Blockade of blocking antibodies in Guillain‐Barré syndromes: “Unblocking” the mystery of action of intravenous immunoglobulin

The Guillain-Barré syndrome(s) (GBS[s]) comprises various forms of acute flaccid paralysis caused by an autoimmune attack against components of the peripheral nerve. The most common pattern is the acute inflammatory demyelinating polyneuropathy (AIDP), in which the putative target antigens are on the myelin sheath. The least common, but better understood forms, are the acute motor (or motor-sensory) axonal neuropathy (AMAN or AMSAN) and the Miller-Fisher syndrome (MFS) with target antigens on motor nerve terminals and axons. Humoral and cell-mediated mechanisms participate in the cause of GBS(s) probably triggered by molecular mimicry between bacterial or viral glycoconjugates and nerve gangliosides. In AIDP, autoreactive T cells may initiate the lesion, but the effector mechanisms are complement deposits and macrophages invading the myelin sheath. In AMAN and MFS, immunoglobulin G (IgG) antibodies against specific gangliosides (GM1, GM1a, GalNac-GD1a, and GM1b in AMAN; GQ1b in MFS) block functionally relevant epitopes for nerve conduction or neuromuscular transmission resulting in axonal injury by an antibody-dependent cellular cytotoxic process. Furthermore, rabbits immunized with GM1 develop AMAN. Therapeutically, the self-limiting course of GBS(s) is significantly shortened by intravenous immunoglobulin (IVIg) or plasmapheresis. The results from these therapies are gratifying, but the mode by which they exert their immunomodulatory action remains a fascinating immunological puzzle. Although plasmapheresis removes circulating immune factors responsible for conduction block, IVIg manipulates the immune system to modify or neutralize these factors either in situ or in the circulation. In this issue, Buchwald and colleagues insightfully demonstrate that in patients with GBS, IVIg exerts a neutralizing effect on the activity of blocking antibodies. They showed, by means of a perfused macropatch clamp electrode in a mouse nerve-muscle preparation, that serum from AMAN and MFS patients contains IgG antibodies that “block” quantal release, confirming their own work. These “blocking” antibodies were neutralized in the serum obtained after IVIg therapy, or in a mixture of preIVIg with post-IVIg serum. Furthermore, the F(ab )2, but not the Fc portion of IgG extracted from the same IVIg lots, neutralized the “blocking” antibodies in a dose-dependent manner. Four patients had AMAN and 2 patients had MFS with GM1 or GQ1b antibodies, which cause conduction block in vitro. Because IVIg blocks the antigen-binding sites of anti–GM1 antibodies and inhibits their binding to GM1, 16,17 the inhibition of neuromuscular blockade noted after IVIg is most likely related to neutralization of GM1 or GQ1b antibodies. In AMAN and AMSAN, the anti-GM1–specific IgG enters freely through the roots and distal nerve terminals, which lack blood-nerve barrier, and recognizes GM1 epitopes at the nodes of Ranvier. 18 The infused IgG molecules also should enter freely at the roots and distal nerve terminals and may quickly neutralize these antibodies even in situ, like the neutralization described in vitro by Buchwald and colleagues. Such antibody blockade supports the fast recovery of patients with AMAN who have IgG GM1 antibodies, compared with those without antibodies, and the reported superiority of IVIg compared with plasmapheresis in this group of patients. The observations of Buchwald and colleagues are novel and significant in elucidating the mode by which IVIg manipulates pathogenic autoantibodies but also call for additional studies. How does IVIg neutralize the blocking antibodies in GBS? Normal humans make IgG antibodies against a wide spectrum of normal proteins and “anti-idiotypic antibodies,” defined as antibodies against the Fab , the antigen-binding region (idiotype), of these antibodies. Because IVIg preparations are derived from large pools of human donors, they contain a wide range of idiotypic and anti-idiotypic antibodies that form dimeric pairs. The larger the pool of donors, the higher the number of the F(ab )2 dimers and the wider the expected spectrum of idiotypic–anti-idiotypic specificities. The anti-idiotypic antibodies supplied by IVIg have the potential to bind and neutralize pathogenic autoantibodies, thereby preventing their interaction with the autoantigen. In AMAN and MFS, IVIg can neutralize the blocking activity of GM1 or GQ1b antibodies because (1) normal human serum, and the various IVIg preparations, contains anti-idiotypic antibodies that recognize anti-GM1 ; and (2) the F(ab )2, but not Fc fragments of IVIg, blocks within minutes the functional activity of sera containing GM1 or GQ1b antibodies. 11,14,16