Childhood systemic lupus erythematosus (SLE) differs from the disease in adults by a higher prevalence of nephritis. We hypothesize that this higher prevalence of nephritis is due to several types of nephritogenic autoantibodies that occur concurrently in the childhood form of SLE. Our 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. We propose that in some patients antibodies to Ro/SSA may also play a nephritogenic role. 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 recently been found to contain subpopulations of antibodies that directly bind and injure cells in culture. This in vitro cell injury is hypothesized to be a surrogate for their immunopathogenic potential in vivo. We propose to define the pathogenic potential of these autoantibodies in individual patients by affinity purifying their autoantibodies and by studying their interaction with renal cells in culture. We will characterize the pattern of intracellular localization and the effects on cell function and viability. We will also characterize the diverse pathogenic mechanism of anti-dsDNA from individual patients as preliminary studies already have shown that some human 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 affect cellular function over a longer period of time. We will correlate these immunopathogenetic properties in vitro with the patients clinical status. We believe such studies may generate data which will foster a new perspective on the mechanism of lupus nephritis in children and may suggest new strategies and interventions for the management of this serious complication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043975-03
Application #
2517517
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1995-09-30
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
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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