Journal of the Neurological Sciences 196 (2002) 1 – 7

www.elsevier.com/locate/jns

Review article
Sialosyl-galactose: a common denominator of Guillain–Barré
and related disorders?
Anthony P. Moran a,*, Martina M. Prendergast a, Edward L. Hogan a,b
a
Department of Microbiology, National University of Ireland, Galway, Ireland
b
Department of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA
Received 6 September 2001; received in revised form 20 December 2001; accepted 5 February 2002

Abstract

The immune reactivity implicated in the pathogenesis of Guillain – Barré syndrome (GBS) and related diseases, which occur following
infection with specific strains of Campylobacter jejuni bearing sialylated lipopolysaccharide structures that cross-react with specific
gangliosides, is consistent with provocation of inflammation via molecular mimicry. In this review, we have focused upon microbial
characteristics and structures, the fine structure of the essential carbohydrate determinants, and the application of our proposed criteria,
modified from those of Koch for causation of infectious and of Witebsky for autoimmune diseases, to the circumstance of infectious
induction of autoimmune disorder. D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Guillain – Barré syndrome; Miller Fisher syndrome; Campylobacter jejuni; Lipopolysaccharides; Anti-ganglioside antibodies; Autoimmune disease;
Peripheral nervous system disorders

1. Perspective: Peripheral nervous system (PNS)
disorder, clinical phenotype, and anti-ganglioside
antibodies
The recent advances in insight into the pathogenesis of
Guillain – Barré syndrome (GBS) includes recognition of the
frequency of preceding infection with Campylobacter
jejuni, the frequency of elevated serum titers to putatively
neuritogenic gangliosides, and the findings of elevated and
specific serum titers to the lipopolysaccharide or lipooligo-
saccharide (LPS/LOS) of certain strains of C. jejuni [1– 4].
The spectrum of clinical syndromes ranges from classical,
largely motor, acute inflammatory demyelinating polyneur-
opathy (AIDP) to a purely motor form called acute motor
axonal neuropathy (AMAN), acute sensory neuropathy
(ASN), and acute motor and sensory axonal neuropathy
(AMSAN) [3] and to the Miller Fisher syndrome (MFS)
manifesting ophthalmoplegia, ataxia, and areflexia [5]. Suc-
cessful therapy for these disorders has often been obtained
*
Corresponding author. Tel.: +353-91-524411x3163; fax: +353-91-
525700.
E-mail address: anthonymoran@nuigalway.ie (A.P. Moran).
with plasmapheresis or intravenous high dose immunoglo-
bulin therapy [6– 8].
Autoimmune disorders of PNS similar to GBS include a
neuropathy induced by parenteral GM1 therapy [9], and
multifocal motor neuropathy (MMN) in which high propor-
tions of anti-GM1 antibodies occur in many patients (range,
22 – 85%) [10]. The wide range of anti-ganglioside antibody
specificities reported in GBS contrasts with the limited range
of antibody specificities found in MMN [11], and the
disorder caused by parenteral ganglioside therapy. In our
literature survey [1], the 44 reports included multiple find-
ings of anti-ganglioside antibodies to GM1, GM1b, GQ1b,
LM1, GalNAc-GD1a, and less frequent findings of antibodies
to GM2, GD1a, GD1b, GT1b, and GA1 (asialo-GM1). Anti-
GQ1b antibodies are found in a high percentage of patients
with MFS (up to 100% of cases) [2]. In contrast to the IgM
isotype of anti-GM1 antibody found in chronic neuropathies,
GBS sera contains IgG or less commonly IgA isotypes [12].
It is noteworthy that the elevated antibody titers in these
chronic neuropathies often decline and disappear during
recovery.
