Revisiting the pathogenesis of rheumatic fever and carditis

Nat Rev Cardiol. 2013 Mar;10(3):171-7. doi: 10.1038/nrcardio.2012.197. Epub 2013 Jan 15.


Rheumatic fever is one of the most-neglected ailments, and its pathogenesis remains poorly understood. The major thrust of research has been directed towards cross-reactivity between streptococcal M protein and myocardial α-helical coiled-coil proteins. M protein has also been the focus of vaccine development. The characteristic pathological findings suggest that the primary site of rheumatic-fever-related damage is subendothelial and perivascular connective tissue matrix and overlying endothelium. Over the past 5 years, a streptococcal M protein N-terminus domain has been shown to bind to the CB3 region in collagen type IV. This binding seems to initiate an antibody response to the collagen and result in ground substance inflammation. These antibodies do not cross-react with M proteins, and we believe that no failure of immune system and, possibly, no molecular mimicry occur in rheumatic fever. This alternative hypothesis shares similarity with collagen involvement in both Goodpasture syndrome and Alport syndrome.

Publication types

  • Review

MeSH terms

  • Animals
  • Antigens, Bacterial / immunology
  • Autoantibodies / biosynthesis
  • Autoimmunity*
  • Bacterial Outer Membrane Proteins / immunology
  • Carrier Proteins / immunology
  • Child
  • Child, Preschool
  • Collagen Type IV / immunology
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / microbiology
  • Endothelium, Vascular / pathology
  • Female
  • Humans
  • Myocarditis / immunology
  • Myocarditis / microbiology*
  • Myocarditis / pathology
  • Myocardium / immunology
  • Myocardium / pathology
  • Protein Binding
  • Rheumatic Fever / immunology
  • Rheumatic Fever / microbiology*
  • Rheumatic Fever / pathology
  • Streptococcus pyogenes / immunology
  • Streptococcus pyogenes / pathogenicity*


  • Antigens, Bacterial
  • Autoantibodies
  • Bacterial Outer Membrane Proteins
  • Carrier Proteins
  • Collagen Type IV
  • streptococcal M protein