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Revisiting the pathogenesis of rheumatic fever and carditis

Nature Reviews Cardiology volume 10, pages 171–177 (2013)Cite this article

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Abstract

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.

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Figure 1: Haematoxylin and eosin staining of the heart and vasculature suggests connective tissue involvement in rheumatic fever.
Figure 2: Molecular architecture of type IV collagen in healthy individuals and in patients with Goodpasture syndrome.
Figure 3: Molecular basis of an interaction between collagen type IV and M protein in rheumatic fever.
Figure 4: Proposed pathogenesis of rheumatic fever.

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Authors and Affiliations

  1. Sitaram Bhartia Institute of Science and Research, B-16, Mehrauli Institutional Area, 110016, New Delhi, India

    Rajendra Tandon

  2. Indian Council of Medical Research, Ansari Nagar, 110029, New Delhi, India

    Meenakshi Sharma

  3. Division of Cardiology, University of Minnesota, VA Medical Center, IIIc, 1 Veterans Drive, Minneapolis, 55417, MN, USA

    Y. Chandrashekhar

  4. Department of Molecular Genetics, Biochemistry, and Microbiology, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, 45267, OH, USA

    Malak Kotb

  5. Imperial College London, Heart Science Centre, Harefield Hospital, Harefield, UB9 6JH, Middlesex, UK

    Magdi H. Yacoub

  6. Mount Sinai School of Medicine, Zena and Michael A. Wiener Cardiovascular Institute and Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, One Gustave L. Levy Place, New York, 10029, NY, USA

    Jagat Narula

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Contributions

R. Tandon, Y. Chandrashekhar, M. H. Yacoub and J. Narula researched data for the article, substantially contributed to discussion of content, wrote the manuscript, and reviewed/edited the manuscript. M. Sharma researched data for the article, substantially contributed to discussion of content, and wrote the manuscript. M. Kotb researched data for the article, substantially contributed to discussion of content, and reviewed/edited the manuscript.

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Correspondence to Jagat Narula.

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Tandon, R., Sharma, M., Chandrashekhar, Y. et al. Revisiting the pathogenesis of rheumatic fever and carditis. Nat Rev Cardiol 10, 171–177 (2013). https://doi.org/10.1038/nrcardio.2012.197

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