Mapping Autoantibodies in Children With Acute Rheumatic Fever

Abstract

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.

Characterization of an experimental model to determine streptococcal M protein–induced autoimmune cardiac and neurobehavioral abnormalities

“…Elevated levels of antibodies against collagens I and IV have been observed in ARF. 7,8,50,51 GAS infection disrupts the extracellular matrix and exposes cryptic collagen epitopes that induce autoantibody response against collagens I and IV. 52,53 Some GAS M proteins contain a peptide motif (peptide associated with rheumatic fever) essential for the Antibodies in pooled sera from rats injected with GAS rM5 (c) and SDSE Stg480 (d) to lysates of the striatum and cerebellum from naïve rats.…”

“…In addition to cross‐reactive antibodies and T cells against GAS M protein, anti‐collagen antibodies may also contribute to the disease progression. Elevated levels of antibodies against collagens I and IV have been observed in ARF 7,8,50,51 . GAS infection disrupts the extracellular matrix and exposes cryptic collagen epitopes that induce autoantibody response against collagens I and IV 52,53 .…”

Human antibody profiling technologies for autoimmune disease

“…Limitations: -Laborious and expensive to produce antigens. The Human ProtoArray >9,000 Nitrocellulose treated glass slide -Type one diabetes [ 8 ] -Parkinson’s disease ([ 51 ] -Systemic lupus erythematosus (SLE) [ 4 ] -Multiple Sclerosis [ 9 ] -Ankylosing spondylitis [ 52 ] -Sjogren’s syndrome [ 53 ] -Alzheimer’s disease [ 54 ] -Acute Rheumatic Fever [ 10 ] -Autoimmune Polyendocrine Syndrome type 1 (APS1) [ 48 ] -APECED [ 37 ] -Paediatric acute disseminated encephalomyelitis [ 55 ] HuProt Array >20,000 Glass slide -Multiple sclerosis [ 12 ] -Acute Rheumatic Fever [ 10 ] -Primary biliary cirrhosis [ 56 ] -Takayasu arteritis [ 57 ] -Multisystem inflammatory syndrome in children with a previous SARS-CoV-2 infection [ 36 ] -Bechet disease [ 49 ] NAPPA 80 to 12,000- Amine coated glass slide -Type one diabetes [ 15 , 16 ] -Ankylosing spondylitis [ 58 ] -Juvenile arthritis [ 59 ] -Osteoarthritis [ 60 ] -Rheumatoid Arthritis [ 17 ] i-Ome Protein Array Kit >1,600 Glass slide -SLE [ 18 , 19 ] -Rheumatoid Arthritis [ 20 ] ImmunoINSIGHTS 80-8,000 Microspheres -SLE [ 23 ] -Rheumatoid arthritis [ 21 , 22 ] In Ho...…”

Therapeutics for rheumatic fever and rheumatic heart disease

“…In less than 10% of the population, infection with Streptococcus pyogenes (group A streptococcus) can trigger autoimmune conditions including acute rheumatic fever or acute post-streptococcal glomerulonephritis days to months after the initial infection. 4 Acute rheumatic fever is not a homogenous condition and shows high immunological 5 and clinical 2 diversity. It can also be subtle and mimic other conditions.…”