Expression profile of proinflammatory genes in neutrophil-enriched granulocytes stimulated with native anti-PR3 autoantibodies.
Granulomatosis with polyangiitis (Wegener's ) is a rare autoimmune disease associated with the presence of antibodies directed against neutrophil antigen, proteinase-3 (PR3). The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCA) may activate neutrophils are still not well understood. In the present study we analyzed neutrophil gene expression profile after anti-PR3 antibodies stimulation. Briefly neutrophils isolated from 12 healthy volunteers, who tested negative for anti-PR3 autoantibodies, were stimulated with anti-PR3 IgG and activation of 147 genes was analyzed with the use of TaqMan low-density arrays. In stimulated neutrophils we observed up-regulation of 13 genes (CCL2, CXCL2, VCAM1, MMP9, PLCB4, PDE4C, PLA2G4C, RAC1, RHOA, IRAK1, CACNA1D, CACNB2, PTGDR), further 11 genes were up-regulated only in some donors (IL13, PF4, IL2RG, ITGB1, CD83, PLA2G7, ALOX12, AXNA1, AXNA5, LTA4H, MCR2) yet two others (HRH3 and PLA2G2D) were up-regulated in a few samples and undetectable in others. The obtained results demonstrate that c-ANCA mediated activation of neutrophils involve several pathways mediated via FcγRs like calcium signaling, phosphatidylinositol 3-kinase AKT pathway or MAPK signaling systems, but also inducts others, like G-protein signaling. Neutrophil is a very sensitive cell, responding to many environment changes. As our results showed, some anti-PR3 responses are highly variable across donors. Perhaps, this variablity also contribute to the susceptibility for granulocyte vasculitis and requires future studies.
Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, Cracow, Poland. msanak@cm-uj.krakow.pl
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D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006098:Granulocytes / Q000276:immunology* / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D053146:Myeloblastin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D007074:Immunoglobulin G; D053146:Myeloblastin