Pooled Normal Human Polyspecific IgM Contains Neutralizing Anti-Idiotypes to IgG Autoantibodies of Autoimmune Patients and Protects From Experimental Autoimmune Disease

Abstract

Normal human serum contains IgM antibodies that regulate the natural autoantibody activity of IgG in autologous serum. In the present study, we show that pooled normal human IgM (IVIgM) purified from plasma of more than 2,500 healthy donors and processed in a similar fashion to that of therapeutic preparations of pooled normal human IgG (IVIg) suppresses activity of IgG autoantibodies purified from the serum of patients with autoimmune diseases in vitro. The inhibitory effect of IVIgM was greater or equivalent to that of IVIg on a molar basis. We show that IVIgM contains anti-idiotypic antibodies directed against idiotypic determinants of autoantibodies, in particular by showing that Sepharose-bound IVIgM selectively retained F(ab′)2 fragments of IgG autoantibodies. The infusion of (Lewis × Brown-Norway) F1 rats with IVIgM protected the animals against experimental autoimmune uveitis induced by immunization with the soluble retinal S antigen, as evidenced by clinical scoring and histopathological analysis. The present findings provide a rationale for considering pooled IgM for immunomodulation of autoimmune disease.

Conditional autoimmunity mediated by human natural anti‐FcεRIα autoantibodies?

“…These autoantibodies were isolated from a nonimmune library and sequence analysis revealed germline VH paired with a slightly mutated VL, thus supporting their classification as natural antibodies (17). Until now, it has been assumed that natural autoantibodies are nonpathogenic under physiological conditions for a variety of reasons, including low-affinity reactions and their role in establishing V region-mediated networks (18). However, our results indicate that natural autoantibodies can have a high affinity.…”

Serum IgM, IgG and IgA block by F(ab′)2‐dependent mechanism the binding of natural IgG autoantibodies from therapeutic immunoglobulin preparations to self‐antigens

“…Our study confirms previous findings regarding the role of IgM in blocking the reactivity of IgG autoantibodies to self-antigens (19,50) and supports the suggestion that a normal pooled human IgM preparation might possess a potent beneficial immunomodulatory activity in selected autoimmune diseases.…”

“…There are conflicting claims regarding the nature of serum proteins that mask the binding of natural IgG autoantibodies in human serum to self-antigens. Some authors maintain that only non-immunoglobulin proteins are responsible (18), while others support only a role for IgM (19)(20)(21), for IgG (22) or claim that self-reactivity is masked by the circulating target self-antigens (23).…”

Theiler's Virus Infection: a Model for Multiple Sclerosis

“…A predominant H-2D b -restricted VP2 [121][122][123][124][125][126][127][128][129][130] viral peptide in BeAn-or DA-infected mice recognized by CTL has been identified (322,354). Two other H-2D brestricted TMEV epitopes (VP [165][166][167][168][169][170][171][172][173] and VP 110-120 ) recognized by CTL have been also described (270). In contrast, only a weak TMEV-specific CTL response is generated in the CNS of TMEV-infected SJL mice (96,242,244).…”