Guillain-Barre syndrome

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  • Schematic illustration of the immune responses in the inflamed peripheral nervous system. Basic principles of the cellular-autoreactive T-cells (T) recognize a specific autoantigen presented by MHC class II and simultaneous delivery of costimulatory signals on the cell surface of antigen-presenting cells, such as macrophages(M)-Activated T-lymphocytes can cross the blood–nerve barrier (BNB) in order to enter peripheral nervous system (PNS)-within PNS, T-cells activate macrophages that enhance phagocytic activity, production of cytokines, and release of toxic mediators, such as nitric oxide (NO), matrix metalloproteinases (MMPs), and proinflammatorycytokines, propagating demyelination and axonal loss-termination of the inflammatory response is mediated, in part, by macrophagesby the induction of T-cell apoptosis and release of anti-inflammatory Th2/Th3 cytokines, such as IL-10 andtransforming growth factor- (TGF).
  • Guillain-Barre syndrome

    1. 1. IMMUNOBIOLOGY OF Guillain-Barre syndrome
    2. 2. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    3. 3. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    4. 4. Guillain-Barre syndrome nerve structure
    5. 5. Guillain-Barre syndrome nerve structure
    6. 6. Guillain-Barre syndrome nerve structure
    7. 7. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    8. 8. Guillain-Barre syndrome clinical features & Variants GBS  acute immune-mediated polyneuropathies  heterogenous condition with several variant forms  clinical features  variants
    9. 9. Guillain-Barre syndrome clinical features & Variants Clinical features  cardinal clinical features  progressive  fairly symmetric muscle weakness accompanied by absent or depressed DTR, usually present few days to week after onset of symptoms  weakness usually starts in proximal legs (10% begin in arms or facial muscle)  facial & oropharyngeal weakness 50% AIDP  oculomotor weakness occurs 15%  prominent severe pain in lower back in AIDP
    10. 10. Guillain-Barre syndrome clinical features & Variants GBS variants ๏ Acute inflammatory demyelinating polyradiculoneuropathy(AIDP) ๏ Miller Fisher syndrome : ophthalmoplegia with ataxia and areflexia ๏Acute motor axonal neuropathy : known as acute motor axonal neuropathy(AMAN) -most preceded by Campylobacter jejuni -DTR preserved, sensory nerves are not affected
    11. 11. Guillain-Barre syndrome clinical features & Variants GBS variants ๏Acute motor and sensory axonal neuropathy (AMSAN) -more severe form of AMAN -both motor & sensory fibers are affected -marked axonal degeneration ๏Other variants
    12. 12. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    13. 13. Guillain-Barre syndrome immunopathology Pathological hallmark of classic GBS “multifocal demyelination of PNS” Spectrum of pathological change Focal or extensive demyelination in presence or absence of cellular infiltration to axonal degeneration with or without demyelination or inflammatory infiltration Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    14. 14. Guillain-Barre syndrome immunopathology Demyelination found typically at nodes of Ranvier ,where there is clustering of M Varies histopathological features  clinical diversity of GBS such as  AIDP : M -mediated demyelination & intense T-cell infiltration  AMAN & AMSAN : M -mediated axonal neuropathy & lymphocytic infiltration are scarce Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    15. 15. Guillain-Barre syndrome immunopathology Why are there self-reactive lymphocyte & autoimmunity?  Immunogenic Ag : Ag that elicit immune response  Tolerogenic Ag : Ag that induce tolerance  normally, microbes are immunogenic and self antigens are tolerogenic  Immunological Tolerance o central tolerance o peripheral tolerance
    16. 16. Guillain-Barre syndrome immunopathology Central tolerance : generative lymphoid organ T cells : in thymus negative selection mutation in AIRE (autoimmune regulator) gene develop into regulatory T cells B cells : in bone marrow receptor editing negative selection Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187 Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439
