Human Polyreactive IgM Monoclonal Antibodies with Blocking Activity Against Self‐Reactive IgG

Abstract

Natural IgM antibodies have been found to be involved in the control of IgG reactivity in normal serum. The authors investigated the blocking 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 dialysis patients, which had shown multispecific properties similar to those observed for natural polyreactive autoantibodies. To achieve this, competitive inhibition assays were performed with these MoAbs on the binding 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 histone and dsDNA, but not to thyroglobulin or RNP, of natural and active or inactive phase disease-associated autoreactive IgG. The inhibitory 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 0 ) 2 fragments of autoreactive IgG to antigens (histone and dsDNA). The blocking of autoantibody activity was dose-dependent with maximal inhibition occurring at a specific molar ratio between the patient's IgG and a given MoAb. In contrast, MoAbs did not inhibit binding of IgG alloantibodies present in the sera of four polytransfused renal dialysis patients to target antigens on the surface of different cells. These results support the concept of a functional idiotypic network regulating autoimmune responses, and suggest that the IgM MoAbs under study may be natural polyreactive antibodies belonging to the physiological network of autoantibodies with highly connected V-regions, capable of binding and functionally neutralizing V-regions of natural and pathologic autoantibodies.

Human amniotic IgA inhibits natural IgG autoantibodies of maternal or unrelated origin

“…Similar inhibitions of the IgG autoAb activity have been reported in the serum of both mice [22,23] and humans [24], where polyclonal and monoclonal IgM were found to inhibit autologous and homologous serum IgG. These IgM-associated inhibitions of IgG were not due to a competition for the same Ag but probably to anti-Fab binding [22].…”

Protective autoantibodies: Role in homeostasis, clinical importance, and therapeutic potential

“…The inhibitory effect of IgM mAb is mediated by V-regiondependent interactions with the autoreactive IgG, as shown by the ability of these antibodies to block the binding of F(abЈ) 2 fragments of autoreactive IgG to their respective autoantigens (15). The blocking activity was found to be dose-dependent, with maximal inhibition occurring at a specific molar ratio between the patient's IgG and a given mAb, supporting the concept of a functional idiotypic network regulating autoimmune responses.…”

Pathogenic Relevance of IgG and IgM Antibodies against Desmoglein 3 in Blister Formation in Pemphigus Vulgaris

“…In the context of autoimmunity, IgM autoantibodies have often been considered to be simply nonpathogenic, but they appear to be actually protective. 34,35 Mice deficient in serum IgM exhibit spontaneous autoimmunity (eg, the production of anti-DNA IgG), indicating the role of IgM in protecting against the development of autoimmunity. 36 Antigen microarray informatics study, however, has demonstrated that the IgM antibodies produced by neonatal humans recognize mostly self molecules that are associated with major autoimmune diseases later in life.…”