Dr. R. Yu
Mechanisms of Disease, Lecture 17
March 9th, 2006
- Autoimmune Neuropathies
- Origins of Autoimmune Neuropathy
- Neuropathies Involving Anti-Glycolipid Antibodies
- The Process of Peripheral Neuropathy
- Infectious agents attacking the nervous system can put the nervous system in danger of immune attack as the immune system attempts to fend off the invading agent.
- Glycosyl conjugates such as proteoglycans, glycolipids, and glycoproteins label the membranes all cells, including neural cells, for recognition as "self" by the immune system.
- Certain oligosaccharides, gangliosides, label central nervous system (CNS, especially brain) tissue.
- Gangliosides consist of an oligomeric branched sugar chain attached to a ceramide "lipid anchor" which holds them to the membrane.
- An immense number of gangliosides are possible, since the stereochemistry of sugar residues allows many positional and linkage isomers, as well as pyranose-furanose isomers.
- Gangliosides serve as highly-specific binding sites for everything from hormones and enzymes t antibodies, glycoproteins, and lectins, and even exogenous toxins, bacteria, and viruses.
- Gangliosides provide epitope for most antibodies involved in autoimmune neuropathies.
- Demyelinating neuropathies (paraproteinemia)
- Demyelinating neuropathis with biclonal gammopathy
- Motoneuron disease (MND) and ALS
- Multifocal motor neuropathy
- Sensory axonal neuropathies
- Sensorimotor neuropathy
- Sensory neuropathy
- Guillain-Barré syndrome (GBS)
- Multiple sclerosis
- Eaton-Lambert syndrome
- Meniere's disease (sensorineural hearing loss, or SNRL)
- Cellular and subcellular localization of antigens should correlate with pathology and clinical symptoms.
- Experimental models can be generated using glycolipid antigens.
- It is unknown how antibodies penetrate the blood-brain and blood-nerve barriers, obtaining access to neural tissue.
- Origins of the autoantibodies are unknown. However, Campylobacter, Helicobacter, Mycoplasma haemophilus, Cytomegalovirus, Epstein-Barre virus, Streptococcus pyogenes (some strain), as well as others, produce glycolipids which mimic human gangliosides.
- This molecular mimicry may precipitate anti-neural autoreactivity.
- Sera (mostly IgM) from patients reacts with glycolipids such as SGGLs and MAG (myelin-associated glycolipid), and symptoms improve with removal of IgM from circulation.
- SGGLs are mainly localized in the peripheral nervous system (PNS) myelin and axolemma.
- IgM deposits are found in lesion sites.
- Rabbits and rats sensitized with SGGLs produce a higher titer of antibodies, greater symptom display, and pathological lesions.
- Intraneural injection of IgM produces complement-dependent demyelination and axonal degeneration in the PnS.
- Localization of SGGLs is observed in brain microvascular endothelial cells and lesions.
- Antibodies likely attack neural vascular endothelium to penetrate the blood-brain barrier.
- Leukocytes extravasate at the same sites, and likely due to the same cues.
- Antisense oligonucleotide therapy could block antibody effects.
- Peptide mimetics, possibly presented by a phage, could "distract" self-reactive antibodies.
- Ariga T and Yu RK, "Antiglycolipid Antibodies in Guillain-Barre Syndrome and Related Diseases: Review of Clinical Features and Antibody Specificities," J Neurosci Res, 80:1-17 (2005).
- Usuki S et al., "Molecular Mimicry: Sensitization of Lewis Rats with Campylobacter jejuni Lipopolysaccharides Induces Formation of Antibody Toward GD3 Ganglioside," J Neurosci Res, 83:274-284 (2006).
- Usuki S et al., "AIDP and CIDP having specific antibodies to the carbohydrate epitope (-NeuAc alpha2-8NeuAc alpha2-3Gal beta1-4Glc-) of gangliosides," J Neurolog Sci.
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