The correlation of anti-ganglioside antibody specificities
with clinical subtypes of GBS are strongest for the associ-
ations of anti-GD1a and anti-GalNAc-GD1a with AMAN
[4,13] although one report disagreed [14], of anti-GM1b

0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 5 1 0 X ( 0 2 ) 0 0 0 3 6 - 9
2 A.P. Moran et al. / Journal of the Neurological Sciences 196 (2002) 1–7
with AMAN in one Japanese study [15], of anti-GQ1b with
MFS [2], and of anti-GT1a with oropharyngeal palsy [16]. In
most instances, there is cross-reactivity of serum antibodies
with several gangliosides.
2. Antecedent C. jejuni infections, LPS/LOS, and GBS
C. jejuni is the most common infectious precursor of GBS
occurring in 32% of GBS patients overall, whereas other
antecedent pathogens include cytomegalovirus (CMV)
[17,18], Epstein –Barr virus (EBV) [19], and mycoplasma
[19,20]. Hepatitis A and B, varicella zoster virus, human
immunodeficiency virus, and herpes simplex virus are linked
by more equivocal data with similar prevalences in the
controls [21]. C. jejuni infection is associated with more
severe GBS and greater residual disability [22]. The fre-
quency of C. jejuni infection in GBS ranges from 14– 66%
(see Ref. [1]), with an overall prevalence of 32% as shown in
Table 1. The duration of excretion of C. jejuni is brief (mean
of 16 days) [23], and the majority of patient stools have
cleared the bacterium by the onset of symptomatic GBS 1 – 3
weeks after the onset of diarrhea [24]. Serological assessment
is a more sensitive marker for detecting the presence of C.
jejuni, but is less specific than stool culture (Table 1).
C. jejuni is a microaerophilic, gram-negative, non-spore-
forming bacterium with a characteristic S-shaped or spiral
morphology [25]. Infection is zoonotic, and the main route
of human infection is by ingestion of undercooked poultry
or untreated water and milk [26]. The usual clinical mani-
festation is acute inflammatory enterocolitis [23,27], and
diarrhea caused by C. jejuni infection exceeds the combined
total for that attributed to Salmonella, Shigella, and Escher-
ichia coli O157:H7 [28]. C. jejuni infection is unquestion-
ably underreported: the published incidence rates vary from
6/100,000 to 290/100,000.
Serotyping of C. jejuni is based upon differences in the
saccharide structure of the bacterial heat-stable antigens, and
strains have been designated as either ‘O’, Penner or heat-
stable (HS) serotypes [29]. Serotyping by passive hemag-
glutination (PHA) is determined by exposing typing antisera
to heated extracts of C. jejuni bound to mammalian red
blood cells [30]. In the past, the typing scheme has been
considered to be solely based upon LPS/LOS-like mole-
cules. However, recent evidence has implicated a role for
extracellular polysaccharides (PSs) as heat-stable antigens
as well. Claims that the heat-stable antigen is not LPS/LOS
Table 1
Association of C. jejuni infection and GBS (reports)a
C. jejuni infection #Infected #GBS Frequency (%)
Stool culture only 108 37 34.3
Serology only 1481 489 33.0
Both stool and culture 113 28 24.8
Total 1702 554 32.6
a
Summarized from Ref. [1].
in nature, but rather capsular polysaccharide (CPS), a
molecule not previously described in C. jejuni, arose after
the identification of a cluster of genes with significant
sequence similarity to the capsular PS genes (kps genes)
of E. coli [31,32]. Interestingly, we have previously chemi-
cally characterized LPS/LOS-independent PS from C. jejuni
HS:3 and HS:41 [34,35] although the role of the PSs in
serotyping was not determined. Determining the role of
LPS/LOS in serotyping has attracted renewed interest
because serotyping of clinical isolates has confirmed an
association between certain serotypes of C. jejuni and
subsequent development of GBS [1]. In general, LPS has
three components: the hydrophobic, membrane-inserted
lipid A, an oligosaccharide (OS) with inner and outer
components, and the externally directed polysaccharide O
chain, whereas LOS lacks the O-chain moiety [12]. C. jejuni
LPS/LOS is more complex than that of comparable enteric
pathogens such as Salmonella in that the core region is
structurally diverse, and sufficiently so to contribute to
differences in serospecificity [36]. Importantly, sialic acid
is present in the core OS of certain C. jejuni strains [37],
particularly those of strains that resemble gangliosides
[1,36,46]. In resolving the molecular basis of the heat-stable
antigen serotyping scheme, we found that LPS/LOS con-
tributes to serospecificity determinant of some strains of C.
