Circumvention of normal constraints on granule protein gene expression in peripheral blood neutrophils and monocytes of patients with antineutrophil cytoplasmic autoantibody-associated glomerulonephritis.
Granulopoiesis-related genes are distinctively upregulated in peripheral leukocytes of patients with antineutrophil cytoplasmic autoantibodies (ANCA)-associated glomerulonephritis. Affymetrix microarrays identified the upregulation of nine neutrophilic primary granule genes, including myeloperoxidase (MPO) and proteinase 3 (PR3), plus five secondary granule genes. Coordinate expression of granulocyte maturation marker CD35, measured by TaqMan PCR, and positive in situ staining for PR3 transcripts in polymorphic neutrophils and monocytes indicate that these genes are expressed in "mature" cells. Increased transcripts correlated with disease activity and absolute neutrophil values but not with "left shift," drug regimen, cytokine levels, hematuria, proteinuria, ANCA titer, serum creatinine, gender, or age. Upregulation of PR3 and MPO transcripts was specifically associated with ANCA disease (n = 56) as these changes were not detected in patients with ESRD (n = 25) or systemic lupus erythematosus (n = 17), as determined by TaqMan PCR. This is the first report of this phenomenon in nonneoplastic cells. The data raise the hypothesis that, in addition to the presence of anti-MPO or anti-PR3 autoantibodies, a second critical component in the cause of this disease is the reactivation of once-silenced genes leading to increased antigen availability.
Division of Nephrology and Hypertension, Department of Medicine, The University of North Carolina at Chapel Hill, CB#7155, 349 MacNider Building, Chapel Hill, NC 27599-7155. jjyang@med.unc.edu
Jia Jin
JJ
Yang
William F
WF
Pendergraft
David A
DA
Alcorta
Patrick H
PH
Nachman
Susan L
SL
Hogan
Robin P
RP
Thomas
Pamela
P
Sullivan
J Charles
JC
Jennette
Ronald J
RJ
Falk
Gloria A
GA
Preston
D000293:Adolescent; D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003594:Cytoplasmic Granules / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D053146:Myeloblastin; D009504:Neutrophils / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D009195:Peroxidase / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D016207:Cytokines; D012333:RNA, Messenger; D009195:Peroxidase; D012697:Serine Endopeptidases; D053146:Myeloblastin