Elsevier

Autoimmunity Reviews

Volume 9, Issue 5, March 2010, Pages A293-A298
Autoimmunity Reviews

The environment, geoepidemiology and ANCA-associated vasculitides

https://doi.org/10.1016/j.autrev.2009.10.008Get rights and content

Abstract

Anti-neutrophil cytoplasmic antibodies, directed against constituents of granules of neutrophils and lysosomes of monocytes, are serological markers of small vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis. These vasculitides are collectively termed ANCA-associated vasculitides (AAV). Environmental factors have been considered important in the development of ANCA, including silica, infection especially with Staphylococcus aureus, and drugs. Accelerated apoptosis of neutrophils induced through intratracheal instillation of silica may act as a trigger in the development of AAV. Inhaled silica may activate alveolar macrophages and not only induce inflammation and activation of fibroblasts, but also stimulate lymphocytes through T-cell receptors and attract neutrophils. Staphylococcus aureus is associated with initiation and relapse of Wegener's granulomatosis. Peptides from complementary PR3 show strong homology with peptides from S. aureus, which could underlie the development of PR3–ANCA. There is increasing recognition that drugs, especially propylthiouracil (PTU), may cause AAV. Patients with PTU-induced AAV have better prognosis than those with primary AAV. The disease spectrum of AAV in various geographic regions is different, which may suggest that the initiating factor in AAV has a different geographical distribution. Differences in genetic background may also be important in determining the response to triggering or initiating factors.

Introduction

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and renal-limited vasculitis (RLV). These disorders are characterized by necrotizing small-vessel vasculitis (Table 1). ANCA are serological hallmarks for the above mentioned small vessel vasculitides. ANCA are autoantibodies directed against constituents of granules of neutrophils and lysosomes of monocytes. By indirect immunofluorescence (IIF) on ethanol-fixed neutrophils, two fluorescence patterns of ANCA are distinguished, the cytoplasmic staining pattern (cANCA) and the perinuclear staining pattern (pANCA). Most patients with a cANCA pattern obtained by IIF have ANCA directed against proteinase-3 (PR3), as determined by antigen-specific ELISA. Patients with pANCA mostly have ANCA directed against one of a variety of antigens, but in primary small vessel vasculitis, the target antigen is almost invariably myeloperoxidase (MPO). The combinations of a cANCA pattern by IIF with PR3–ANCA by ELISA and a pANCA pattern by IIF with MPO–ANCA by ELISA are very specific for AAV. The widespread availability of the ANCA test has resulted in increased recognition of small vessel vasculitis [1].

Increasing evidence supports a pathogenic role for ANCA in AAV. Transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis [2]. Recent data also suggest that antibodies to complementary proteinase-3 (cPR3), probably cross-reacting with plasminogen, may induce PR3–ANCA [3]. Furthermore, a new ANCA, directed against human lysosome membrane protein-2 (LAMP-2), concurrent with PR3–ANCA or MPO–ANCA, was described as a sensitive and specific marker for renal AAV. The anti-LAMP-2 antibody can also induce pauci-immune necrotizing crescentic glomerulonephritis in rats. Rats developed both cross-reactive antibodies to LAMP-2 and crescentic glomerulonephritis when immunized with FimH, an adhesin from Gram-negative bacteria which has strong homology with human LAMP-2 [4], [5].

The pathogenesis of ANCA-associated vasculitides has not yet been fully elucidated. Two monozygotic twins developing ANCA necrotizing glomerulonephritis have been reported [6], indicating that genetic factors might be involved in the disease pathogenesis. Environmental factors have been considered important in the development of ANCA, including: silica exposure, bacterial infection in particular with Staphylococcus aureus, viral infection such as infection with parvovirus B19, and exposure to drugs such as propylthiouracil (PTU). There are striking geographic differences in the incidence of the different AAV. This review will focus on advances in the understanding of the environmental etiology and geoepidemiology of ANCA-associated vasculitides.

Section snippets

Silica

Exposure to silicon-containing compounds has long been recognized as dangerous. Silica (silicon dioxide, SiO2) dust exposure has been associated with a variety of autoimmune disorders including scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and ANCA-associated vasculitides. Silica is the earth's most abundant mineral, which occurs in sand, grass, grain, wood, cotton, wool, quartz, flint, soil, rock, etc. When these materials are processed and subsequently used, the workers can

Geoepidemiology

The classification of AAV and (classic) polyarteritis nodosa for epidemiological studies is confusing. Using the American College of Rheumatology (ACR) criteria, the Chapel Hill Consensus Conference (CHCC) definitions, and the Lanham criteria results in overlapping and conflicting classifications, which makes it difficult to compare data on incidences. Watts et al. recently produced an algorithm [37], which uses both the ACR criteria and the CHCC definitions. This new algorithm has been proven

Conclusion

Many environmental factors have been suggested to be involved in the pathogenesis of ANCA-associated vasculitides, including silica exposure, bacterial or viral infectious agents and drugs. Different triggers could induce different antigenic specificities of ANCA. S. aureus probably triggers predominantly PR3–ANCA-associated vasculitis and silica predominantly MPO–ANCA-associated vasculitis. Different incidences of AAV depending on the geographic region may also suggest an environmental agent,

Conflict of Interests

None declared.

Take-home messages

  • Environmental factors have been considered important in the development of ANCA, including: silica exposure, bacterial infection in particular with Staphylococcus aureus, viral infection, and exposure to drugs such as propylthiouracil.

  • The striking geographic differences in incidence of the various AAV suggest that the initiating factor in AAV has a different distribution or magnitude between countries, and/or that genetic factors are involved.

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