jejuni, whereas in others, extracellular PS alone is respon-
sible for the heat-stable serotype [47]. Moreover, in other C.
jejuni serotypes, LPS/LOS together with extracellular PS,
contribute to serospecificity. Thus, while both LPS/LOS and
extracellular PS are involved in serotyping, whether only
one molecule or both together are responsible for serospe-
cificity is dependent on the particular C. jejuni serotype.
Numerous C. jejuni serotypes have been reported in
association with GBS. A strong association was reported
by Kuroki et al. [38] with a predominance of serotype HS:19,
an uncommon serotype in patients with gastroenteritis, in
81% of their GBS population. In addition, Fujimoto et al.
[39] described four C. jejuni HS:19 isolates from GBS.
Serotype HS:19 was also isolated from GBS patients in
Ireland [40], and in the US where it comprised 33% of GBS
isolates [41]. Another serotype, C. jejuni HS:41, was isolated
from 6/9 GBS patients in South Africa [42], which is in
striking contrast to its overall rarity (only 12/7119 isolates of
C. jejuni). Other C. jejuni serotypes identified in association
with GBS include HS:1, HS:2, HS:2/44, HS:4, HS:4/59,
HS:5, HS:10, HS:13, HS:15, HS:16, HS:18, HS:21, HS:24,
HS:30, HS:37, HS:44, and HS:64 [1]. For MFS, the sero-
types HS:2, HS:10, and HS:23 have been reported [43 – 45].
N-acetylneuraminic acid (Neu5Ac) was discovered in C.
jejuni strains by Moran et al. [37] in 1991 and subsequent
#Reports chemical studies have revealed that structures in the termi-
4
nal regions of the core OS of specific serotypes mimic the
18 structures of gangliosides purified from brain of vertebrates
3 including humans (Table 2). The structural similarity
25 spawned the idea that the immune-mediated response to
C. jejuni epitopes elicits cross-reactive anti-ganglioside
 A.P. Moran et al. / Journal of the Neurological Sciences 196 (2002) 1–7 3

Table 2 from a patient we studied [52] who developed GBS after

C. jejuni LPS/ganglioside structural mimicrya
parenteral administration of gangliosides cross-reacted with
Heat-stable serotype Gangliosideb Reference the serotype HS:2, HS:4, HS:19, and HS:41 LPSs and this
HS:1 GM1 [36] was in the absence of a preceding infection with C. jejuni.
HS:2 Several [36] This clearly demonstrates that gangliosides and LPS from C.
HS:4 GD1a [36]
jejuni GBS-associated serotypes are cross-reactive [52].
HS:10 MFS GD3 [45]
HS:19 GD1a, GM1 [46] Moreover, IgM anti-GM1 monoclonal antibodies (MAbs)
HS:19 GBS GT1a [46] from patients with MMN react with LPSs from serotype
HS:19 GBS GD3 [46] HS:4, HS:19, and HS:50 strains [53]. We found GM1-
HS:19 GBS GM1 [40] mimetic epitopes in LPS/LOS of serotype HS:41 GBS
HS:19 GBS GD1a [40]
isolates using a panel of anti-GM1 MAbs cloned from
HS:19 GBS GM1 [40]
HS:23 GM2 [36] patients with MMN [54]. The pattern of binding indicated
HS:23 MFS GD2, GD3, GM2 [47] that there was substantial heterogeneity among the serotype
HS:36 GM2 [36] HS:41 strains in GM1 epitope expression. In this study, it was
HS:41 GBS GM1 [48] first shown that the MAbs reacted exclusively with the core
a
Summarized from Ref. [1]. OS of LPS/LOS and not with lipid A or the polysaccharide
b
Ganglioside that C. jejuni LPS mimics. moiety. In GBS, IgG subclasses are normally restricted to
IgG1 and IgG3, which has been taken to indicate T cell-
antibodies that target neural cells and tissues bearing ganglio- dependent responses to protein antigen. However, we and
sides. However, due to the fact that gangliosides are widely others have observed the production of these IgG subclasses
distributed throughout the nervous system, there should be a in response to glycolipid antigens, including LPS/LOS
high level of B cell tolerance to structurally similar C. jejuni [55,56].
