Pathogenic natural anti-cardiolipin antibodies: the experience from monoclonal gammopathy.

Anti-cardiolipin antibodies (ACA) were detected in 19% of sera from patients with monoclonal gammopathies (MG). ACA were purified from the sera of patients with MG. One of the IgG-ACA was found to be monospecific with high affinity for cardiolipin, and to carry a pathogenic ACA Id (1.10). Active immunization of naive BALB/c mice with the purified IgG-ACA was followed by production in the mice of sustained high titres of ACA, associated with prolonged activated partial thromboplastin time (APTT) (61 +/- 14s versus 31 +/- 2s in control mice; P < 0.001) and thrombocytopenia (468,000 +/- 224,000/mm3 versus 994,000 +/- 92,000/mm3 in controls; P < 0.001). The titres of other autoantibodies (e.g. anti-DNA, anti-histones), although being high after immunization, decreased rapidly and were undetected after 1 month following the boost injection. The mice immunized with the IgG-ACA exhibited low fecundity (36% of mice became pregnant versus 62% observed in the group immunized with control IgG). The pregnant mice had increased resorption rate (the equivalent of fetal loss in the human) of 52 +/- 8% (versus 5 +/- 4% in the control group). The mean (+/- s.d.) embryo and placental weights in mice with anti-phospholipid syndrome (APLS) were significantly lower compared with the mice injected with control IgG (682 +/- 304 mg and 102 +/- 12 mg versus 1303 +/- 105 mg and 145 +/- 8 mg, respectively; P < 0.001). Serum monoclonal immunoglobulins having autoantibody activity may be regarded as an expansion of clones producing natural autoantibodies. Our results confirm the pathogenic role of natural ACA in the pathogenesis of the anti-phospholipid syndrome.