The Cause Is Hidden, but the Result Is Known

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis: The Cause Is Hidden, but the Result Is Known


Image result for microscopic polyangiitis

  1. Ingeborg M. Bajema*





Antineutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing vasculitis was probably first described in 1866 by Kussmaul and Maier (1) as “polyarteritis nodosa.” It was not until the early 1930s when the first case of what was later named Wegener's granulomatosis (WG) was described (2). The disease was named after Friedrich Wegener, who described it as an entity in 1939 (3). In 1985, antibodies associated with the disease were detected and later became known as ANCA (4). WG is a systemic autoimmune disease that can cause damage in various organs. Later, microscopic polyangiitis (MPA) was distinguished as a separate ANCA-associated vasculitis. The disease—or its immunosuppressive treatment—can cause high levels of morbidity and death, especially in patients with renal involvement.


 Silica

Background

Silica is probably the most extensively studied environmental factor hypothesized to play a causative role in the pathogenesis of ANCA-associated glomerulonephritis, predominantly in MPA. After oxygen, silicon (Si) is the most prominent element of the earth's crust (9). Silicates (SiO4) occur in glass and cement, and silicic acid (H4SiO4) is one of the main constituents of soil water, soil itself, and grasses (42). When interpreting studies on the relationship between ANCA-associated vasculitis and silica exposure, the route of silica exposure and silica source may be relevant. In earlier studies of the relationship between silica exposure and disease, only exposure to mineral silica was evaluated. Since the 1980s, biologic forms of silica, such as sand, grass, grain, wood, cotton, wool, quartz, flint, and “coal,” have been considered indicative of silica exposure. Jobs that have high exposure to silica dust and that have been associated with the occurrence of ANCA-associated vasculitis are farming, mill and textile work, sandblasting, lumber work, and drilling (43). Exposure to mineral silica is frequent in jobs such as mining and quarrying and construction work that involves cement, stone, brick, or concrete and also in pottery or china manufacturing (9,43,44).

Silica and Vasculitis

Already by the early 1950s, silica exposure was described as being associated with renal insufficiency (45). In the 1980s, several case reports of rapidly progressive glomerulonephritis in patients who were previously exposed to silica appeared (46–50). When ANCA testing became available, the first reports on silica exposure in ANCA-positive patients appeared in the early 1990s (51,52). In patients with pulmonary silicosis and renal failure, a renal biopsy revealed a pauci-immune necrotizing crescentic glomerulonephritis in a number of studies (52–57). ANCA positivity was later confirmed in these patients (52,57–61), who received a diagnosis of ANCA-associated glomerulonephritis (58,62–64). Silica-induced ANCA-positive disease is often associated with a perinuclear (P-ANCA) staining pattern under indirect immunofluorescence and with antibodies directed against MPO (52,65). Although silica-induced disease has been reported in patients with C-ANCA and anti–PR3-ANCA, as well (52,66), the clinical picture for these patients usually justifies a diagnosis of microscopic polyangiitis but very rarely of WG.
Although it has been found that silicosis is a risk factor for developing ANCA, as determined by indirect immunofluorescence, the presence of ANCA need not necessarily be accompanied by clinical vasculitis (67–69). In fact, the titers of anti-PR3 and anti-MPO, as determined by ELISA, are usually negative or very low. The explanation for this could be that in 50% of patients with silicosis, antinuclear antibodies are present, allowing an interpretation of P-ANCA. Moreover, many of these patients have a high percentage of rheumatoid factor and high Ig levels (9).
Silica exposure is also associated with other systemic diseases, in particular Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus (70), although for the last, the association is disputed (43). Next to silica, asbestos exposure was reported to be associated with ANCA positivity (71), but this finding was contradicted in case-control studies (72,73); however, patients who are exposed to asbestos can be exposed to silica in the same occupations (74).

