Abstract

Antiphospholipid antibody (aPL) is closely associated with recurrent fetal death, thrombosis, and thrombocytopenia. The mechanisms by which the antibody causes the complications remain unexplained. The specific goals of this proposal are: 1. To characterize the idiotypes of human polyclonal and mouse monoclonal aPL antibodies and to define """"""""pathogenic"""""""" public idiotypes. Anti-id will also be used to detect aPL in the placenta and other tissues by immunofluorescence. 2. To define the pathophysiology aPL. The effect of aPL on the activity of the placental anticoagulant protein (PAP) will be analyzed by ELISA as well as PL-dependent coagulation assays, KCT and APTT. The interaction of aPL with the lupus cofactor (apolipoprotein H) will be evaluated by ELISA and KCT and APTT coagulation assays. The levels of cofactor in patients' sera will be determined by ELISA and the co factor isoforms identified by isoelectric focusing. Associations between PAP levels, cofactor levels, cofactor isoforms and clinical complications will be assessed. 3. To explore the pathogenic nature of the antibody in spontaneous (MRL/lpr) and induced mouse models. Human polyclonal and mouse monoclonal antibodies will be administered to normal pregnant mice, or antiphospholipid antibodies will be induced in normal mice by immunization with apolipoprotein H. The effect on pregnancy (number of pups) and hematology (platelets, thrombosis) will be determined. To suppress aPL production, anti-id antibodies will be administered to MRL/lpr mice and circulating aPL levels, platelets and pregnancy outcome monitored. 4. To determine the VH sequences of aPL genes so as to define the genetic origins of aPL in MRL mice. The characterization and functional evaluation of PAP, lupus cofactor, and anti-id antibodies will determine whether aPL antibodies are directly involved in the pathogenesis of the syndrome and may uncover their pathogenesis. Identification of pathogenic idiotypes and the genetic origin of aPL may provide tools to identify patients at risk.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032929-09
Application #
3156454
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1984-04-01
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Louisiana State University Hsc New Orleans
Department
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112

  Publications

Gharavi, E E; Chaimovich, H; Cucurull, E et al. (1999) Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides. Lupus 8:449-55
Gharavi, A E; Pierangeli, S S; Colden-Stanfield, M et al. (1999) GDKV-induced antiphospholipid antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. J Immunol 163:2922-7
Magid, M S; Kaplan, C; Sammaritano, L R et al. (1998) Placental pathology in systemic lupus erythematosus: a prospective study. Am J Obstet Gynecol 179:226-34
Gharavi, A E; Cucurull, E; Tang, H et al. (1998) Effect of antiphospholipid antibodies on beta(2) glycoprotein I-phospholipid Interaction. Am J Reprod Immunol 39:310-5
Gharavi, A E; Pierangeli, S S (1998) Origin of antiphospholipid antibodies: induction of aPL by viral peptides. Lupus 7 Suppl 2:S52-4
Gharavi, A E; Pierangeli, S S; Gharavi, E E et al. (1998) Thrombogenic properties of antiphospholipid antibodies do not depend on their binding to beta2 glycoprotein 1 (beta2GP1) alone. Lupus 7:341-6
Molina, J F; Gutierrez-Urena, S; Molina, J et al. (1997) Variability of anticardiolipin antibody isotype distribution in 3 geographic populations of patients with systemic lupus erythematosus. J Rheumatol 24:291-6
Molina, J F; Molina, J; Garcia, C et al. (1997) Ethnic differences in the clinical expression of systemic lupus erythematosus: a comparative study between African-Americans and Latin Americans. Lupus 6:63-7
Morse, J H; Barst, R J; Fotino, M et al. (1997) Primary pulmonary hypertension, tissue plasminogen activator antibodies, and HLA-DQ7. Am J Respir Crit Care Med 155:274-8
Garcia, C O; Kanbour-Shakir, A; Tang, H et al. (1997) Induction of experimental antiphospholipid antibody syndrome in PL/J mice following immunization with beta 2 GPI. Am J Reprod Immunol 37:118-24

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