Studies proposed in this component project will focus on the biosynthesis of IgA1 by antibody-producing cells at various stages of disease, family members, patients with other glomerular diseases, and healthy controls. Accumulation of recent results from several laboratories indicates that IgA1 molecules display a defect in glycosylation (deficiency of galactose in O-linked glycans in the hinge region) and that such aberrant molecules are present in the form of immune complexes (IC) in patients' peripheral blood.
In Specific Aim 1, we propose to determine the stage of differentiation of B cells into plasma cells where galactose-deficient IgA1 is produced. Using biochemical and immunological reagents and assays, we shall analyze lymphocytes before and after in vitro stimulation with respect to their differentiation stage and production of galactose-deficient IgA1 and activity of intracellular enzymes involved in immunoglobulin glycosylation.
In Specific Aim 2, we propose to determine the production of galactose-deficient IgA1 molecules is due to the imbalance of enzymes-glycosyltransferase in IgA1 producing cells in IgAN patients. Specifically, we shall determine whether the enzyme alpha 2,6 sialyltransferase (alpha 2, 6 ST) is selectively increased in IgA1-producing cells of IgAN patients, and whether its increased activity is responsible for """"""""premature"""""""" sialylation of N-acetylgalactosamine, thus preventing regular galactosylation of this monosaccharide. Alternatively, decreased levels of a galactose- transferring enzyme, beta1, 3 galactosyltransferase (beta1, 3 GalT) may be responsible for this defect. Because the addition of glycans and proteins is greatly influenced by endogenous (e.g., cytokines), and exogenous agents (bacterial products), we propose to study in Specific Aim 3 such factors and their influence on the glycosylation of IgA1 in antibody-producing cells. The effect of such selected agents on the secretion of galactose-deficient IgA1 molecules and intracellular activity of glycosyltransferase in IgA1-secreting cells will be studied. Finally, the effects of drugs known to influence the expression of intracellular glycosyltransferase and able to restore a regular glycosylation pathway will be evaluated using cultured and stimulated cells from IgAN patients. These studies may provide information concerning the molecular basis of familial IgAN and may provide a rational approach to the future treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK061525-01
Application #
6555234
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Tamouza, Houda; Chemouny, Jonathan M; Raskova Kafkova, Leona et al. (2012) The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy. Kidney Int 82:1284-96
Novak, Jan; Raskova Kafkova, Leona; Suzuki, Hitoshi et al. (2011) IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. Nephrol Dial Transplant 26:3451-7
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Gomes, Michelle M; Suzuki, Hitoshi; Brooks, Monica T et al. (2010) Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study. Biochemistry 49:5671-82
Good, David M; Zürbig, Petra; Argilés, Angel et al. (2010) Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease. Mol Cell Proteomics 9:2424-37
Lavigne, K A; Woodford, S Y; Barker, C V et al. (2010) Familial IgA nephropathy in southeastern Kentucky. Clin Nephrol 73:115-21
Hastings, M Colleen; Moldoveanu, Zina; Julian, Bruce A et al. (2010) Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol 5:2069-74
Suzuki, Hitoshi; Fan, Run; Zhang, Zhixin et al. (2009) Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest 119:1668-77
Mischak, Harald; Coon, Joshua J; Novak, Jan et al. (2009) Capillary electrophoresis-mass spectrometry as a powerful tool in biomarker discovery and clinical diagnosis: an update of recent developments. Mass Spectrom Rev 28:703-24

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