Upregulation of the immunoproteasome in peripheral blood mononuclear cells of patients with IgA nephropathy.
In order to present an antigen to T-cells, the antigen must first be degraded by proteasomes. Following exposure to interferons, some proteasome subunits (ss1,ss2,ss5) are replaced by others (LMP2, LMP7, MECL-1) that have more optimal catalytic properties for peptide presentation; this more efficient organelle is termed the immuno-proteasome. Here we measured gene expression of various subunits in peripheral mononuclear cells of patients with IgA nephropathy, a disease with features of immune dysregulation. We used quantitative PCR to measure the expression of proteasomal subunit mRNA in mononuclear cells from IgA nephropathy patients, a group of proteinuric control patients with idiopathic nephrotic syndromes, and healthy controls. A significant switch in the expression of trypsin- and chymotrypsin-like proteasome subunits to corresponding immuno-proteasome subunits was found in patients as compared to healthy controls. Further, we found that nuclear translocation of NF-kappaB p50 and p65 was significantly greater in the IgA nephropathy patients, but this did not correlate with the switch to the immuno-proteasome phenotype. Patients with proteinuria greater than 0.5 g/1.73 m(2)/day had a significant switch of the chymotryptic-like beta5 protease to the LMP7 subunit, but this did not occur in patients with idiopathic nephrotic syndrome. The switch to an immuno-proteasome in peripheral blood mononuclear cells of patients with IgA nephropathy suggests an increased efficiency of antigen processing and presentation. This switch appears to be independent of a coincidental activation of the NF-kappaB pathway but is associated with high levels of proteinuria, a well known risk factor for progression of IgA nephropathy.
Coppo
Rosanna
R
Nephrology, Dialysis and Transplantation Unit, Regina Margherita Children's Hospital, University of Turin, Turin, Italy. rosanna.coppo@unito.it
Camilla
Roberta
R
Alfarano
Alda
A
Balegno
Sabrina
S
Mancuso
Domenico
D
Peruzzi
Licia
L
Amore
Alessandro
A
Dal Canton
Antonio
A
Sepe
Vincenzo
V
Tovo
Pierangelo
P
D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D017951:Antigen Presentation; D001773:Blood Cells; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002918:Chymotrypsin; D005260:Female; D005922:Glomerulonephritis, IGA / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D011507:Proteinuria; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation; D055815:Young Adult
D009097:Multienzyme Complexes; D016328:NF-kappa B; D021122:Protein Subunits; D012333:RNA, Messenger; D002918:Chymotrypsin; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex