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Multiple Sclerosis Allied Demyelinating Diseases Neuroimmunology & Glycobiology

Multiple Sclerosis Allied Demyelinating Diseases Neuroimmunology & Glycobiology. 蔡清標 副教授 Msci MD 國立陽明大學 台北榮民總醫院. Figure 2. BI 2004 Essential Animal Cell Biology. Cell membranes 1 The lipid bilayer. Dr Gordon McEwan Department of Biomedical Sciences. Lipid bilayer. Lipid bilayer

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Multiple Sclerosis Allied Demyelinating Diseases Neuroimmunology & Glycobiology

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  1. Multiple Sclerosis Allied Demyelinating DiseasesNeuroimmunology & Glycobiology 蔡清標 副教授 Msci MD 國立陽明大學 台北榮民總醫院

  2. Figure 2

  3. BI 2004 Essential Animal Cell Biology Cell membranes 1 The lipid bilayer Dr Gordon McEwan Department of Biomedical Sciences

  4. Lipid bilayer Lipid bilayer (5 nm) Protein molecule Lipid molecule Adapted from ECB Fig 11-4

  5. Myelin antigen : proteins and lipids • PROTEINS • proteolipid protein • myelin basic protein • wolfgram fraction • myelin associated glycoprotein MAG

  6. Myelin antigen : proteins and lipids • LIPIDS • Glycolipid • galactocerebroside • sulfatide • gangliosides. GM1 GM4 etc

  7. glycosphingolipids in peripheral neuroapthies • glycosphingolipids --cell surface molecules • hydrophilic sugar moiety • hydrophobic ceramide • as autoantigens development of certain autoimmune diseases • antigen reaction side at sugar moiety

  8. Glycolipid terminology and structure • long chain aliphatic amine sphingosine (acylated ceramide) • attached to one or more sugars • ceramide immersed in the lipid bilayer • carbonhydrate structure exposed extracellularly

  9. Glycolipid structures • cerebroside -- monohexosyl ceramide • galactocerebroside -- galactosyl ceramide • sulfatide -- galactocerebroside sulfated in the carbon-3 position main antigen in sensory predominantly neuropathies

  10. Glycolipid structures • gangliosides • complex glycosphingolipids • sialic acid residues M mono D di T tri GM1 G ganglioside M mono sialic acid 1 sequence of migration by TLC

  11. Gangliosides in the brain • four major gangliosides in the brain • GM1 • GD1a • GD1b • GT1b

  12. Metabolic Defect Fabry’s Disease

  13. Vascular Endothelium SevereendothelialGL-3 accumulation

  14. Neurologic Dermatologic Ocular Gastrointestinal Renal Cardiac Cerebrovascular Multisystemic Manifestations Progressive accumulation of GL-3 causes increasing involvement of multiple organ systems.

  15. Signs and Symptoms Early ischemic stroke Left ventricular hypertrophy Hypohidrosis Progressive renal insufficiency Angiokeratomas Acroparesthesia Acroparesthesia

  16. Demyelination and Dysmyelination • Adrenoleukodystrophy • X-linked recessive 1/20,000 • Impairment in peroxismal oxidation of very long chain fatty acids • Accumulation in the brain and adrenal gland

  17. Adrenoleukodystrophy • 4 y/o bronzing skin • 7 y/o dysarthria, dysphonia, quadriparesis • 8 Y/o seizure • Decerebrate posture bed ridden before death

  18. glycolipids • autoantigens for the development of autoimmune diseases • demyelinating polyneuropathy • motor neuron disease • multiple motor neuropathy with conduction block • AIDP CIDP

  19. Reaction site of glycolipid antibody • react with epitopes on the carbonhydrate region • shared reactivity for bacterial lipopolysaccharides • react with SGPG and MAG

  20. Anti-glycolipid antibodies are pathogenic • improved disease progression and clinical S/S accompanying a decreased antibody titer • therapeutic reduction of these antibodies by plasmapheresis immunosuppressents

  21. Ganglioside antibodies in patients with neuropathy • Acute inflammatory demyelinating polyneuroapthy AIDP 30% with GM1 Ab • Chronic inflammatory demyelinating polyneuropayhy CIDP • multiple motor neuropathy with conduction block MMN • Lower motor neuron syndrome LMNS • GQ1b in Miller Fisher Syndrome 90% GBS 2.7%

  22. Figure 1

  23. glycosphingolipids in peripheral neuroapthies • MAG Myelin associated glycoprotein and SGGL • MGUS monoclonal gammopathy • Sulfatide antibody • Sensory neuronopathy • GQ1b ganlioside • Miller-fisher syndrome

  24. Antibodies to sulfatides • Pestronk et al 1991 sulfatide antibodies • Sensory neuropathy esp in sensory axonopathy • primary Sjogren syndrome • first case report in Taiwan • bind to DRG neuron sensory axon • acidic glycolipid SGGL MAG

  25. glycosphingolipids in peripheral neuroapthies • glycosphingolipids are constituents of nerve cells • antibodies to glycosphingolipids found in certain autoimmune disorders • GM1 in • GBS Guillain-Barre syndrome • MMN multiple motor neuropathy • MND motor neuron disease • LMN lower motor neuron syndrome

