Mapping Autoantibodies in Children With Acute Rheumatic Fever

Frontiers in Immunology

Michael G. Baker¹  Julie Bennett¹  Nicole J. Moreland²  Reuben McGregor²  Martin J. Middleditch³  Jeremy M. Raynes⁴  Paulina Hanson-Manful⁴  Lauren H. Carlton⁴  Mei Lin Tay⁴  Wasan O. Forsyth⁴  William John Martin⁵  Nigel Wilson⁶  Diane T. Brewster⁷  Polly Atatoa Carr⁸ 

[1] Department of Public Health, University of Otago, Wellington, New Zealand;Maurice Wilkins Centre, The University of Auckland, Auckland, New Zealand;School of Biological Sciences, The University of Auckland, Auckland, New Zealand;School of Medical Sciences, The University of Auckland, Auckland, New Zealand;Science for Technological Innovation Science Challenge, Callaghan Innovation, Wellington, New Zealand;Starship Children’s Hospital, Auckland, New Zealand;The Plant and Food Research Institute, Auckland, New Zealand;Waikato District Health Board and Waikato University, Hamilton, New Zealand;

关键词: autoantibody;    rheumatic fever;    protein array;    immunoassay;    autoantigen;    streptococcus A;   

DOI  :  10.3389/fimmu.2021.702877

来源: DOAJ

【 摘 要 】

BackgroundAcute rheumatic fever (ARF) is a serious sequela of Group A Streptococcus (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease.MethodsThis study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand.ResultsGlobal analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens.ConclusionsThe broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity.

【 授权许可】

Unknown