Epidemiologic Studies

To find epidemiologic evidence for a relationship between silica exposure and renal failure, several case-control studies have been performed (44,52,75,76). The results showed that among patients with ANCA-associated rapidly progressive glomerulonephritis or WG, 22 to 46% were previously exposed to silica (43,44,52,72,73). Silica exposure in each study was significantly more frequent in patients compared with control subjects. Most of the studies defined silica exposure in terms of duration rather than intensity. Recently, this choice was justified by the finding that duration was more important than intensity in the onset of ANCA-associated vasculitis (77), although other reports contradicted this finding (78,79). Of note is the difference between silica exposure and silicosis. At time of diagnosis with vasculitic disease, some patients exhibit a picture of pulmonary silicosis, whereas others do not. This difference may arise from the limitations of imaging techniques. Moreover, predisposition to vasculitis does not require the presence of severe pulmonary lesions (9,74).

Risk Factors

The finding that farming and livestock exposure are risk factors for primary systemic vasculitides (73,79) supports the causative role of silica in their pathogenesis. Other environmental risk factors are exposure to fumes or materials from construction; pesticides (29); exposure to hydrocarbons such as paint, solvent, cleaning agents, and diesel (80); and air pollution after an earthquake (81). The association between silica and ANCA-associated vasculitis is not always obvious, however. In a survey (23) among 701 patients with ANCA-associated vasculitis, no association with environmental exposure, occupation, or hobby was found. Among those who were exposed to silica, there was no increased frequency of ANCA compared with control subjects (67). The different outcomes of these studies probably arise from differences in methods of establishing silica exposure.

Hypotheses

Although silica exposure has been shown to evoke an immune response (82–85) and inflammatory reactions (86), its role in the cause of ANCA-associated glomerulonephritis is not well understood. Several hypotheses have been described. It has been suggested that at the site of pulmonary lesions, which can be caused by silica exposure, cytokines released by activated macrophages can attract polymorphonuclear cells. These cells can express the ANCA antigens PR3 and MPO and are taken up by pulmonary macrophages (87–89). Another hypothesis is that alveolar macrophages that are exposed to silica, especially quartz, release a large amount of lysosomal enzymes, such as PR3 and MPO, and reactive oxygen species (90–92). Release of these compounds is even greater when the macrophage or monocyte enters apoptosis (93). Silica can cause apoptosis of monocytes and macrophages and probably also of neutrophils by rupturing their phagolysosomal membrane (93,94). Binding of ANCA to their antigens on apoptotic cells amplifies the release of lysosomal enzymes and reactive oxygen species (95). Furthermore, silica may decrease total lymphocyte counts, which might explain the observed lymphopenia reported in some studies (96). In addition, in vitro silica inactivates α1-antitrypsin (97), the natural inhibitor of PR3. Although not all associations between silica exposure and vasculitis are clear-cut, these findings may suggest a causative role of silica in ANCA-associated glomerulonephritis and vasculitis.
One explanation for the geographic differences in vasculitis incidence is the climate. If silica or farming is related to the development of (predominantly MPO-associated) vasculitis, then it would be expected that in wet weather, silica particles would be scattered to a lesser extent than in dry weather. This difference could explain the relatively higher prevalence of vasculitis with MPO-ANCA in warmer countries, illustrated by a high incidence of patients with ANCA directed against MPO in Kuwait (18). The high incidence of MPO-ANCA–associated vasculitis may be explained by the amount of sand present in the air in this region. The role that farming plays in a society might also explain differences in mainly MPO-ANCA–associated vasculitis. This weather-related hypothesis is supported by the higher incidence of vasculitis with MPO-ANCA in Spain combined with the fact that 6% of the population engages in agricultural employment, as opposed to 2% in the United Kingdom (98).
These climate-based considerations could be applied only to exposure to silica dust (e.g., farming, air pollution), not to people who are exposed to occupational mineral silica. Geographic differences could arise from the almost exclusive link between silica exposure and P-ANCA/anti–MPO-positive MPA that is prevalent in southern Europe and Japan.

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