7. IMMUNOBIOLOGY OF
Guillain-Barre syndrome
OUT LINES
oNerve structure
oClinical features & Variants
oImmunopathology
oImmunobiology
oCellular immunity
oHumural immunity
oNew therapeutic strategy
8. Guillain-Barre syndrome
clinical features & Variants
GBS
acute immune-mediated polyneuropathies
heterogenous condition with several variant
forms
clinical features
variants
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. 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. 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. IMMUNOBIOLOGY OF
Guillain-Barre syndrome
OUT LINES
oNerve structure
oClinical features & Variants
oImmunopathology
oImmunobiology
oCellular immunity
oHumural immunity
oNew therapeutic strategy
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. 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. 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
17. 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
20. 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
25. 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
26. 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
30. IMMUNOBIOLOGY OF
Guillain-Barre syndrome
OUT LINES
oNerve structure
oClinical features & Variants
oImmunopathology
oImmunobiology
oCellular immunity
oHumural immunity
oNew therapeutic strategy
31. 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
32. 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
33. 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
34. 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
35. 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
36. 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
37. 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
39. IMMUNOBIOLOGY OF
Guillain-Barre syndrome
OUT LINES
oNerve structure
oClinical features & Variants
oImmunopathology
oImmunobiology
oCellular immunity
oHumural immunity
oNew therapeutic strategy
40. 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
41. 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
42. 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
43. 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
44. 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
45. 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
49. 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
50. 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
51. 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
52. 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
53. 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
54. 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
60. 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
61. 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
62. 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
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).