Mechanisms of Action of Anti‐GM₁and Anti‐GQ_1bGanglioside Antibodies in Guillain‐Barré Syndrome

Abstract

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

Guillain–Barré syndrome: a century of progress

“…Numerous investigators over several decades and several continents have attempted to determine whether these antibodies are pathogenetic and how they mediate damage. In summary, many collaborative efforts have demonstrated that anti-GM1 and anti-GQ1b antibodies bind to peripheral nerve and neuromuscular junctions 64,65 , and anti-GD1a antibodies bind to the nodes of Ranvier, paranodal myelin and neuromuscular junction 66,67,68 . Upon binding, the antibodies activate the complement cascade, resulting in formation of the membrane attack complex, disruption of sodium channel clusters at the node of Ranvier with disruption of nodal architecture 69 , and calcium influx and calpain-dependent neuronal and glial injury at the neuromuscular junction 70,71 .This injury can be ameliorated with complement inhibitors 72,73 .…”

Ganglioside Mimicry ofCampylobacter jejuniLipopolysaccharides Determines Antiganglioside Specificity in Rabbits

“…Earlier studies demonstrated the lack of binding of monoclonal anti-GM2 antibodies with O:23 LPS in Western blot or TLC, indicating the absence of a GM2-mimic (28,39). Another explanation may be that differences in the density of GM2-mimics and the adjuvant properties of the lipid A portion and/or O-chain influence the induction of antiglycolipid antibodies and the presentation of the GM2-mimics in the Western blot between the O:1, O:23, and O:36 serostrains (28,33).…”

“…The Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) are frequently preceded by an infection with C. jejuni, and GBS and MFS patients have crossreactive antibodies against LPS and gangliosides (16,36). These antibodies have been implicated to play a role in the pathogenesis of both neurological diseases (30,33). In contrast to patients with GBS and MFS, patients with an uncomplicated C. jejuni enteritis do have a low-titer antibody response against LPS, but they do not have a cross-reactive antiglycolipid response (10,15).…”

Molecular Mimicry

“…Mimicry between cardiac myosins, other a helical proteins such as laminin and tubulin, the streptococcal carbohydrate and M protein is the most likely aetiology of the disease (Cunningham, 2000;Galvin et al, 2000;Kirvan et al, 2003Kirvan et al, , 2007. Other autoimmune diseases associated with a potential infectious aetiologies include insulin-dependent diabetes mellitus (Tian et al, 1994;von Herrath et al, 2003), ankylosing spondylitis (Fielder et al, 1995), Guillain-Barre syndrome (Oomes et al, 1995;Willison et al, 1997Willison et al, , 2008Goodyear et al, 1999;Hartung et al, 2002;Jacobs et al, 2002Jacobs et al, , 2008, primary biliary cirrhosis (Shimoda et al, 1995) and multiple sclerosis (Wucherpfennig and Strominger, 1995;von Herrath et al, 2003). The rheumatic autoimmune diseases include systemic lupus erythematosus (James et al, 1997;Arbuckle et al, 2003), rheumatoid arthritis (Holoshitz et al, 1986), Sjogren syndrome (Talal, 1990) and others are potentially due to an infectious aetiology.…”

“…Specific monoclonal antibody molecules may recognize peptides and carbohydrates Shikhman and Cunningham, 1997), carbohydrates and deoxyribonucleic acid (DNA) (Kabat et al, 1986) or proteins and DNA (Cunningham and Swerlick, 1986;Gaynor et al, 1997;Putterman and Diamond, 1998). Gangliosides are also found to be important targets of antibodies against the group A streptococcal carbohydrate (Kirvan et al, 2003) or lipopolysaccharide components of Campylobacter jejuni in Guillain-Barre syndrome (Willison and Kennedy, 1993;Willison et al, 1997Willison et al, , 2008Goodyear et al, 1999). The basis of these diverse crossreactions may be due in part to structural characteristics of the antigenic epitope as well as germline configurations of the antibody molecule.…”