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Although it is clear that acute rheumatic fever is an autoimmune disease, the exact nature of the
pathogenesis of acute rheumatic fever has still to be determined.
It is believed that both cross-reactive antibodies and cross-reactive T cells play a role in the disease.
Molecular mimicry between group A Streptococcus pyogenes antigens and human host tissue is thought
to be the basis of this cross-reactivity. Putative cross-reactive epitopes on S pyogenes include the Mprotein and N-acetyl glucosamine. Monoclonal antibodies against these antigens cross-react with cardiac
myosin and other alpha-helical cardiac proteins such as laminin, tropomyosin, keratin, and vimentin, as
well as proteins in other target organs and tissues such as synovium, neuronal tissue, subcutaneous, and
dermal tissues.
It has been proposed that the carditis of acute rheumatic fever is initiated by cross-reactive antibodies that
recognise the valve endothelium and laminin. Vascular cell adhesion-molecule-1 is up-regulated at the
valve and aids in recruitment and infiltration of these T cells. The T cells initiate a predominantly TH1
response with the release of beta-interferon (IFN). Inflammation leads to neovascularisation, which
allows further recruitment of T cells. It is believed that epitope spreading may occur in the valve whereby
T cells respond against other cardiac tissues such as vimentin and tropomyosin, leading to granulomatous
inflammation and the establishment of chronic rheumatic heart disease.
Proposed pathological mechanism of valvular inflammation in acute rheumatic fever (IL, interleukin;
VCAM, vascular cell adhesion molecule)
Rheumatic inflammation in the heart may affect the pericardium (often asymptomatic), the myocardium
(rarely contributes to cardiac failure), or the endocardium (the most common and the most important [i.e.,
the valvular tissue]). Rheumatic granulomatous inflammation manifests in the myocardium as Aschoff
bodies. These may disrupt the electrical conduction pathways leading to prolongation of the PR interval
on electrocardiogram.