft

doi:10.3389/fmicb.2016.01119

Abstract

Acute rheumatic fever (ARF) is an autoimmune response to Group A Streptococcus (GAS) infection. Repeated GAS exposures are proposed to ‘prime’ the immune system for autoimmunity. This notion of immune-priming by multiple GAS infections was first postulated in the 1960s, but direct experimental evidence to support the hypothesis has been lacking. Here, we present novel methodology, based on antibody responses to GAS T-antigens, that enables previous GAS exposures to be mapped in patient sera. T-antigens are surface expressed, type specific antigens and GAS strains fall into 18 major clades or T-types. A panel of recombinant T-antigens was generated and immunoassays were performed in parallel with serum depletion experiments allowing type-specific T-antigen antibodies to be distinguished from cross-reactive antibodies. At least two distinct GAS exposures were detected in each of the ARF sera tested. Furthermore, no two sera had the same T-antigen reactivity profile suggesting that each patient was exposed to a unique series of GAS T-types prior to developing ARF. The methods have provided much-needed experimental evidence to substantiate the immune-priming hypothesis, and will facilitate further serological profiling studies that explore the multifaceted interactions between GAS and the host.

Highlights

Acute rheumatic fever (ARF) is an autoimmune condition that can develop after a Group A Streptococcus (GAS) infection
The T-antigen shows significantly less antigenic variation than the M protein, with a recent survey of GAS isolates in New Zealand finding that tee genes fall into 18 major clades or tee-types (Steemson et al, 2014)
The results suggest the siblings were infected with GAS strains of different tee-types immediately prior to developing ARF

Summary

INTRODUCTION

Acute rheumatic fever (ARF) is an autoimmune condition that can develop after a Group A Streptococcus (GAS) infection. It has been postulated that repeated infections with GAS are needed to ‘prime’ the immune system before the first episode of ARF occurs (Carapetis et al, 2005, 2016) This may partly explain the lack of disease in pre-school children. Zabriskie described a single case of recurrent ARF, where two GAS infections had occurred in the 8 years between the child’s first and second hospital admission for ARF Based on this observation Zabriskie speculated that repeated GAS episodes were necessary for disease to occur. ARF patients have elevated antibody titres to selected GAS antigens and human heart proteins compared with healthy controls (Cunningham et al, 1989; Martins et al, 2006; Ellis et al, 2010) It follows that repeated GAS infections would be required to generate molecular mimicry, a loss of tolerance and eventually autoimmunity. In order to systematically explore the basis of immune priming, new approaches are needed to accurately determine the frequency of GAS exposures in children with ARF

A SEROLOGICAL APPROACH TO EXAMINE IMMUNE PRIMING

DISCUSSION

CONCLUDING REMARKS