core OS structures. Therefore, tolerance to gangliosides is Furthermore, MFS is of great interest because of the
broken, but the underlying mechanisms of why this happens specific correlation with anti-GQ1b antibodies. There have
have not been addressed experimentally. The supportive been reports of cross-reactivity of GQ1b ganglioside and
findings for the hypothesis of molecular mimicry include LPS/LOSs from C. jejuni HS:2 and HS:23 strains [33,
that the most frequently isolated LPS/LOSs of C. jejuni- 43,44], though it is important to remember that none of
associated GBS are GM1 and GD1a-bearing structures the purified LPS/LOSs from neuropathy-associated strains
[36,40,46,49,50] and also that anti-GM1 antibodies are the have yielded a complete GQ1b structure. The finding of
most frequently observed antibodies in GBS [1]. Other C. GD2/GD3 ganglioside mimicry in a C. jejuni HS:23 strain
jejuni LPS/LOSs bear structural resemblances with GD3, may be relevant because GD3 bears the terminal trisacchar-
GD2, GM2, GM3, and GT1a gangliosides [45,46,48]. The ide Neu5Aca2 ! 8NeuAca2 ! 3Gal, and this is identical
minimal primary structure or ‘‘lowest common denomina- to the terminal of GQ1b ganglioside, a moiety that is
tor’’ for all of these gangliosides is the structure: Neu5- repeated internally [48].
Aca2 ! 3Galh1 ! 4-. How or whether the heterogeneity in The repeated finding of ganglioside epitopes in C. jejuni
ganglioside structure, stemming from variation in sialylation LPS/LOS by cross-reactivity with GBS anti-ganglioside
and in the location on the oligosaccharide of the minimum serum is interpreted then as further justifying the conclusion
sialosyl-galactose unit, i.e., bound proximally or distally, that molecular mimicry determines the neuritogenicity of C.
affects the neuritogenic potency is unclear. However, judg- jejuni.
ing from the cluster epidemiology in northern China and
Japan, and the more severe disability in these GBS patients
[22,50], the relatively undecorated determinant (i.e., GM1
ganglioside) and disialylated determinant (i.e., GD1a or
GalNAc-GD1a ganglioside structures) is the most neurito-
genic. This also applies to correlation of C. jejuni LPS/LOS
structure with clinical GBS severity and derives a corollary
hypothesis that the determinant’s potency increases in the
unmasked, sialosyla2 – 3galactose, and/or doubled, sialo-
syla2 –8sialosyla3 – 2galactose, structures (Fig. 1).
Serological studies are consistent with the mimicry
hypothesis. For example, Oomes et al. [62] demonstrated
that anti-ganglioside antibodies in GBS sera recognized
surface epitopes on whole C. jejuni bacteria in a strain-
specific fashion. With Schwerer et al. [51], we showed that
Fig. 1. Ganglioside core motif associated with Guillain – Barré and Miller
IgA antibodies from C. jejuni-infected patients recognized Fisher syndromes. Schematic representation of gangliosides: Q, galactose;
GM1 and C. jejuni HS:2, HS:4, and HS:19 LPS. Serum IgG E, N-acetylneuraminic acid.
