Anti-GM1 antibodies as a model of the immune response to self-glycans

Nores, Gustavo A.; Lardone, Ricardo Dante; Comín, Romina; Alaniz, Maria Eugenia; Moyano, Ana Lis; Irazoqui, Fernando J.

doi:10.1016/j.bbagen.2007.09.008

Cited by 27 publications

(32 citation statements)

References 113 publications

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“…8 It has been hypothesized that autoimmunity may develop through molecular mimicry and binding site drift. 7 In a recent study of 539 patients at a neuropathy clinic in Italy, GM1 antibodies were found relatively frequently in patients with MMN (n ¼ 12), neuropathy with elevated M protein (n ¼ 10), chronic inflammatory demyelinating polyneuropathy [CIDP (n ¼ 6)], and motor neuron disease (n ¼ 6). 11 Less frequently (n < 4 for each diagnosis) anti-GM1 antibodies were found in patients diagnosed with IgG monoclonal gammopathy, POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), mononeuritis multiplex, radiculopathy or plexopathy, and undiagnosed neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Demyelinating symmetric motor polyneuropathy with high titers of anti‐GM1 antibodies

2010

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High titers of anti-GM1 ganglioside antibodies have been associated with multifocal motor neuropathy, a chronic asymmetric and exclusively motor disorder. We describe a patient with a progressive selective motor but symmetric polyneuropathy, followed over 5 years, with markedly elevated titers of anti-GM1 antibodies. The electrophysiological changes suggestive of motor demyelination were widespread, beyond conduction block alone, and involved contiguous nerve segments with complete sparing of sensory conduction. Progressive, predominantly motor, symmetric, demyelinating polyneuropathy may be an unusual relative of multifocal motor neuropathy, associated with anti-GM1 antibodies.

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Section: Discussionmentioning

confidence: 99%

Demyelinating symmetric motor polyneuropathy with high titers of anti‐GM1 antibodies

2010

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“…With respect to the antibody induction phase of the illness, it is clearly established that anti-GM1 antibodies can arise through molecular mimicry with structurally homologous Campylobacter jejuni lipooligosaccharides (LOS) (15)(16)(17)(18). In contrast, examination of the effector pathways through which anti-GM1 antibodies selectively bind to and induce injury in motor nerve membranes, while avoiding damage to other neural and non-neural plasma membranes containing abundant GM1, is confounded by inconsistent and often counterintuitive data (9,(19)(20)(21)(22). In particular, the sensitivity or resistance of the membrane toward undergoing anti-GM1 antibody-mediated injury cannot be fully explained by the presence and density of plasma membrane GM1.…”

Section: Introductionmentioning

confidence: 99%

The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Greenshields¹,

Halstead²,

Zitman³

et al. 2009

J. Clin. Invest.

105

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Anti-GM1 ganglioside autoantibodies are used as diagnostic markers for motor axonal peripheral neuropathies and are believed to be the primary mediators of such diseases. However, their ability to bind and exert pathogenic effects at neuronal membranes is highly inconsistent. Using human and mouse monoclonal anti-GM1 antibodies to probe the GM1-rich motor nerve terminal membrane in mice, we here show that the antigenic oligosaccharide of GM1 in the live plasma membrane is cryptic, hidden on surface domains that become buried for a proportion of anti-GM1 antibodies due to a masking effect of neighboring gangliosides. The cryptic GM1 binding domain was exposed by sialidase treatment that liberated sialic acid from masking gangliosides including GD1a or by disruption of the live membrane by freezing or fixation. This cryptic behavior was also recapitulated in solid-phase immunoassays. These data show that certain anti-GM1 antibodies exert potent complement activation-mediated neuropathogenic effects, including morphological damage at living terminal motor axons, leading to a block of synaptic transmission. This occurred only when GM1 was topologically available for antibody binding, but not when GM1 was cryptic. This revised understanding of the complexities in ganglioside membrane topology provides a mechanistic account for wide variations in the neuropathic potential of anti-GM1 antibodies.

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“…Monach and colleagues (15) have recently reported that IgG fractions purified from joint immune complexes bound a diverse subset of proteins and peptides from synovium and cartilage. Elevations of a variety of antiglycan Abs, including IgG, IgA, IgE, and IgM classes, have been demonstrated in a number of inflammatory autoimmune diseases (16)(17)(18)(19). However, of studies on the diagnostic value, Ag specificity, and pathogenic potential of autoantibodies correlated to the development of RA in humans, very few touched upon glycanspecific autoantibodies (20)(21)(22), even though carbohydrate structures represent a substantial portion of tissue Ags in the joints and could be targeted, just like any other autoantigens, by arthritogenic autoantibodies.…”

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confidence: 99%

Disease Association and Arthritogenic Potential of Circulating Antibodies against the α1,4-Polygalacturonic Acid Moiety

Dai

Dong

Gong

et al. 2014

The Journal of Immunology

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Much progress has been made in recent years on the diagnostic value, Ag specificity, and pathogenic roles of autoantibodies correlated to the development of rheumatoid arthritis (RA) in humans. However, carbohydrate Ag-specific autoantibodies that may also play important roles in RA have largely been ignored. In this article, we report that serum levels of Abs capable of recognizing α1,4-polygalacturonic acid [(PGA); major structural component of pectin] strongly correlate with RA in humans. The measurements of PGA-specific Abs (PGA-Abs) in sera are comparable to rheumatoid factors and anti–cyclic citrullinated peptide Abs as serological diagnostic markers for RA in terms of sensitivity and specificity. Immunohistochemical staining results indicate that the PGA-Abs selectively bound synovial membrane cells and chondrocytes in the joints of both humans and rabbits (but not rodents). Induction of PGA-Abs by s.c. immunization of rabbits with carrier protein–conjugated synthetic PGA led to severe inflammatory reactions (synovial hyperplasia, small vessel proliferation, and inflammatory cell infiltration) in the joints. Injection of affinity purified anti-PGA IgG into the synovial cavity of rabbits resulted in accumulation of proinflammatory cytokines such as TNF-α, IL-8, and IL-1β in synovial fluid, as well as local pathological damage. We conclude that the PGA–cross-reactive moiety represents a major autoantigen in the joints and can be targeted by autoantibodies capable of triggering arthritogenic responses in vivo.

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Anti-GM1 antibodies as a model of the immune response to self-glycans

Cited by 27 publications

References 113 publications

Demyelinating symmetric motor polyneuropathy with high titers of anti‐GM1 antibodies

Demyelinating symmetric motor polyneuropathy with high titers of anti‐GM1 antibodies

The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Disease Association and Arthritogenic Potential of Circulating Antibodies against the α1,4-Polygalacturonic Acid Moiety

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