Pathogenic mechanisms implicated in the development of vasculitides are only partly understood and some are probably still unknown. Deposition of circulating immune complexes in the vessel walls seems to be relevant in hepatitis B virus (HBV)-related PAN, Henoch-Schonlein purpura, mixed cryoglobulinemic vasculitis and the ne-crotizing vasculitis of rheumatoid arthritis (Gower et al., 1978).
More specific antibody-mediated immunity is implied in some vasculitides, mainly by ANCA, but perhaps also by other autoantibodies, like anti-endothelial cell autoantibodies. ANCA were first detected in patients with pauci-immune glomerulo-nephritis (Davies et al., 1982). They are specific to peptides in neutrophil granules and monocyte lyso-somes (Falk and Jennette, 1988). Target antigens, recognized and identified by antigen-specific enzyme-linked immunosorbent assays (ELISA), are proteinase 3 (PR3) for C-ANCA, myeloperoxidase (MPO) for 90% of the P-ANCA, and elastase, cathepsin G, lactoferrin and lysozyme for the remaining P-ANCA (Specks et al., 1993). The pathogenic role of ANCA is supported by the development of necrotizing glomerulonephritis in re-combinase-activating gene-2-deficient (rag2_/_) mice, but also in wild-type C57BL/6J mice, after injection of purified anti-MPO IgG (Heeringa et al., 1998; Xiao et al., 2002); and by the enhancement, after injection of anti-mouse PR3 antibodies, of the subcutaneous panniculitis induced by intradermal injection of tumor necrosis factor-alpha (TNFa) into wild-type mice (Pfister et al., 2004). Moreover, ANCA titers seem to fluctuate with the disease activity, at least in WG but, at present, must not be used as a tool to initiate or modify therapy because this relationship is not constant (Girard et al., 2001; Tervaert et al., 1990).
Conversely, T-cell-mediated immunity may contribute to the development of granulomatous vasculitides, i.e. WG and CSS. Infiltration by T helper 1 (Th1) lymphocytes secreting pro-inflammatory cytokines, essentially interferon (IFN)g, has been observed in granulomatous lesions of the nasal mucose of WG patients. Thus, in WG, an imbalance between Th1 and Th2 lymphocyte-regulated pathways may be involved, with Th1 lymphocytes playing a major role in localized and granulo-matous upper respiratory tract involvement, whereas a shift toward Th2 lymphocyte involvement would tend to be more predominant in systemic forms (Balding et al., 2001; Csernok et al.,
1999), which are thought to have a poorer prognosis (Bligny et al., 2004).
Cytokine (Sundy and Haynes, 2000; Tesar et al., 1998) and adhesion-molecule (Sundy and Haynes,
2000) cascades may be perturbed, with, e.g., high levels of soluble endothelial cell receptors for neutrophils (intercellular adhesion molecule (ICAM)-1, E-selectin and vascular cell-adhesion molecule (VCAM)-1) in patients with active WG or MPA (Ara et al., 2001; Ohta et al., 2001).
Finally, viral agents such as HBV for PAN, genetic susceptibility and exposure to some drugs or environmental factors (especially silica and livestock) may also be involved in the development of various vasculitides (Lane et al., 2003; Watts et al., 1995).
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