Factors defining target specificity in antibody-mediated neuropathy: Density-dependent binding of anti-GD1a polyclonal IgG from a neurological patient

Kremer, David; López, Pablo H.H.; Mizutamari, R.K.; Kremer, Leonardo J.; Bacile, Elizabeth Alejandra Bacile; Nores, Gustavo A.

doi:10.1002/(sici)1097-4547(19970315)47:6<636::aid-jnr9>3.0.co;2-e

Cited by 9 publications

(3 citation statements)

References 28 publications

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“…Each nerve of the peripheral nervous system has a specific function, and the experienced symptom/s in a neurological disease are determined by the type of nerve/s affected. There are various other factors that influence a neurological disease triggering: antibody affinity [50, 51], antigen density [52], membrane cholesterol content [53], sub-neuronal location of antigen [53], lipid environment [28], ceramide length [54], among others. The appearance of diverse antibody populations (as was also verified from the varied co-occurrences of IgG populations against the different self glycans) would constitute a random process [2] that, confluencing with the aforementioned factors could decide which nerve (or cell) will be targeted by an anti-self glycan autoimmune response.…”

Section: Discussionmentioning

confidence: 99%

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

2019

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Background Different neurological disorders frequently display antibodies against several self-glycans. Increasing evidence supports their pathogenic role; however, far less is known about their origin. Meanwhile, antibodies recognizing non-self glycans appear in normal human serum during immune response to bacteria. Methods Using high performance thin layer chromatography-immunostaining, we comparatively evaluated humoral immune response (IgG and IgM immunoreactivity) against glycolipids carrying self-glycans (GM3/GM2/GM1/GD1a/GD1b/GD3/GT1b/GQ1b) and non-self glycans (Forssman/GA1/“A” blood group/Nt7) in sera from 383 patients with neurological disorders along with 87 healthy controls. Results In contrast to no healthy controls having anti-self glycan IgG antibodies, one-fifth of patients’ sera had anti-self glycan IgG antibodies: remarkably, 60% of these occurred without IgM antibodies of the same specificity. Contrary to this unusual fact (anti-self glycan IgG occurrence without simultaneous presence of IgM having the same specificity ~ IgG/IgM discordance), all IgG antibodies against non-self glycans occurred simultaneously with their IgM antibody counterpart (i.e. 0% discordance). When analyzed closer, the IgG/IgM discordance frequency for anti-self glycans exhibited a dual trend: below 40% for IgG antibodies against GM2, GM1 and GD1b, and greater than 53% for IgG antibodies against the remaining self glycans. Interestingly, this discordance behavior was common to several different neurological disorders. Conclusions Classic immunology principles indicate this anti-self glycan IgG/IgM discordance should not occur in an antibody response; its unusual presence is discussed within the “binding site drift hypothesis” context, where anti-self glycan IgG antibodies could originate from pre-existing IgG recognizing structurally-related non-self glycans. Electronic supplementary material The online version of this article (10.1186/s12929-019-0562-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

2019

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“…33 Severe sensory ataxia: GD1a. 49 Acute motor axonal neuropathy (AMAN): GD1a; 50 GM1 (IgG). 51 Acute inflammatory demyelinating polyneuropathy (AIDP): GM1 (IgG).…”

Section: Antiglycolipid Antibodies In Immune‐mediated Neurological DImentioning

confidence: 99%

The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Action^a

Yu¹,

Ariga²

1998

Annals of the New York Academy of Sciences

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Specific criteria that are required for understanding the significance of glycosphingolipid (GSL) antibodies, as well as mechanisms that may underlie the immunopathogenesis of these disorders, are proposed. These criteria are illustrated by describing the role of a unique family of acidic GSLs, the sulfated glucuronosyl glycolipids (SGGLs), in the pathogenic mechanisms of peripheral neuropathy with IgM paraproteinemia. High anti-SGGL antibody titers are detected in patients suffering from this disorder. It is demonstrated that SGGLs, which possess a common carbohydrate epitope with myelin-associated glycoprotein (MAG), several low-molecular-weight glycoproteins in the PNS, and a number of cell adhesion molecules, are potential target antigens for the neuropathy. Evidence is provided that sensitization of laboratory animals with pure SGGLs elicits experimental peripheral neuropathies that exhibit remarkable similarities with respect to antibody specificity, and electrophysiological and pathological features to the human conditions. By intraneural injection of antibodies into the sciatic nerve of rats, it is demonstrated that pathological changes consisting of demyelination and axonal degeneration are mediated by an antibody- and complement-dependent process. To elucidate the mechanisms of antibody penetration from circulation into the endoneurial space, it is further shown that brain microvascular endothelial cells express SGGLs. Moreover it has been found that inflammatory cytokines are capable of upregulating the expression of SGGLs on the endothelial cell surface, resulting in a greater attachment of leukocytes. This latter observation suggests that SGGLs may also participate in cell-mediated responses in certain inflammatory neurological disorders.

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“…However, as is well documented in studies with antitumour‐glycolipid antibodies, 22,36 the antibody‐mediated effect is likely to be antigen‐density dependent. Kremer et al , 37 showed that serum‐antibodies from a patient with severe sensory ataxia reacted to ganglioside GD1a in a density‐dependent manner. Thus, a threshold level of antigen might be necessary to cause an effect.…”

Section: Location and Accesibility Of Glycolipid Antigensmentioning

confidence: 99%

The Role of Antiglycolipid Antibodies in Neurological Disorders^a

Fredman

1998

Annals of the New York Academy of Sciences

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Glycolipids have been shown to be antigens for circulating antibodies in autoimmune processes affecting the nervous system like neuropathy associated with IgM paraproteinemia, Guillain Barré syndrome (GBS), multifocal neuropathy, and variants thereof. The antibody titers, the Ig-classes, and the antibody specificity vary between studies and disease groups. The immunogens are in general unknown. However, GBS is often associated with an infection with Campylobacter jejuni, which expresses a lipopolysaccharide structure similar to the carbohydrate epitopes in sialic acid containing glycolipids and gangliosides and thus a potential primary antigen for antiganglioside antibodies. The antiglycolipid specificity will most likely reflect the primary antigen carbohydrate epitopes, which also determine the target cell or tissue structure and the pathology. These factors might add to the inconsistent results obtained and that have led to the question: Are antiglycolipid antibodies of any clinical significance?

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Factors defining target specificity in antibody-mediated neuropathy: Density-dependent binding of anti-GD1a polyclonal IgG from a neurological patient

Cited by 9 publications

References 28 publications

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Action^a

The Role of Antiglycolipid Antibodies in Neurological Disorders^a

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Factors defining target specificity in antibody-mediated neuropathy: Density-dependent binding of anti-GD1a polyclonal IgG from a neurological patient

Cited by 9 publications

References 28 publications

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

Most of anti-glycolipid IgG-antibodies associated to neurological disorders occur without their IgM counterpart

The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Actiona

The Role of Antiglycolipid Antibodies in Neurological Disordersa

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Product

Resources

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The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Action^a

The Role of Antiglycolipid Antibodies in Neurological Disorders^a