Childhood systemic lupus erythematosus (SLE) differs from the disease in adults by a higher prevalence of nephritis. The investigators hypothesize that this higher prevalence of nephritis is due to several types of nephritogenic autoantibodies that occur concurrently in the childhood form of SLE. Two major candidates for these autoantibodies are those directed against dsDNA which have long been recognized to play a role in adult lupus nephritis and autoantibodies to ribosomal """"""""P"""""""" protein which have not been reported previously to be associated with either adult or pediatric lupus nephritis. Aside from recent preliminary clinical and animal data that support a role for anti-P in lupus nephritis, both anti-dsDNA and anti-ribosomal """"""""P"""""""" antibodies have been found to contain subsets that directly bind and injure cells in culture. According to the investigators, this antibody-mediated, in vitro cell injury phenomenon could be a surrogate for their immunopathogenic potential in vivo. The investigators propose to define the pathogenic potential of the autoantibodies in individual patients by affinity purifying their autoantibodies and by studying their interaction with various cell types in culture and the effects on cell function and viability. In preliminary studies, they have reproduced previous work by showing that some human anti-dsDNA antibodies injure cells by a complement dependent mechanism at the cell surface, and others penetrate the cell, localize in either the nucleus or the cytoplasm, and like anti-P, inhibit protein synthesis. The investigators will correlate these immunopathogenetic properties in vitro with the patients' clinical status. They propose to expand their studies of the idiotypic regulation of these antibodies in patients with anti-P antibodies. Parallel studies in adults suggest that, like children, the presence of both anti-dsDNA and anti-P antibodies greatly increase the risk of active nephritis. The investigators also have preliminary data that anti-P may be enriched in human glomerular eluates and propose to expand these studies. Lastly, they propose to develop an animal model to assess the nephritogenic potential of induced anti-P antibodies. They hope that these studies would expand perspectives on the immunopathogenesis of nephritis in both children and adults with SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043975-07
Application #
6511872
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Serrate-Sztein, Susana
Project Start
1995-09-30
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
7
Fiscal Year
2002
Total Cost
$303,620
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Zhang, Wei; Reichlin, Morris (2005) A peptide DNA surrogate that binds and inhibits anti-dsDNA antibodies. Clin Immunol 117:214-20
Reichlin, Morris (2005) Serological correlations with nephritis in systemic lupus erythematosus. Clin Immunol 117:12-4
Zhang, Wei; Reichlin, Morris (2005) Production and characterization of a human monoclonal anti-idiotype to anti-ribosomal P antibodies. Clin Immunol 114:130-6
Reichlin, Morris; Wolfson-Reichlin, Marianne (2003) Correlations of anti-dsDNA and anti-ribosomal P autoantibodies with lupus nephritis. Clin Immunol 108:69-72
Reichlin, Morris; Fesmire, James; Quintero-Del-Rio, Ana I et al. (2002) Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus. Arthritis Rheum 46:2957-63
Anderson, C J; Neas, B R; Uchiumi, T et al. (2001) Autoantibodies to the 20-kDa ribosomal proteins: identification, characterization, and new aspects on prevalence in systemic Lupus erythematosus. Clin Immunol 98:249-57
Alberdi, F; Dadone, J; Ryazanov, A et al. (2001) Cross-reaction of lupus anti-dsDNA antibodies with protein translation factor EF-2. Clin Immunol 98:293-300
Zhang, W; Winkler, T; Kalden, J R et al. (2001) Isolation of human anti-idiotypes broadly cross reactive with anti-dsDNA antibodies from patients with Systemic lupus erythematosus. Scand J Immunol 53:192-7
Takeda, I; Rayno, K; Movafagh, F B et al. (2001) Dual binding capabilities of anti-double-stranded DNA antibodies and anti-ribosomal phosphoprotein (P) antibodies. Lupus 10:857-65
Panush, R S; Levine, M L; Reichlin, M (2000) Do I need an ANA? Some thoughts about man's best friend and the transmissibility of lupus. J Rheumatol 27:287-91

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