Primary IgA nephropathy is the most common of the primary glomerulonephritides worldwide, with a significant number of patients progressing to end-stage renal disease. Other disorders, such as Henoch-Schoenlein purpura and dermatitis herpetiformis, share the characteristic immunopathology of this disease, i.e., mesangial deposition of IgA as the most prevalent immunoglobulin isotype; together all of these disorders are called the IgA nephropathies (IgA NP). The pathogenesis of IgA NP is unknown. However, because most patients with IgA NP have elevated levels of circulating immune complexes (CIC) containing IgA (often co- complexed with IgG), and because the C3 component of complement is usually found codeposited with IgA in the kidney, many investigators have speculated that the IgA NP are immune complex- mediated diseases. Characterization of the CIC would be expected to provide insight into pathogenetic mechanisms of IgA NP. Thus it is the objective of the proposed investigation to describe fully the CIC of patients with this disease, with specific respect to the immunoglobulin molecules contained within the complex matrices. Therefore, we will perform spectrotypic analyses of IgA and IgG proteins (in serum, saliva, CIC, lymphoid cells, and mesangial deposits) of IgA NP as well as determine the presence of disease- specific idiotypic markers of these immunoglobulins. We will also search for crossreactive idiotypes on IgA rheumatoid factors as well as study the possibility that autologous IgG anti-idiotypic antibodies specific for IgA rheumatoid factors contribute to the formation of the CIC. Further, we will ascertain the potential contribution to the antibodies specific for Fab of autologous IgA. All of these studies will be performed on longitudinal samples obtained from a large population of patients, many of whom have familial disease. Other studies will characterize both immunoglobulin heavy chain and light chain restrictions previously reported in IgA NP: we will determine IgG subclasses in serum and CIC and in IgG codeposited in mesangia with IgA; further, putative lambda chain restriction will be studied with respect to definition of variable region subgroups. Finally, we will study the potential functional significance of the CIC by examining the effects on B and T cells in vitro. The proposed experiments are designed to define the clonal origins of CIC-bound immunoglobulins in IgA NP and ultimately elucidate the pathogenesis of these disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040117-04
Application #
3240217
Study Section
Pathology A Study Section (PTHA)
Project Start
1989-01-15
Project End
1993-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Hunley, T E; Julian, B A; Phillips 3rd, J A et al. (1996) Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int 49:571-7
Crowley-Nowick, P A; Campbell, E; Schrohenloher, R E et al. (1996) Polyethylene glycol precipitates of serum contain a large proportion of uncomplexed immunoglobulins and C3. Immunol Invest 25:91-101
Crowley-Nowick, P A; Campbell, J E; Mullins, A L et al. (1995) Human IgA1 and IgA2 have distinct spectrotypes but display subclass similarities between individuals. Adv Exp Med Biol 371A:591-3
Mestecky, J; Tomana, M; Crowley-Nowick, P A et al. (1993) Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib Nephrol 104:172-82
Julian, B A; Barker, C (1993) Alternate-day prednisone therapy in IgA nephropathy. Preliminary analysis of a prospective, randomized, controlled trial. Contrib Nephrol 104:198-206
van den Wall Bake, A W; Bruijn, J A; Accavitti, M A et al. (1993) Shared idiotypes in mesangial deposits in IgA nephropathy are not disease-specific. Kidney Int 44:65-74
Moreland, L W; Pratt, P W; Sanders, M E et al. (1993) Experience with a chimeric monoclonal anti-CD4 antibody in the treatment of refractory rheumatoid arthritis. Clin Exp Rheumatol 11 Suppl 8:S153-9
Kozlowski, P A; Jackson, S (1992) Serum IgA subclasses and molecular forms in HIV infection: selective increases in monomer and apparent restriction of the antibody response to IgA1 antibodies mainly directed at env glycoproteins. AIDS Res Hum Retroviruses 8:1773-80
van den Wall Bake, A W; Black, K P; Kulhavy, R et al. (1992) Transforming growth factor-beta inhibits the production of IgG, IgM, and IgA in human lymphocyte cultures. Cell Immunol 144:417-28
van den Wall Bake, A W; Crowley-Nowick, P A; Kulhavy, R et al. (1992) Cytokine-induced immunoglobulin production in primary IgA nephropathy. Am J Kidney Dis 20:611-7

Showing the most recent 10 out of 14 publications