4 A.P. Moran et al. / Journal of the Neurological Sciences 196 (2002) 1–7
3. Postulation of anti-ganglioside pathogenicity in
Guillain –Barré syndrome
The proposal that an autoimmune disease is induced by
infection requires rigorous criteria for proof. An important
clinical criterion for establishing the existence of an anti-
body-mediated autoimmune disorder in man is successful
treatment with reduction of disability attributed to and/or
termination of progression of acute neuropathy by removal
of circulating antibodies via plasmapheresis, or by intravenous
administration of polyvalent immunoglobulins, where the
mechanism of action is still unclear [57,58]. Successful
therapy by both modalities has been found in several clinical
studies carried out with rigorous criteria for unbiased con-
clusions [6 –8,57,58].
Criteria for determination of causation are of course
essential for assessing the validity of proposed biological
mechanisms. Robert Koch’s principles for establishing a role
for a pathogen in disease causation requires that: (1) the
pathogen be present, (2) be isolated from the host, (3) the
disease be reproduced in an experimental host, and (4) the
pathogen be recovered from the experimental host. They
were extended to autoimmunity by Witebsky et al. [59] in
1957 in a study of both Hasimoto’s and experimental auto-
immune thyroiditis. They introduced criteria for autoimmun-
ity although not directed at the role of infection [60] that
include: (1) demonstration of free circulating antibodies, (2)
recognition of the target antigen, (3) production of antibodies
in experimental animals against this target antigen, and (4)
the appearance of pathological changes in the corresponding
tissues of an actively sensitized animal that are basically
similar to the human disease.
In a similar fashion, we propose a set of rules for
establishing that an autoimmune disorder stems from a
specific infection. These postulates are considered in rela-
tion to the GBS paradigm in the following.
(1) Antecedent infection is established in the host. We
add the caveats that: (a) the temporal association may vary
in different infection/autoimmune paradigms, and (b) the
infection may be occult. This is fulfilled in GBS by the
isolation of C. jejuni, and the high incidence of occurrence
of cross-reactivity of anti-ganglioside antibodies with spe-
cific C. jejuni LPS/LOSs that are structurally homologous to
gangliosides.
(2) Cross-reactivity of the pathogen with a host target
molecule should be demonstrated. The serological cross-
reactivity of anti-ganglioside antibodies and the ganglioside-
mimicking C. jejuni LPS/LOSs show this directly. However,
ganglioside-like structures have also been demonstrated in
C. jejuni strains from patients with uncomplicated enteritis
[3,40,49,61]. Thus, the humoral response to cross-reactive
epitopes in C. jejuni LPS/LOS is different in GBS, as
patients with enteritis rarely develop anti-ganglioside anti-
bodies [63]. The cross-reactivity of specific anti-ganglioside
antibodies obtained from patients with MMN [54], and from
those patients developing polyradiculoneuropathy after
parenteral administration of gangliosides with the C. jejuni
LPS/LOS provide strong corollary evidence [52].
(3) Experimental disease reproduction in an animal host
by administration of the tissue target antigen, a molecular
mimic, or anti-target antibodies. In this regard, a central
assumption is that there is interspecies conservation of the
tissue target antigen. Antibodies to gangliosides [9,64 – 66]
and those raised to C. jejuni LPS/LOS [56] bind to the node
of Ranvier and to the neuromuscular junction [55,65,67,68].
