Pathogenesis, Biology

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Even though association between GAS pharyngitis and the ARF is fairly well established, the exact pathogenic mechanisms are not clearly understood. However, two mechanisms are postulated.

1) An abnormal immune response of the host to the GAS antigens.

2) Toxic effect of extracellular toxin of GAS on target organs such as synovium, valves, myocardium and brain.

The GAS is a complex micro-organism which produces plenty of somatic and extracellular antigens. Some of our body tissues have antigenic similarities to the GAS antigens with the result that antibodies produced against GAS antigens cross react with these tissue antigens to produce an auto-immune response. The cross reactivity postulation of ARF is supported by following facts:

a) Group specific polysachharide of GAS wall is antigenically akin to glycoprotein found in human and bovine cardiac valves.

b) The somatic antigens of the GAS cell wall and cell membrane are similar to human myocardial sarcolemma.

c) The M protein of GAS cross reacts with human heart tissues particularly sarcolemmal membrane proteins and cardiac myosin as it shares certain common aminoacid sequences.

d) In chorea, antibodies directed against GAS cell membrane cross react with tissues in the caudate nucleus of the brain.

There are two types of immunity:

1) Humoral Immunity: Host cross reacting (HCR) antibodies are not only identified against tissue structures form ARF patients (as mentioned above) but are also seen in the sera of patients with previous GAS sorethroat who did not proceed to develop ARF.

Therefore, the exact role of those HCR antibodies in the pathogenesis of ARF is not clear.

2) Cellular Immunity: During episodes of ARF, various markers of cell mediated immunity (CMI) have been shown to be elevated. These markers are raised CD4/CD8 cell ratio, raised B cell levels, and natural killer cell counts and increase in C3, C4 complements. Aschoff nodules (a classical marker) in the heart of ARF patients, are due to CMI process. ARF patients with carditis show infiltration by mononuclear phagocytes expressing CD3/CD4 marker proteins. These mediators of CMI seem to be responsible for continuing pancarditis. 

It is not understood why some persons only suffer from AFR following GAS pharyngitis.  It is postulated that there are certain genetic influences that play a role as only 3 per cent of persons develop ARF following GAS sore throat.  Monozygotic twins seem to have higher concordance for development of ARF. 

The pathologic hallmark of rheumatic carditis (which is always a pancarditis) is the Aschoff body which is typically seen in myocardium. It comprises of a perivascular infiltrate of large cells arranged in a rossette form around an avascular area of fibrinoid necrosis. These Aschoff bodies are usually seen during subacute or chronic phases but not during acute stage of rheumatic carditis. On gross examination, on opening the left atrium, one sees a thickened patch of tissue just above the base of posterior mitral leaflet termed as "MacCallum's patch".  

Valvulitis is the cardinal lesion that leads to various valvular disorders. There is oedema, cellular infiltration of the valves and the cardiac tendinae causing verrucae formation and hyaline degeneration that results in regurgitant valves. Eventually there is fibrosis and calcification leading to stenotic lesions (mitral, aortic). In large majority cases, fibrinous or fibrinoserous pericarditis is seen. There is generalised vasculitis, i.e., responsible for chorea, pulmonary and renal lesions in ARF. As regards joints, there is serositis which recovers without any deformity.


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