Page 159 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Nomenclature and Pathologic Features of Vasculitides 135

By routine light microscopy, neutrophils often are not conspicuous at sites of necrosis,
probably because they are destroyed in the process of activation and necrosis. However, in
some lung specimens, more overt pulmonary capillaritis with influx of neutrophils is
observed [18]. Approximately a third of patients with anti-GBM disease also have ANCA,
usually MPO-ANCA [19]. They have an initial renal outcome more like anti-GBM disease
than AAV with a higher rate of progression to end stage [19]. Renal biopsy specimens with
from patients with concurrent anti-GBM and ANCA may reveal necrotizing arteritis as well
as glomerulonephritis. Cryoglobulinemic vasculitis (CV) is defined as vasculitis with
cryoglobulin immune deposits affecting small vessels (predominantly capillaries, venules, or
arterioles) and associated with cryoglobulins in serum [1]. Skin, glomeruli and peripheral
nerves are often involved. Localization of cryoglobulins in vessel walls incites inflammation
(vasculitis) by complement activation [20, 21]. Monoclonal cryoglobulins (type I) are not as
effective at activating inflammatory mediator systems as are mixed cryoglobulins (types II
and III), which are immune complexes composed of anti-antibodies or rheumatoid factors
(RF) bound to target antibodies. An important cause for cryoglobulinemia is hepatitis C virus
(HCV) infection [21]. Acute CV affecting venules, arterioles and small arteries typically has
neutrophilic infiltration with leukocytoclasia (Figure 9). The inflammation may be
accompanied by luminal or vessel wall deposits of PAS-positive hyaline material that
represent coagula of cryoglobulins (Figure 9). Cryoglobulinemic glomerulonephritis occurs as
a renal limited process and as a component of systemic CV. Cryoglobulinemic
glomerulonephritis usually has a membranoproliferative pattern but may have other patterns
of proliferative glomerulonephritis. A frequent finding is hyaline material in glomerular
capillary lumens (“hyaline thrombi”) that are coagula of cryoglobulins.

Although glomerulonephritis is a frequent component of many forms of immune complex
SVV, the glomerular lesions, including immunopathologic features, are very helpful in
distinguishing among them, for example, CV with membranoproliferative lesions and
IgG/IgM deposits, IgAV with IgA deposits, anti-GBM disease with necrosis and linear IgG,
and AAV vasculitis with necrosis and a paucity of immunoglobulin deposits. IgAV is defined
as vasculitis, with IgA1-dominant immune deposits (Figure 5), predominantly affecting small
vessels such as capillaries, venules, and arterioles [1].

Often involves skin and gastrointestinal tract, and frequently causes arthritis.
Glomerulonephritis indistinguishable from IgA nephropathy may occur. The shift in
terminology to IgA vasculitis is prompted in part by mounting evidence that abnormally
reduced glycosylation of the O-linked glycans in the hinge region of IgA1 molecules play a
pivotal pathogenic role in IgA vasculitis and IgA nephropathy [22, 23].

In patients with these diseases, serum IgA1 has reduced terminal galactosylation and
sialylation, resulting in increased exposure of N-acetylgalactosamine at the ends of the hinge
region glycans. There also is evidence that patients have autoantibodies that recognize these
abnormally glycosylated IgA1 hinge regions, which could result in immune complex
formation. In addition to forming pathogenic immune complexes, abnormal glycosylation of
the glycans in the hinge region of IgA1 molecules could play a pathogenic role through a
variety of other mechanisms, such as reduced clearance from the circulation because of lack
of receptor engagement by the abnormal IgA, increased aggregation of IgA in the circulation
resulting in mesangial trapping, and increased affinity of the abnormal IgA for mesangial
matrix.

Complimentary Contributor Copy