    17. 17. Guillain-Barre syndrome immunopathology Peripheral tolerance : peripheral lymphoid tissue T cells anergy engage to inhibitory receptoe (CTLA-4) immune suppression by Treg deletion : activation-induced cell death B cells anergy : do not receive T cell help Exclusion of anergic B cells from lymphoid follicles Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187 Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439
    18. 18. Guillain-Barre syndrome immunopathology  Failure to tolerance in what cell type, which do you Self think important for autoimmunity? polysaccharides, lipids, nucleic acid are T- T cells independent Ag & not B cells recognized by T cells  induce tolerance in B  Why? cells
    19. 19. Guillain-Barre syndrome immunopathology Autoimmunity : factors ◘ Inheritance of susceptibility genes ◘ Defective negative selection of T cells ◘ Peptide antigens presented by susceptibility genes fail to stimulate Treg ◘ Abnormal expression of costimulatory molecules in other cells ◘ Sequestered antigen : Ag from immune privileged site ◘ Lack of suppressor activity from Treg ◘ Abnormal in cytokine production ◘ Environmental triggers Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187 Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439
    20. 20. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    21. 21. Guillain-Barre syndrome cellular immunity  In 1988 identified peripheral nervous system(PNS) myelin proteins : P2 is minor component protein, 2- 15% of total protein T.Alwyn Jones, et al.The EMBO journal 1988;7:1597-1604  Found activation T cell in EAN & GBS pateints  Other PNS myelin proteins found such as myelin protein zero, peripheral myelin protein 22(PMP 22) : both are major structure protein of peripheral myelin Snipes GJ, et al.The journal of cell biology 1992;117(1):225-38 D’Urso,D.et al.The Journal of Neuroscience 1999;19(9):3396-3403
    22. 22. Guillain-Barre syndrome cellular immunity  Activation of T cells in periphery in EAN (animal model for GBS) by adoptive transfer experiments but can not detect specific sensitization of T- lymphocytes to nerve antigens in patients with GBS  But there had evidence  by augmented expression of HLA-DR antigen, transferrin receptor, and IL-2 receptor on surface of peripheral blood T cells  by increased serum concentrations of IL-2 & soluble IL-2 receptor Hans-Peter Hartung, et al. The Annals of Neurology 1990;27(Suppl):S57–63
    23. 23. Guillain-Barre syndrome cellular immunity  Detected T-cells in nerve biopsies from GBS  V 8/ 1 T-cell was defined in pt. with demyelinating GBS, suggesting that gut-associated lymphocytes are critically involved in pathogenesis  Increased serum & CSF levels of soluble adhesion molecules, chemokines, matrix metalloproteinases  reflecting active T-cell can migrate across blood-nerve barrier  expression of CCR-1, CCR-5, MMP-7, MMP-9 by endoneurial M  expression of CCR-2, CCR-4, CXCR-3 localized to invading T-cell Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    24. 24. Guillain-Barre syndrome cellular immunity Distinct subsets of Tcells, based on their TCR - and -chain variable gene segment usage differentially distributed in different tissues and show dramatic changes with age In adult humans V 9V 2 TCR is predominantly found among peripheral blood T cells majority of intestinal Tcells expressV 1 chains associated with one of several -chains Murine and human selective accumulations of T cell subsets at different body locations are result of peripheral selection and expansion by locally expressed antigens Tony Kenna.Clinacal Immunology 2004;113:56-63
    25. 25. Guillain-Barre syndrome cellular immunity  Some study on archival autopsy  large numbers of CD8+ T-cells  pointing to role of cytotoxic T-cell response in myelin damage in GBS Wanschitz J, et al. Brain 2003;126:2034–204  Identified nuclearfactor-kappaB(NF- B) as critical role in mediating inflammatory reaction  Also identified inhibitory molecule(I B) in both T-cells & M in inflammatory neuropathy but I B found mainly in Schwann cells in noninflammatory cases Andorfer B, et al. Journal of Neuroimmunol ogy 2001;116:226–232
