Trends in Immunology
ReviewGlycolipid antigens and autoantibodies in autoimmune neuropathies
Section snippets
Interface between natural and neuropathogenic antibodies
Antibody repertoires have the capacity to bind a wide range of lipids, glycolipids, and glycans of almost unlimited structural diversity. A large proportion of the human natural antibody repertoire secreted by innate-like B cells contains glycan-binding specificities, both for host and microbial glycans. Indeed 1% alone of the repertoire is estimated to bind the α gal epitope – the Galα1-3Galβ1-(3)4GlcNAc-R saccharide widely expressed in New World monkeys and non-primate mammals, but not
Antiganglioside antibodies in autoimmune neuropathy
The prototypic antiglycolipid autoimmune neuropathy is the postinfectious paralytic disorder, Guillain–Barré syndrome (GBS) in which the predominant targets discovered to date are the sialic-acid-bearing glycosphingolipids termed gangliosides. Glycolipids, and in particular gangliosides, were first discovered to be prominent targets for autoantibodies in autoimmune neuropathies including GBS in the 1980s. Around 50 structurally distinct gangliosides are synthesised through stepwise addition of
Natural antibodies to carbohydrate epitopes
Natural antibodies are the product of a range of innate-like B cells that include B1 and marginal zone B cells 26, 27. An over-riding reactivity in this subset of immunoglobulin is to carbohydrate residues, which comprise a normal physiological aspect of the antibody repertoire. They have a range of functions in both organism homeostasis and assistance in the innate and adaptive immune response to infection. A prime example of this anticarbohydrate response is illustrated by the ABO blood group
Immune environment responsible for a break in tolerance to gangliosides
A wealth of data has shown that, at least in a proportion of GBS cases, crossreactive antiglycolipid antibodies are generated via molecular mimicry during infection, which subsequently leads to a postinfectious nerve injury 31, 32. About two-thirds of GBS patients experience a preceding upper airway or gastrointestinal infection; the latter being frequently caused by C. jejuni. LOSs present on GBS-associated C. jejuni isolates contain ganglioside-like structures including GM1, GD1a, GT1a, and
Antibodies that solely bind to glycolipid complexes
An intriguing conceptual shift in thinking about antiglycolipid antibodies emerged from recent studies 20, 21, 22, 23. In GBS sera that did not harbour any conventionally detectable antibodies to single glycolipids, the authors found categories of antiglycolipid antibodies that only bound to heteromeric complexes of two different glycolipids admixed in 1:1 molar ratios, such as GM1:GD1a. Heteromeric complexes are defined as structurally distinct glycolipids that interact to form new molecular
Local lipid environment within the plasma membrane as a modulator of antibody–glycolipid interactions
The molecular orientation of particular glycolipids within specialised domains in the living plasma membrane may favour the binding of certain antiglycolipid antibodies, yet inhibit the binding of others. Important lateral (cis) and trans interactions for glycans on cell surfaces that influence lectin binding and signalling have been proposed for many years 54, 55. In the case of anti-GM1 antibodies, the modifying influence of cerebrosides, neutral lipids, and cholesterol is long recognised,
Antibodies to glycolipid complexes: evolution of new methodologies
Importantly, the number of potential glycolipid ligands is dramatically increased when heteromeric associations are considered, which raises new methodological challenges. For example, from 20 single glycolipids, 190 heteromeric pairings can be generated, making current ELISA techniques impractical, being handling intensive, insensitive, and wasteful of scarce reagents. To address this, a combinatorial glycoarray was developed that miniaturises this heteromeric complex screening procedure into
Concluding remarks
In conclusion, the emergence of a class of antiglycolipid antibodies that favour binding to particular and specific clusters of glycans rather than single oligosaccharides heralds a new dawn in autoimmune neuropathy biomarker discovery. Such ‘pattern-recognition antibodies’ differ substantially from the classical view of antibody binding to a single glycan antigen. Although a substantial amount of progress has been made, some important questions remain, both at the fundamental immunological
References (64)
Repertoire of human natural anti-glycan immunoglobulins. Do we have auto-antibodies?
