Vasculitis secondary to infections. Antibodies to microbial constituents can form immune complexes that circulate and deposit in vascular lesions. For example, in up to 30% of patients with polyarteritis nodosa (discussed in greater detail later), the vasculitis can be ascribed to immune complexes composed of hepatitis B surface antigen (HBsAg) and anti-HBsAg antibody.
Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic antigens, so-called “anti-neutrophil cytoplasmic antibodies (ANCAs).” ANCAs are a heterogeneous group of autoantibodies directed against constituents (mainly enzymes) of neutrophil primary granules, monocyte lysosomes, and ECs. ANCAs are very useful diagnostic markers; their titers generally mirror clinical severity, and a rise in titers after periods of quiescence is predictive of disease recurrence. Although a number of ANCAs have been described, two are most important. These are classified according to their antigen specificity:
Anti-proteinase-3 (PR3-ANCA), previously called c-ANCA. PR3 is a neutrophil azurophilic granule constituent that shares homology with numerous microbial peptides, possibly explaining the generation of PR3-ANCAs. PR3ANCAs are associated with granulomatosis with polyangiitis (see later).
Anti-myeloperoxidase (MPO-ANCA), previously called p-ANCA. MPO is a lysosomal granule constituent involved in oxygen free radical generation (Chapter 3). MPO-ANCAs are induced by several therapeutic agents, particularly propylthiouracil (used to treat hyperthyroidism). MPO-ANCAs are associated with microscopic polyangiitis and Churg-Strauss syndrome (see later).
The close association between ANCA titers and disease activity suggests a pathogenic role for these antibodies. Of note, ANCAs can directly activate neutrophils, stimulating the release of reactive oxygen species and proteolytic enzymes; in vascular beds, this may lead to EC injury. While the antigenic targets of ANCA are primarily intracellular (and therefore not usually accessible to circulating antibodies), it is now clear that ANCA antigens (especially PR3) either are constitutively expressed at low levels on the plasma membrane or are translocated to the cell surface in activated and apoptotic leukocytes.
A plausible pathogenic sequence for the development of ANCA vasculitis involves the following:
Drugs or cross-reactive microbial antigens induce ANCA formation; alternatively, leukocyte surface expression or release of PR3 and MPO (in the setting of infection) incites ANCA development in a susceptible individual.
Subsequent inflammatory stimuli elicit the release of cytokines such as TNF that upregulate the surface expression of PR3 and MPO on neutrophils and other cell types.
ANCAs bind to these cytokine-activated cells, causing further neutrophil activation.
ANCA-activated neutrophils cause EC injury by releasing granule contents and elaborating reactive oxygen species.
The ANCA auto-antibodies are directed against cellular constituents and do not form circulating immune complexes, nor do the vascular lesions typically contain demonstrable antibody and complement; therefore ANCA-associated vasculitides often are described as “pauci-immune.” Of interest, ANCAs directed against proteins other than PR3 and MPO are sometimes seen in patients with non-vasculitic inflammatory disorders (e.g., inflammatory bowel disease, sclerosing cholangitis, and rheumatoid arthritis).
Antibodies to ECs underlie certain vasculitides, such as Kawasaki disease (discussed later). Autoreactive T cells cause injury in some forms of vasculitides characterized by formation of granulomas.