Guillain-Barre syndrome

IMMUNOBIOLOGY OF Guillain-Barre syndrome

นพ.สุ�รสุฤษดิ์ ขาวละออ5/3/2010


OUT LINESoNerve structureoClinical features & VariantsoImmunopathologyoImmunobiology

oCellular immunityoHumural immunity

oNew therapeutic strategy 2





Guillain-Barre syndromenerve structure

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Guillain-Barre syndromeclinical features & Variants

GBS acute immune-mediated polyneuropathies heterogenous condition with several variant forms clinical features variants

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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% oculomotor weakness occurs 15% prominent severe pain in lower back in AIDP

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AIDP


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

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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

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Guillain-Barre syndromeimmunopathology

Pathological hallmark of classic GBS “multifocal demyelination of PNS”

Spectrum of pathological changeFocal or extensive demyelination in

presence or absence of cellular infiltration to axonal degeneration with or without demyelination or inflammatory infiltration

13Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156


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



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 Toleranceo central toleranceo peripheral tolerance

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Central tolerance : generative lymphoid organT cells : in thymus

negative selection mutation in AIRE (autoimmune regulator) gene develop into regulatory T cells

B cells : in bone marrowreceptor editingnegative selection

17Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187

Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439


Peripheral tolerance : peripheral lymphoid tissueT cells

anergy engage to inhibitory receptoe (CTLA-4) immune suppression by Treg deletion : activation-induced cell death

B cellsanergy : do not receive T cell helpExclusion of anergic B cells from lymphoid follicles

20Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439


Failure to tolerance in what cell type, which do you think important for autoimmunity?

Why?

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T cells B cells

Self polysaccharides, lipids, nucleic acid are

T-independent Ag & not recognized by T cells induce tolerance in B

cells


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

26Abul K. Abbas.Basic Immunology 3rd edition 2009;9:173-187Abul K. Abbas.Cellular and Molecular Immunology 6th edition 2007;18:432-439





Guillain-Barre syndromecellular 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 pateintsOther 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):225-38D’Urso,D.et al.The Journal of Neuroscience 1999;19(9):3396-3403

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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

32Hans-Peter Hartung, et al. The Annals of Neurology 1990;27(Suppl):S57–63


Detected T-cells in nerve biopsies from GBS V8/1 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



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 humansV9V2 TCR is predominantly found among peripheral blood T cellsmajority of intestinal Tcells expressV1 chains associated with one of several -chains

Murine and humanselective accumulations of T cell subsets at different body locations are result of peripheral selection and expansion by locally expressed antigens

34Tony Kenna.Clinacal Immunology 2004;113:56-63


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(IB) in both T-cells & M in inflammatory neuropathy but IB found mainly in Schwann cells in noninflammatory cases

Andorfer B, et al. Journal of Neuroimmunol ogy 2001;116:226–23236


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

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M (not Schwann cells) express MHC class II gene may function as o antigen presenterso 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-38Hans-Peter Hartung, et al. The Annals of Neurology 1990;27(Suppl):S57–63






Guillain-Barre syndromehumoral immunity

Various observation suggest that humoral factors are involved

Plasmapheresis & intravenous Ig(IVIG) clinical improveCirculating Ab targeting structures on peripheral nerve Deposition of Ig & complement be demonstrated on myelinated fibers

Molecular mimicry is one hypothesis for explaining


Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319


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

42Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156Kazue Ogawara, et al.annals of Neurology 2000;48:624-631


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

43Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156Kazue Ogawara, et al.annals of Neurology 2000;48:624-631


Antibodies can act with various way such as1) Antibodies against epitopes on outermost surface of

Schwann cell or axolemma bind complement & stimulate complement activation

epitopes on outer surface are gangliosidesClassical 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 frequentlyFor example : anti-GQ1b antibodies in MFS(diagnostic marker)

44Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319


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




GM1 present at node of Ranvier GQ1b is enriched in oculomotor nerves GalNAc-GD1a minor ganglioside in human brain & peripheral nerve

46Willison Hugh J, et al. journal of Neuroimmunology 2008:172-182

Bernd C kieseier, et al. MUSCLE & NERVE 2004;30:131-156Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319

47 Kenichi Kaida,et al.Glycobiology 2009 ;19(7): 676–692

48 Kenichi Kaida,et al.Glycobiology 2009 ;19(7): 676–692

49Kenichi Kaida & Susumu Kusunaki.Expert Review Neurotherapy 2009;9(9):1307-1319


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 RanvierIn 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 nodesAnti-GM1 antibodies induce blockade of Nav in a complement-mediated manner




3) Antibodies involved calcium ion channels GalNAc-GD1a is target molecule in pure motor variantIgG anti-GalNAc-GD1a caused complement-independent presynaptic inhibition of Ach release at neuromuscular junction due to presynaptic inhibitory effect of voltage-gated Ca channel currentsSera from AMAN pts. can block Cav in cerebellar Purkinje cells but those from AIDP pts. Did not




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



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 microdomains2) Promote breakdown of blood-nerve barrier by binding various ligands

on membranes of vascular endothelial cells3) Reversible conduction block through Nav channels at nodes or through

complement activation direct breakdown of Nav function or both



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



AIDP until nowIn AIDP no characteristic pattern of antiganglioside antibodiesSome glycolipids such as GD1b, LM1 or galactocerebroside have been proposed as target AgSera from pts. with AIDP show Ab to various peripheral nerve myelin, but not clear about mechanism of conduction failure and demyelination








Guillain-Barre syndromenew therapeutic strategy


Guillain-Barre syndromesummary



• 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


• 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


• 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

TGF-β

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IMMUNOGLOBULIN EPITOPE

Allotypes

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Guillain-Barre syndrome