HUMAN POLYREACTIVE IGM MONOCLONAL-ANTIBODIES WITH BLOCKING ACTIVITY AGAINST SELF-REACTIVE IGG

Natural IgM antibodies have been found to be involved in the control o f IgG reactivity in normal serum. The authors investigated the blockin g activity of four human IgM monoclonal antibodies (BY-2, BY-7, BY-10 and IRM-7) derived from B-cells from blood samples of three renal dial ysis patients, which had shown multispecific properties similar to tho se observed for natural polyreactive autoantibodies. To achieve this, competitive inhibition assays were performed with these MoAbs on the b inding of IgG purified from a healthy control, three patients with SLE , and two patients with autoimmune thyroiditis, to histone, dsDNA, RNP and thyroglobulin. MoAbs inhibited binding of self-reactive IgG to hi stone and dsDNA, but not to thyroglobulin or RNP, of natural and activ e or inactive phase disease-associated autoreactive IgG. The inhibitor y effect of the MoAbs was mediated by V-region dependent interactions with autoreactive IgG, as shown by the ability of these MoAbs to block the binding of F(ab')(2) fragments of autoreactive IgG to antigens (h istone and dsDNA), The blocking of autoantibody activity was dose-depe ndent with maximal inhibition occurring at a specific molar ratio betw een the patient's IgG and a given MoAb. In contrast, MoAbs did not inh ibit binding of IgG alloantibodies present in the sera of four polytra nsfused renal dialysis patients to target antigens on the surface of d ifferent cells. These results support the concept of a functional idio typic network regulating autoimmune responses, and suggest that the Ig M MoAbs under study may be natural polyreactive antibodies belonging t o the physiological network of autoantibodies with highly connected V- regions, capable of binding and functionally neutralizing V-regions of natural and pathologic autoantibodies.