Biochim. Biophys. Acta
(2012)Combinatorial ganglioside biosynthesis
J. Biol. Chem.
(2002)- et al.
Gangliosides: structure, isolation, and analysis
Methods Enzymol.
(1982) Autoimmune diseases of the peripheral nervous system
Autoimmun. Rev.
(2012)- et al.
Guillain–Barré syndrome
Lancet
(2005) Anti-ganglioside complex antibodies associated with severe disability in GBS
J. Neuroimmunol.
(2007)- et al.
Antibodies to gangliosides and ganglioside complexes in Guillain–Barré syndrome and Fisher syndrome: mini-review
J. Neuroimmunol.
(2010) Functional polymorphisms in LPS receptors CD14 and TLR4 are not associated with disease susceptibility or Campylobacter jejuni infection in Guillain–Barré patients
J. Neuroimmunol.
(2004)- et al.
Immunoglobulin subclass distribution and binding characteristics of anti-GQ1b antibodies in Miller Fisher syndrome
J. Neuroimmunol.
(1994) Polysaccharide processing and presentation by the MHCII pathway
Cell
(2004)
Mucosal-associated invariant T cells: unconventional development and function
Trends Immunol.
BAFF aids generation of IgG anti-ganglioside antibodies in response to Campylobacter jejuni lipo-oligosaccharide
J. Neuroimmunol.
Origin of ganglioside complex antibodies in Guillain–Barré syndrome
J. Neuroimmunol.
Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to define tumor malignancy
FEBS Lett.
ABO blood group and related antigens, natural antibodies and transplantation
Tissue Antigens
Autoimmune hemolytic anemia
Am. J. Hematol.
Autoantibodies in immune-mediated neuropathies
Curr. Opin. Neurol.
Ganglioside structures and distribution: are they localized at the nerve ending?
J. Supramol. Struct.
The role of GM1 and other gangliosides in neuronal differentiation. Overview and new finding
Ann. N. Y. Acad. Sci.
Guillain–Barré syndrome
N. Engl. J. Med.
Guillain–Barré syndrome – a classical autoimmune disease triggered by infection or vaccination
Clin. Rev. Allergy Immunol.
Peripheral neuropathies and anti-glycolipid antibodies
Brain
Ganglioside antibodies and neuropathies
Curr. Opin. Neurol.
Anti-Gal-C antibody in autoimmune neuropathies subsequent to mycoplasma infection
Muscle Nerve
Campylobacter jejuni: molecular biology and pathogenesis
Nat. Rev. Immunol.
Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy
J. Clin. Invest.
Immunogenicity of liposomal model membranes
Ann. N. Y. Acad. Sci.
Cell surface accessibility of individual gangliosides in malignant melanoma cells to antibodies is influenced by the total ganglioside composition of the cells
Cancer Res.
Ganglioside complexes as new target antigens in Guillain–Barré syndrome
Ann. Neurol.
GM1/GalNAc-GD1a complex: a target for pure motor Guillain–Barre syndrome
Neurology
The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice
J. Clin. Invest.
Combinatorial glycoarray
Methods Mol. Biol.
Cited by (50)
Multifocal motor neuropathy is not associated with altered innate immune responses to endotoxin
2023, Journal of the Neurological SciencesPathophysiological and diagnostic aspects of Guillain-Barré syndrome
2022, Revue de Medecine InterneAnti-GM2 antibody positive Guillain-Barré syndrome presenting with ataxia in a pediatric patient: An atypical manifestation
2021, Brain and DevelopmentCitation Excerpt :Three main GBS variants are acute motor axonal neuropathy (AMAN), Miller-Fischer syndrome (MFS), and acute inflammatory demyelinating neuropathy (AIDP) [2]. These variants can be clinically distinguished, furthermore delineated by profiling antibodies against several glycolipids, mainly gangliosides [3]. Detecting these antibodies can help understand the course of disease and pathophysiology.
Treatment and Management of Autoimmune Neuropathies
2021, Neuromuscular Disorders: Treatment and Management