    26. 26. Guillain-Barre syndrome cellular immunity  Li-jun Chi, et al. reported that Treg(CD4+CD25high T-cell) showed significantly reduced numbers in acute-stage of AIDP & AMAN as compared with healthy donors (but marked improvement was observed in stable-stage patients with GBS, concomitantly with improvement of neuropathic symptoms) Li-jun Chi, et al.journal of neuroimmunology 2007;192:206-214
    27. 27. Guillain-Barre syndrome cellular immunity  M (not Schwann cells) express MHC class II gene may function as o antigen presenters o amplification and effector phase o damage myelin sheath by phagocytic attack o release of inflammatory mediators (toxic oxygen radicals, arachidonic acid metabolites, complement, or hydrolases) o m activation in EAN is achieved by interferon- Hans-Peter Hartung, et al. The Annals of Neurology 1990;27(Suppl):S57–63
    28. 28. Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    29. 29. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    30. 30. Guillain-Barre syndrome humoral immunity  Various observation suggest that humoral factors are involved Plasmapheresis & intravenous Ig(IVIG)  clinical improve Circulating Ab targeting structures on peripheral nerve Deposition of Ig & complement be demonstrated on myelinated fibers  Molecular mimicry is one hypothesis for explaining Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    31. 31. Guillain-Barre syndrome humoral immunity  Antiglycolipid Ab are frequently found at low levels in normal sera(naturally autoantibody) but preceding infection such as Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae, H. influenza can trigger production of these autoantibodies  Lipopolysaccharide fraction of C. jejuni contains side chain with same structures as some of gangliosides, especially GM1, GD1a, GD3, GT1a then molecular mimicry between C.jejuni lipopolysaccharide and ganglioside plays a key role in induction of antiganglioside Ab Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kazue Ogawara, et al.annals of Neurology 2000;48:624-631
    32. 32. Guillain-Barre syndrome humoral immunity  in China 76% of AMAN, 42% of AIDP carried C.jejuni antibodies compared to 17% in general population  C.jejuni was relatively more common in GBS pts. With pure motor symptoms or axonal electrophysiology compared to other GBS cases  Other infectious agents  CMV was documented in 8-13% of GBS patients  EBV was documented in 2-10% of GBS patients  Mycoplasma pneumoniae was documented 5% of GBS patients  H.influenza was documented 13% of GBS patients Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kazue Ogawara, et al.annals of Neurology 2000;48:624-631
    33. 33. Guillain-Barre syndrome humoral immunity Antibodies can act with various way such as 1) Antibodies against epitopes on outermost surface of Schwann cell or axolemma bind complement & stimulate complement activation epitopes on outer surface are gangliosides Classical pathway activation with MAC formation is in experimental model of GBS & MFS Deposit of MAC & damage of perisynaptic Schwann cells and neurofilaments at nerve terminals were more frequently For example : anti-GQ1b antibodies in MFS(diagnostic marker) Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    34. 34. Guillain-Barre syndrome humoral immunity Gangliosides  N-acetylneuraminic acid(sialic acid)-containing glycosphingolipids  Concentrate on surface of neurons with oligosaccharide portion expressed on cell surface  Organized in clusters form membrane microdomains together with cholesterol & glycosylphosphatidylinositol(GPI)-anchored proteins  Microdomains also called lipid rafts or detergent-resistant membranes  Always form larger platforms  facilitate variety of membrane-mediated functions such as cell adhesion, signal transduction Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    35. 35. Guillain-Barre syndrome humoral immunity  GM1 present at node of Ranvier  GQ1b is enriched in oculomotor nerves  GalNAc-GD1a minor ganglioside in human brain & peripheral nerve Willison Hugh J, et al. journal of Neuroimmunology 2008:172-182 Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    36. 36. Kenichi Kaida,et al.Glycobiology 2009 ;19(7): 676–692
    37. 37. Kenichi Kaida,et al.Glycobiology 2009 ;19(7): 676–692