Using experimental in vitro systems to prove that anti-
ganglioside antibodies are relevant factors in GBS patho-
genesis has been fraught with difficulties. Exposure of
isolated nerve preparations to human and rabbit anti-GM1
antibodies gives variable results, with some studies reporting
acute conduction block of myelinated nerve fibres [69,70],
whereas other studies report the absence of significant nerve
changes [71]. However, a similar study by this group
demonstrated that anti-GM1-containing sera from patients
with MMN blocked conduction in mouse nerves [72]. Most
reports of intraneural injection of GBS sera into animal
nerves observe a rapid conduction block and demyelination
[69,70,73– 77], an effect that appears to be complement-
dependent [64,67]. In fact, the presence of complement has
been demonstrated at axonal sites and on myelin sheath
[78,79], and the presence of IgG antibodies has been shown
at presynaptic terminals in GBS patients [9,80] and on the
axon [81]. With regard to MFS, sera with GQ1b antibodies
induce complement-mediated electrophysiological and im-
munological abnormalities [55,64,67]. In contrast, Buch-
wald et al. [80] demonstrated that these effects could be
achieved with anti-GQ1b-negative sera, but state that an IgG
antibody factor, not directed against known gangliosides, is
responsible for the nerve damage [80,82]. These results
suggest that nerve damage in GBS/MFS may not be exclu-
sively attributed to one determinant. Moreover, the role of
antibody in GBS pathogenesis may be in an antibody-
dependent cellular cytotoxicity capacity. Despite these seem-
ingly contradictory results, cumulative evidence supports a
role for anti-ganglioside antibodies and complement in GBS
pathogenesis, and that the neuromuscular junction and nodes
of Ranvier are important target sites for the action of humoral
factors. How T cells contribute to the pathophysiology of
GBS, and the mechanisms by which they do so is unclear.
Preliminary evidence suggests that C. jejuni LPS/LOS acti-
vates T cell clones by a CD1-dependent mechanism and
independent of MHC restriction [83]. Activated T cells may
produce a nonspecific, cytokine-mediated response, which
increases the permeability of the blood – nerve barrier allow-
ing access of anti-ganglioside antibodies. Although clinical
neuropathy has not been produced in experimental animals
by passive or active immunization employing either GM1 or
C. jejuni LPS/LOSs, it is intriguing that parenteral injection
of GD1b causes ‘‘sensory ataxic neuropathy’’ in rabbits
[13], and passive transfer of GD1b into rabbits produces
axonal degeneration and macrophage infiltration resembling
AMAN [84]. Recently, there has been a report of the in vivo
 A.P. Moran et al. / Journal of the Neurological Sciences 196 (2002) 1–7
induction of demyelinating neuropathy after a median inter-
val of 43 days in rabbits with either a mixture of bovine brain
ganglioside or GM1 and both keyhole limpet hemocyanin
and complete Freund’s adjuvant [81]. This study would, in
our opinion, fulfill this postulate and would make us less
cautious in regard to fulfilling the postulate of antigen
induction of experimental disease.
(4) Disease reproduction in an experimental host by the
pathogen. No infectious animal model has yet been estab-
lished for production of peripheral neuropathy in laboratory
species. A report by Li et al. [85] that 30% of chickens
exposed to a C. jejuni HS:19 strain, isolated from a Chinese
patient with AMAN, developed paralysis awaits confirma-
tion. Previous studies on the structure of the glycoconjugates
in the chicken central nervous system indicated that the
ganglioside OSs differ fundamentally from vertebrates and
are not conserved [86] which raises similar concern for PNS
gangliosides and glycolipids. Thus, this criterion, which is
the most formidable because of species molecular differ-
ences in carbohydrates, etc., is not considered satisfied.
However, to fulfill this requirement, it is necessary to have
an animal model allowing colonization by the infectious
agent plus a humoral response mimicking that of humans and
found to produce a relevant pathology in animals. This is
proving to be difficult.
In summary, there is now a substantial body of data
indicating that there is a structural similarity of sialosyl
determinants in gangliosides by C. jejuni LPS/LOS from
certain and specific strains, and that this correlates signifi-
cantly with the occurrence of GBS and related diseases. On
the other hand, it is clear that other attributes of the host and/
or bacterium, in addition to molecular mimicry, are impor-
tant in the occurrence or progression of disease. These un-
determined factors may affect whether GBS develops
following infection with the ganglioside-mimicking strain
of C. jejuni. The evidence is that many the PNS disorders
initiated by C. jejuni are autoimmune, and are examples of
molecular mimicry in the context of infection and induction
of the neurological disorder.
Acknowledgements
These studies were supported by grants from the Irish
Health Research Board (Grant 12-99 to A.P.M. and
M.M.P.), the NIH (NS31676), and the SC Appropriation
for Medical Research (E.L.H.).
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