The pathogenic role of anti-phosphatidylserine antibodies: active immunization with the antibodies leads to the induction of antiphospholipid syndrome.
Primary antiphospholipid syndrome (pAPS) can be experimentally induced in mice by immunization with anti-cardiolipin (aCL) antibodies (Abs). Recently, we have pointed to the pathogenic role of antiphosphatidylserine (aPS) Abs by inducing an experimental model of pAPS in naive mice following passive transfer of human aPS to the tail vein of ICR mice. The aim of the present study was to induce experimental pAPS in mice following active immunization with aPS. Mice were immunized with IgG and IgM aPS, purified from two patients with pAPS. The sera of the mice were examined for the presence of different antiphospholipid Abs, and the beta 2 GPI dependency of aPS, using an enzyme-linked immunosorbent assay (ELISA). Inhibition ELISA studies, with silica beads coated with phospholipids, were used to detect cross-reactivity of aPS or aCL to other phospholipids. The mice were also tested for the presence of thrombocytopenia, prolonged activated partial thromboplastin time (APTT), and the percentage of fetal resorptions. The purified IgG aPS but not IgM aPS had a strong lupus anticoagulant activity. Both IgG and IgM aPS were beta 2 GPI dependent and did not bind PS in the absence of the glycoprotein. The mice immunized with IgG aPS, but not IgM aPS, developed high titers of mouse aPS. The mice generated polyspecific Abs, cross-reacting with aCL and aPS, as well as individual aPS or aCL Abs. Only the mice immunized with IgG aPS developed clinical parameters of pAPS: prolonged APTT, thrombocytopenia, and an increased fetal resorption rate. In conclusion, active immunization with IgG, but not IgM, aPS induces experimental pAPS in naive mice, thus pointing to the participation of aPS in the idiotypic network.
Yodfat
O
O
Department of Medicine B, Sheba Medical Center, Tel-Hashomer, Israel.
Blank
M
M
Krause
I
I
Shoenfeld
Y
Y
D000328:Adult; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000008:administration & dosage* / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000209:etiology* / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007110:Immunity, Active; D007116:Immunization, Passive; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010718:Phosphatidylserines / Q000276:immunology*
D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; D010718:Phosphatidylserines