Autoantibodies to c1 inhibitor in acquired cl inhibitor deficiency: significance of associated m components and affinity characteristics

Autoantibodies to Cl inhibitor (Cl-INH)and various type of B cell proliferative disorders are the conditions most frequently described in patients with acquired Cl-INH deficiency who suffer from recurrent angioedema symptoms (Acquired Angioedema, AAE). Whether those 2 conditions may coexist remains to be elucidated. We report 13 patients with AAE and the affinity characteristics of the anti-Cl-INH autoantibodies, isolated from serum of 6 of them. No associated disease was identified in 3 patients, 1 had liver idatidosis, 1 breast cancer, 1 chronic lymphocytk leukemia, 7 serum M components that in 2 fulfilled the criteria for diagnosis of Waldenstroem macroglobulinemia. Cl-INH and C4 were constantly low at repeated controls in all patients. Anti-Cl-INH immunoglobulins (Igs) were measured both as Igs binding to Cl-INH immobilized onto microtiter plates (ELISA) and as Igs blocking the capacity of Cl-INH to inhibit the esterolytic activity of its target protease Cls (functional assay). In 12 patients both assays were positive, in 1 anti-ClINH Igs were detectable only by functional assay. Immunoblotting analysis of SDS-PAGE separated plasma, showed that in the 12 patients with autoantibodies, but not in the 1 without, Cl-INH circulated in its cleaved form of 96 kD. Agarose electrophoresis of plasma of 7 patients with paraproteins was transferred onto Immobilon sheets and blotted with purified Cl-INH that was subsequently revealed by monospecific antibody: in 5 plasma the bands representing the M components were able to bind Cl-INH. To evaluate the antigen/autoantibody binding-affinity we measured the amount of purified Cl-INH, added in fluid phase to the affinity-purified autoantibody, necessary to saturate its binding to the immobilized protein. The molar ratio of Cl-INH-autoantibody interaction, measured with the autoanti bodies of 6 different patients, ranged between 28 and 770. In conclusion the majority of our AAE patients have autoanti bodies to Cl-INH. When proliferating B cell clones secrete monoclonal immunoglobulins they frequently represent the autoantibodies to Cl-INH. These autoantibodies have variable, but generally very low affinities for the soluble antigen.