The role of metals in autoimmune vasculitis: epidemiological and pathogenic study.
BACKGROUND
A possible relationship between Silica (Si) exposure and antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis has been reported. Furthermore, tuberculosis (TBC) has been frequently described in patients with silicosis, and TBC infection shares with ANCA-associated vasculitis the formation of granulomas. Therefore, an intriguing network including Silica, Vasculitis, TBC and ANCA might be hypothesized. The aim of this work was to further investigate these correlations using both epidemiological and pathogenic approaches.


METHODS
Study I--epidemiological study. A case-control study to compare the occupational histories of 31 cases of biopsy proven vasculitis (18 pauci-immune crescentic glomerulonephritis, 9 microscopic polyangitis, 4 Wegener's granulomatosis) with those of 58 age, sex and residence-matched controls (affected by other kidney diseases), was performed. Occupational Health physicians designed an appropriate questionnaire in order to evaluate a wide spread of exposures and calculate their entity by the product of Intensity x Frequency x Duration. Study II--tuberculosis association. A case-control study to evaluate the frequency of a previous history of tuberculosis (TBC) in 45 patients with vasculitis and 45 controls were performed. Study III--ANCA positivity. A case-control study to evaluate the presence of ANCA was performed by testing blood samples of 64 people with previous professional exposure and 65 sex/age matched patients hospitalized in a General Medicine Unit. Furthermore, the same evaluation was made in a pilot study in 16 patients with ongoing or previous TBC. Study IV--experimental study. The oxygen free radicals (OFR) and IL-12 production (both involved in the pathogenesis of vasculitis) from human phagocytic cells stimulated with an amorphous (diatomaceous earth) and a crystalline (quartz) form of Si at the doses of 10 and 100 microg ml(-1) was evaluated.


RESULTS
Study I--a positive history of exposure to Si resulted in significantly more present in cases (14/31 = 45%) than in controls (14/58 = 24%, P = 0.04, OR = 2.4) and no other significant exposure association was found (including asbestos, mineral oil, formaldehyde, diesel and welding fumes, grain and wood dust, leather, solvents, fungicides, bitumen, lead and paint). Study II--past TBC infection was significantly more present in patients with vasculitis (12/45 = 26%) than in controls (4/45 = 8%, P < 0.05). Study III--ANCA was present in 2/64 exposed people (vs. 0/65 controls, P = NS) and 0/16 patients with TBC. Study IV--both amorphous and crystalline Si forms represented a stimulus for OFR and IL-12 production, but quartz resulted as a greater inductor.


CONCLUSIONS
We conclude that Si exposure might be a risk factor for ANCA-associated vasculitis, possibly enhancing endothelial damage by phagocyte generation of oxygen free radicals and Th1 differentiation by an excessive IL-12 phagocyte production. Frequency of TBC was significantly higher in vasculitis patients. ANCA was not frequent in the preliminary examination of people with previous professional exposure or patients with TBC, but the number of samples evaluated is too small to allow conclusions.
Stratta
P
P
Department of Internal Medicine, University of Torino, S. Giotanni Molinette Hospital, Italy. strattanefro@hotmail.com
Messuerotti
A
A
Canavese
C
C
Coen
M
M
Luccoli
L
L
Bussolati
B
B
Giorda
L
L
Malavenda
P
P
Cacciabue
M
M
Bugiani
M
M
Bo
M
M
Ventura
M
M
Camussi
G
G
Fubini
B
B
D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood* / Q000187:drug effects; D001327:Autoimmune Diseases / Q000453:epidemiology* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects; D010865:Pilot Projects; D012822:Silicon Dioxide / Q000633:toxicity*; D014376:Tuberculosis / Q000150:complications*; D014657:Vasculitis / Q000453:epidemiology* / Q000276:immunology* / Q000473:pathology
D019268:Antibodies, Antineutrophil Cytoplasmic; D005609:Free Radicals; D018664:Interleukin-12; D012822:Silicon Dioxide