    38. 38. Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    39. 39. Guillain-Barre syndrome humoral immunity 2) Antibodies disrupted voltage-gated sodium channel clusters at nodes voltage-gated sodium channel(Nav) : locate and cluster at high densities on axonal membrane at node of Ranvier In AMAN : IgG antibody to GM1, GM1b, GALNAc-GD1a maked axonal excitability marked refractoriness (increase in threshold) due to dysfunction of Nav but can be reversible if no structural destruction of nodes Anti-GM1 antibodies induce blockade of Nav in a complement- mediated manner Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    40. 40. Guillain-Barre syndrome humoral immunity 3) Antibodies involved calcium ion channels GalNAc-GD1a is target molecule in pure motor variant IgG anti-GalNAc-GD1a caused complement-independent presynaptic inhibition of Ach release at neuromuscular junction due to presynaptic inhibitory effect of voltage-gated Ca channel currents Sera from AMAN pts. can block Cav in cerebellar Purkinje cells but those from AIDP pts. Did not Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    41. 41. Guillain-Barre syndrome humoral immunity 4) Antibodies of ganglioside complexes in GBS & its variants in 2006 Kaida K, et al. detected IgG Ab to ganglioside complex(GSC) in some GBS & MFS : 8 in 100 pts. In 2007 Kaida K, et al. detected Ab to GSC in 39 from 234 pts.(17%) GSC consisted of 2 different gangliosides such as GD1a-GD1b complex(GD1a/GD1B) pts. With anti-GD1a/GD1b or antiGD1b/GT1b are predisposed to severe disability Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    42. 42. Guillain-Barre syndrome humoral immunity 4) Antibodies of ganglioside complexes in GBS & its variants(cont.) mechanism of anti-GSC antibody-mediated nerve injury remains unclear 1) Dysfunction of nerve cells through binding to GSC in microdomains 2) Promote breakdown of blood-nerve barrier by binding various ligands on membranes of vascular endothelial cells 3) Reversible conduction block through Nav channels at nodes or through complement activation direct breakdown of Nav function or both Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    43. 43. Guillain-Barre syndrome humoral immunity  Presence of these antibodies varies according to clinical phenotype, and titers tend to decline after acute phase of disease  Critical aspect is cross-reactivity of these antibodies with related structures such as  IgG anti-GM1 cross-reacted with asialo-GM1, GM1b, GD1b, GALNAc-GD1a in 19-52% of cases  IgG anti-GQ1b cross-react with GT1a in most cases Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    44. 44. Guillain-Barre syndrome humoral immunity AIDP until now In AIDP no characteristic pattern of antiganglioside antibodies Some glycolipids such as GD1b, LM1 or galactocerebroside have been proposed as target Ag Sera from pts. with AIDP show Ab to various peripheral nerve myelin, but not clear about mechanism of conduction failure and demyelination Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156 Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    45. 45. Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156
    46. 46. IMMUNOBIOLOGY OF Guillain-Barre syndrome OUT LINES oNerve structure oClinical features & Variants oImmunopathology oImmunobiology oCellular immunity oHumural immunity oNew therapeutic strategy
    47. 47. Guillain-Barre syndrome new therapeutic strategy Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319
    48. 48. Guillain-Barre syndrome summary
    49. 49. Guillain-Barre syndrome summary
    50. 50. Guillain-Barre syndrome summary • Pathological hallmark of classic GBS is multifocal inflammatory demyelination of PNS, but now found spectrum of pathological changes • GBS is autoimmune diseases that self-tolerance breaks down • Molecular mimicry is one theory for explaining this order
    51. 51. Guillain-Barre syndrome summary • However, clinical spectrum & laboratory finding can not be explained solely by molecular mimicry hypothesis • GBS be considered as organ-specific immune-mediated disorder from synergistic interaction of CMI & HMI but mechanism still incompletely understood
    52. 52. Guillain-Barre syndrome summary • T-cells & M play role in CMI,but recently, many antibodies were found at different level of peripheral nerve • New therapeutics were in preclinical development
    53. 53. TGF-β
    54. 54. IMMUNOGLOBULIN EPITOPE Allotypes 66

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