  26. Serum anti-GM1 antibodies in patients with motor neuron disease • A Pestronk USA 1988 Neurol • High GM1 Ab in ALS • ALS 42/74 57% normal control 2/23 9% • Lower ALS 21/29 72% Upper ALS 1/15 7% Upper and Lower ALS 20/30 67%

  27. Serum anti-GM1 antibodies in patients with motor neuron disease • Salazar-Grueso USA 1990 Ann Neurol • MND 9/48 19% OND -- Other neurological disease 4/40 10% • As frequent as other neurological disease • Markedly elevated titer -- more significant

  28. Clinical correlations of anti-GM1 antibodies in ALS and Neuropathy • Nancy L LAMB USA 1991 Muscle & Nerve positive titer • ALS 7/16 44% 57 • ALS and gammopathy 6/6 100% 246 • Motor CIDP 10/13 77% 562 • Motor neuropathy 7/9 78% 556

  29. Serum anti-GM1 antibodies in patients with motor neuron disease • C.Voumvourakis Athens Greece 1992 E.Neurol • 100 individuals 20 with MND 25 with PN and 40 controls • significant P<0.05 IgM GM1 Ab in MND

  30. Serum anti-GM1 antibodies in patients with motor neuron disease • W-J HSU Hsu-Chuan China 1992 • Lower ALS 4/6 67% Upper ALS 4/6 67% Upper and Lower 9/14 64.2 Control 2/18 11.1% P<0.001

  31. Population based case control study • Willison HJ UK 1993 J. Neurological Sciences • 82 cases of MND and matched for age sex and geographical area • GM1 antibodies in 26% MND and 18% Controls no significant autoimmune basis in sporadic ALS

  32. Serum anti-GM1 antibodies in patients with motor neuron disease • C-P TSAI TAIWAN 1994 CMJ • MND 32/52 62% PN 10/38 26% • Upper and Lower ALS 7/22 32% Lower ALS 25/30 83% All ALS 32/52 62%

  33. Diagnostic value of GM1 antibodies in motor neuron disorders • Van Schaik IN The Netherlands 1995 Neurology • The frequency of GM1 antibodies ranged from MMN 0-100% GBS 0-33% ALS 0-65% LMN 0-81% CIDP 0-77%

  34. Diagnostic value of GM1 antibodies in motor neuron disorders • RK YU Richmond USA • anti-GM1 antibody titer in most cases of ALS are considerably lower than those in LMN and motor neuropathy

  35. Pathogenesis of GM1 antibodies • antibodies to GM1 at the nodes of Ranvier in human and experimental autoimmune neuropathy Microscopy Research and Technique 1996 • anti-GM1 M-protein damage human spinal cord neurons co-cultured with muscles Journal of the Neurological Sciences 1993

  36. Pathogenesis of GM1 antibodies • antibodies to GM1 at the nodes of Ranvier in human and experimental autoimmune neuropathy Microscopy Research and Technique 1996 • anti-GM1 M-protein damage human spinal cord neurons co-cultured with muscles Journal of the Neurological Sciences 1993

  37. Conclusion • GM1 antibodies elevated in many cases with neurological disease • ALS -- elervated but low titer • Lower motor neuron syndrome -- high titer • MMN with conduction block -- high titer • Treatment not effective in cases without conduction block

  38. Guillain-Barre syndromeclinical spectrum • AIDP • AMSAN C. Jejuni cross reaction GM1 axonal loss axolemma at nodes of Ranvier • Miller-Fisher some C. Jejuni strain GQ1b nodal region of 3 rd nerve and cerebellar neuron

  39. Figure 1 Figure 1 GQ1b and LPS core OS structures. The entire structure for GQ1b is shown. Other gangliosides and core LPSs are highlighted. NeuAc = N-acetyl neuraminic acid; Gal = galactose; GaINAc = N-acetyl galactosamine; X = Glc (1->1) ceramide (gangliosides) or the remaining core OS/lipid A (LPSs). From:   Goodyear: J Clin Invest, Volume 104(6).September 1999.697-708

  40. Guillain-Barre syndrome • Diagnosis criteria 1.Required progressive weakness and areflexia 2.supporting progressive days to weeks realtively symmetry mild sensor cranial nerve autonomic dysfunction and CSF protein

  41. Guillain-Barre syndrome • Epidemiology 1.3-1.9/100,000 Taiwan 400/year • occur in all ages • peak in adult • another peak in the elderly 8.6/100,000 over 70Y/O

  42. Guillain-Barre syndrome • preceding events • antecedent infection 2/3 patients had URI or GI disturbance eg. diarrhea • onset to peak plateau 11days • virus: CMV 10-20% EB 10% • Campylobacter Jejuni 20-40% HS-19 AMSAN 60% • GM1 AMSAN GQ1b MFS

  43. Guillain-Barre syndrome • vaccine and GBS • rabies antigen 1890 • Swine-flue influenza 1976 slightly elevated risk of GBS • Recent studies at N Eng J Med no relationship

  44. Guillain-Barre syndrome • AMSAN and AMAN • 10-20% of GBS • primary immune reaction attack directed on nerve axons EMG showed CMAPs • more severe form • ventilation in 2-4 days • poor recovery • biospy: axonal degeneration

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