Trends in Immunology
Volume 34, Issue 9, September 2013, Pages 453-459
Journal home page for Trends in Immunology

Review
Glycolipid antigens and autoantibodies in autoimmune neuropathies

https://doi.org/10.1016/j.it.2013.05.001Get rights and content

Highlights

Autoantibodies to glycans present on glycolipids mediate the postinfectious paralytic disease, Guillain–Barré syndrome (GBS). These glycans are also found on lipo-oligosaccharides (LOSs) of GBS-inducing microbes, suggesting molecular mimicry as a mechanism for disease induction. How B lymphocyte tolerance to self-glycans is regulated during the initiation phase of the disease is currently under investigation. The discovery of antiglycolipid antibodies that bind to heteromeric glycolipid complexes has generated new insights in this field. Heteromeric complexes are structurally distinct glycolipids that interact to form new molecular shapes capable of either enhancing or attenuating recognition by autoantibodies. Although the principles emerging from this phenomenon have a substantial impact on diagnostics methods, they also raise intriguing questions about the diversity of innate antibody repertoires, mechanisms of tolerance, and autoantibody targeting of neural membranes.

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)

  • L. Le Bourhis

    Mucosal-associated invariant T cells: unconventional development and function

    Trends Immunol.

    (2011)
  • Y. Matsumoto

    BAFF aids generation of IgG anti-ganglioside antibodies in response to Campylobacter jejuni lipo-oligosaccharide

    J. Neuroimmunol.

    (2010)
  • M.L. Kuijf

    Origin of ganglioside complex antibodies in Guillain–Barré syndrome

    J. Neuroimmunol.

    (2007)
  • S. Hakomori et al.

    Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to define tumor malignancy

    FEBS Lett.

    (2002)
  • J. Milland et al.

    ABO blood group and related antigens, natural antibodies and transplantation

    Tissue Antigens

    (2006)
  • B.C. Gehrs et al.

    Autoimmune hemolytic anemia

    Am. J. Hematol.

    (2002)
  • G. Chavada et al.

    Autoantibodies in immune-mediated neuropathies

    Curr. Opin. Neurol.

    (2012)
  • R.W. Ledeen

    Ganglioside structures and distribution: are they localized at the nerve ending?

    J. Supramol. Struct.

    (1978)
  • R.W. Ledeen

    The role of GM1 and other gangliosides in neuronal differentiation. Overview and new finding

    Ann. N. Y. Acad. Sci.

    (1998)
  • N. Yuki et al.

    Guillain–Barré syndrome

    N. Engl. J. Med.

    (2012)
  • E. Israeli

    Guillain–Barré syndrome – a classical autoimmune disease triggered by infection or vaccination

    Clin. Rev. Allergy Immunol.

    (2012)
  • H.J. Willison et al.

    Peripheral neuropathies and anti-glycolipid antibodies

    Brain

    (2002)
  • S. Rinaldi et al.

    Ganglioside antibodies and neuropathies

    Curr. Opin. Neurol.

    (2008)
  • S. Kusunoki

    Anti-Gal-C antibody in autoimmune neuropathies subsequent to mycoplasma infection

    Muscle Nerve

    (1995)
  • K.T. Young

    Campylobacter jejuni: molecular biology and pathogenesis

    Nat. Rev. Immunol.

    (2007)
  • S.N. Fewou

    Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

    J. Clin. Invest.

    (2012)
  • S.C. Kinsky

    Immunogenicity of liposomal model membranes

    Ann. N. Y. Acad. Sci.

    (1978)
  • K.O. Lloyd

    Cell surface accessibility of individual gangliosides in malignant melanoma cells to antibodies is influenced by the total ganglioside composition of the cells

    Cancer Res.

    (1992)
  • K-I. Kaida

    Ganglioside complexes as new target antigens in Guillain–Barré syndrome

    Ann. Neurol.

    (2004)
  • K. Kaida

    GM1/GalNAc-GD1a complex: a target for pure motor Guillain–Barre syndrome

    Neurology

    (2008)
  • K.N. Greenshields

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

    J. Clin. Invest.

    (2009)
  • S. Rinaldi

    Combinatorial glycoarray

    Methods Mol. Biol.

    (2012)
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