Increased generation of TRAP expressing multinucleated giant cells in patients with granulomatosis with polyangiitis.
BACKGROUND
Tissue-infiltrating multinucleated giant cells (MNGs) within geographic necrosis are pathologic hallmarks of granulomatosis with polyangiitis (GPA). However, the origin, phenotype, and function of these cells in GPA remain undefined.


RESULTS
MNG phenotype in GPA lung tissue was examined by immunohistochemistry using antibody directed against cathepsin K and calcitonin-receptor. Tartrate-resistant-acid-phosphatase (TRAP) expression was assessed using enzymatic color reaction. Peripheral blood mononuclear cells (PBMCs) from 13 GPA patients (5 with localized and 8 with systemic disease) and 11 healthy controls were cultured in the presence of RANKL and M-CSF for 9 days, and TRAP+ MNGs containing 3 or more nuclei were identified. GPA lung granulomata contained numerous MNGs that expressed osteoclastic TRAP and cathepsin K but not calcitonin receptors. In the presence of RANKL and M-CSF, PBMCs of GPA patients formed significantly more MNGs than healthy controls (114 ± 29 MNG/well vs. 22 ± 9 MNG/well, P = 0.02). In a subgroup analysis, patients with systemic disease generated significantly more MNGs than patients with localized disease (161 ± 35 MNG/well vs. 39 ± 27 MNG/well, P<0.01) or healthy controls (P<0.01). MNG production did not differ between localized GPA and control subjects (P = 0.96).


CONCLUSIONS
MNGs in granulomata in the GPA lung express osteoclastic enzymes TRAP and cathepsin K. GPA patients have a higher propensity to form TRAP+ MNGs from peripheral blood than healthy controls. These data suggest that (i) the tendency to form MNGs is a component of the GPA phenotype itself, and (ii) that lesional MNGs might participate in the destructive process through their proteolytic enzymes.
Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. jinkyunpark@gmail.com
Jin Kyun
JK
Park
Frederic
F
Askin
Jon T
JT
Giles
Marc K
MK
Halushka
Antony
A
Rosen
Stuart M
SM
Levine
D000135:Acid Phosphatase / Q000235:genetics*; D000328:Adult; D000368:Aged; D001706:Biopsy / Q000379:methods; D016022:Case-Control Studies; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015726:Giant Cells / Q000166:cytology* / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000201:enzymology* / Q000503:physiopathology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D010010:Osteoclasts / Q000378:metabolism; D010641:Phenotype; D053245:RANK Ligand / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
D007527:Isoenzymes; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase