Wegener's Granulomatosis - Pathophysiology

Pathophysiology

Inflammation with granuloma formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.

It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in Wegener's. The typical ANCAs in Wegener's are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes. This type of ANCA is also known as cANCA, with the c indicating cytoplasmic (in contrast to pANCA, which is perinuclear).

In vitro studies have found that ANCAs can activate neutrophils, increase their adherence to endothelium, and induce their degranulation that can damage endothelial cells. In theory, this phenomenon could cause extensive damage to the vessel wall, particularly of arterioles. However, the presence of ANCA bound to circulating neutrophils has never been found, the activation status of neutrophils from patients with high ANCA titer does not differ from normal individuals and the presence of ANCA is not always associated with development of vasculitis.

The exact cause for the production of ANCAs is unknown, although some drugs have been implicated in secondary forms of Wegener's. As with many autoimmune disorders, the cause is probably genetic predisposition combined with molecular mimicry caused by a virus or bacterium.