Rheumatology Advance Access originally published online on May 16, 2006
Rheumatology 2006 45(7):833-841; doi:10.1093/rheumatology/kel118
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Overlapping humoral autoimmunity links rheumatic fever and the antiphospholipid syndrome
1 Research Center for Autoimmune Diseases, Sheba Medical Center and 2 Department of Medicine ‘E’, Rabin Medical Center, Beilinson Campus; Sackler Faculty of Medicine, Tel-Aviv University, Israel, 3 Heart Institute (InCor), School of Medicine, University of Sao Paulo and 4 Institute for Immunology Investigation, Millennium Institute, Sao Paulo, Brazil, 5 Hvidovre Hospital, Hvidovre, Denmark, 6 Institute of Immunology, University of Rostock, Schillingallee 70, 18055 Rostock, Germany, 7 Department of Microbiology and Immunology, Biomedical Research Center, University of Oklahoma Health Sciences Center, OK 73104, USA and 8 Incumbent of the Laura Schwarz-Kipp Chair for Autoimmunity, Tel Aviv University, Israel.
Correspondence to: Y. Shoenfeld, MD, Department of Medicine B, Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail: Shoenfel{at}post.tau.ac.il
Objective: Rheumatic fever (RF) and the antiphospholipid syndrome (APS) are autoimmune diseases that share similar cardiac and neurological pathologies. We assessed the presence of shared epitopes between M protein, N-acetyl-ß-D-glucosamine (GlcNAc) and ß2 glycoprotein-I (ß2GPI), the pathogenic molecules engaged in these autoimmune conditions.
Methods: Sera from the APS patients were affinity-purified on ß2GPI and ß2GPI-related peptide columns. Sera from RF patients were affinity-purified on protein G column. The ß2GPI and M protein-related peptides were prepared by conventional solid-phase peptide synthesis. The enzyme-linked immunosorbent assay direct binding and inhibition studies were performed on the RF and APS sera for the presence, and cross-reactivity, of antibodies against ß2GPI, ß2GPI-related peptides, streptococcal M protein, M-derived peptides and GlcNAc.
Results: Antibodies (Abs) to ß2GPI were found in 24.4% of 90 RF patients. Antibodies against various ß2GPI-related peptides were found in 1.1–36.7% of the patients. The immunoglobulin G sera from RF patients possessed significant anti-ß2GPI activity, while sera from APS patients contained a considerable anti-streptococcal M protein as well as anti-GlcNAc activity. Furthermore, affinity-purified anti-ß2GPI and anti-ß2GPI-related peptide Abs from APS patients cross-reacted with streptococcal M protein and M5 peptide, while ß2GPI and ß2GPI-related peptides inhibited anti-streptococcal M protein activity from RF patients. The results were confirmed by immunoblot analyses. The ß2GPI also inhibited anti-GlcNAc activity from APS patients with chorea.
Conclusions: The results of our study, showing a considerable overlap of humoral immunity in RF and APS, support a hypothesis that common pathogenic mechanisms underlie the development of cardiac valve lesions and Central Nervous System abnormalities in both diseases.
KEY WORDS: Streptococcal infection, Anti-ß2GPI Abs, Anti-M-protein Abs, Carditis, Chorea