Verbatim): IgA nephropathy (IgAN), the most common glomerulonephritis in the world is characterized by elevated levels of IgA1 in its polymeric form in circulation, presence of circulating immune complexes (CIC) and deposition of IgA1, frequently with C3 component of complement and IgG and/or IgM in glomerular mesangium. Earlier studies have shown that IgA1 in IgAN patients displays aberrant structural features in the heavy chain hinge region glycans. Carbohydrate analysis and lectin-binding studies have shown that the hinge region glycans bound by O-glycosidic bonds to Ser or Thr residues are deficient in galactose (Gal), resulting in an increased exposure of N-acetylgalactosamine (GalNAc). Furthermore, our earlier studies have shown that Gal deficient IgA1 molecules are present mainly in high molecular mass CIC that also contain IgG molecules. Our preliminary studies indicate that the interaction of Gal-deficient IgA1 with IgG, and probably other major isotypes, is based on antigen (IgA1) and antibody (IgG) recognition. Experimental approaches proposed in this application are designed to test the following hypothesis: An altered glycosylation of IgA1 hinge region results, due to the Gal deficiency, in exposure of GalNAc-Ser/Thr associated antigenic determinant(s) which are recognized by ubiquitous, naturally occurring antibodies, predominantly of the IgG isotype, which are involved in the formation of CIC and mesangial depositions. The following specific aims are proposed to test this hypothesis: 1) Determine the localization of antigenic determinants in IgA1 with aberrantly glycosylated hinge region glycans, involved in the formation of CIC; 2) Examine whether the Gal-deficient molecules are of systemic or mucosal origin; 3) Characterize the specificities and molecular properties of IgG, IgA, and IgM antibodies that bind to epitopes in the aberrantly glycosylated IgA1 hinge region; 4) Investigate the biological consequences of the formation of CIC containing Gal-deficient IgA1 and IgG. With GalNAc-Ser/Thr specificity; 5) Determine whether immune complexes composed of Gal-deficient IgA1-IgG with GalNAc-Ser/Thr binding activity are present in mesangial deposits of patients with IgAN; and 6) Correlate levels of Gal-deficient serum or secretory IgA1 and levels of IgG, IgA1, or IgM antibodies with GalNAc-Ser/Thr specificity with disease activity. Results of these studies may lead to the elucidation of molecular defects of IgA1 in IgAN and provide experimental basis for rational approach to the treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057750-04
Application #
6697263
Study Section
Special Emphasis Panel (ZRG1-HEM-1 (04))
Program Officer
Moxey-Mims, Marva M
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2006-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$290,588
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Lau, Keith K; Wyatt, Robert J; Moldoveanu, Zina et al. (2007) Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schonlein purpura. Pediatr Nephrol 22:2067-72
Moldoveanu, Z; Wyatt, R J; Lee, J Y et al. (2007) Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int 71:1148-54
Zurbig, Petra; Renfrow, Matthew B; Schiffer, Eric et al. (2006) Biomarker discovery by CE-MS enables sequence analysis via MS/MS with platform-independent separation. Electrophoresis 27:2111-25
Matousovic, Karel; Novak, Jan; Yanagihara, Takeshi et al. (2006) IgA-containing immune complexes in the urine of IgA nephropathy patients. Nephrol Dial Transplant 21:2478-84
Moore, Jennifer S; Wu, Xueling; Kulhavy, Rose et al. (2005) Increased levels of galactose-deficient IgG in sera of HIV-1-infected individuals. AIDS 19:381-9
Novak, Jan; Tomana, Milan; Matousovic, Karel et al. (2005) IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int 67:504-13
Renfrow, Matthew B; Cooper, Helen J; Tomana, Milan et al. (2005) Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation fourier transform-ion cyclotron resonance mass spectrometry. J Biol Chem 280:19136-45
Chandrakantan, Arun; Ratanapanichkich, Piti; Said, Mowaffaq et al. (2005) Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil. Nephrol Dial Transplant 20:1214-21
Julian, Bruce A; Novak, Jan (2004) IgA nephropathy: an update. Curr Opin Nephrol Hypertens 13:171-9

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