Page 291 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Systemic Vasculitis and the Kidney 265

[IFN]-?) and anti-inflammatory (IL-10, tumor growth factor [TGF]-?) cytokines. Chronic
T-cell activation was observed in cultured PBMC of silicosis patients in Japan [32].
In particular, activation of T responder cells (Tresp) resulted in later entry into the peripheral
CD4+25+ population, whereas activation of FoxP3+ regulatory T-cells (Treg) led to more
rapid and higher levels of apoptosis. The net effect was reduced inhibitory function. Silica
may also contribute to immune dysregulation by increasing oxidative stress, as suggested by a
study of denim sandblasting workers with silicosis in Turkey [33]. Patients had a 1.4-fold
higher level of superoxide dismutase (SOD), a possible marker for increased reactive oxygen
species generation in these patients. Taken together, these data suggest a somewhat
generalized disruption in immune homeostasis in silica-exposed individuals. However,
studies to date have not specifically addressed the mechanisms by which silica may cause or
promote disease in AAV. By extrapolation, silica is more likely to have an adjuvant effect in
patients with predisposition to AAV rather than to be a primary trigger.

Infection

Wegener considered infection as a potential factor in the cause of GPA in the first half of
the 20th century [34]. Since then Staphylococcus (S.) aureus has received particular attention.
The first study comparing the rates of GPA relapse with carriage of S. aureus found that 36 of
57 (63%) patients were chronic carriers of S. aureus, and analysis demonstrated an adjusted
relative risk (RR) for relapse of 7.16 (95% CI 1.63-31.50) independent of other factors. [35]
A 2008 study of Polish patients with limited disease [36] found that 17 of 28 (60%) patients
were chronic nasal carriers of S. aureus, independently conferring a relative hazard risk (HR)
for relapse of 4.56 (CI 2.45-7.65). A third study compared nasal carriage of S. aureus in
patients with GPA to those with rheumatoid arthritis (RA) and chronic rhinosinusitis with
nasal polyps (CRS), as well as to hospital staff and subjects without regular exposure to a
hospital environment, noting that 72% of patients with GPA had S. aureus nasal colonization,
versus 28% of those with CRS, and 25% of patients without regular hospital exposure [37].
Patients with RA and hospital workers had S. aureus carriage rates of 46% and 58%
respectively, but the differences were statistically insignificant. Colonized GPA patients had
significantly higher rates of endoscopically-proven endonasal activity, with more frequent
upper respiratory tract involvement at first presentation, and with significantly higher relapse
rates compared to uncolonized patients.

The mechanism(s) by which infection may incite disease has not been fully elucidated,
but early investigations have yielded intriguing possibilities. Molecular mimicry, which leads
to cross-reactivity of antibodies to both pathogen-derived and self-antigens with substantial
structural homology, has been implicated as an etiopathogenic factor in AAV.
Such cross-reactivity has been observed in several other diseases; streptococcal M proteins
and cardiac myosin, as well as other proteins, cross-react in rheumatic fever [38, 39];
Campylobacter jejuni epitopes and peripheral gangliosides cross-react in Guillain-Barré
syndrome [40]; and Epstein Barr virus epitopes and Mycobacterium avium paratuberculosis
cross-react with myelin basic protein in multiple sclerosis [41]. A peptide or protein
homologous to complementary PR3 (cPR3), transcribed and translated from the antisense
strand of PRTN3 DNA, is thought to be an inciting antigen in a subset of patients with
PR3-ANCA disease. In those who are predisposed, antibodies are generated to cPR3.

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