Guillain–Barré Syndrome—A Classical Autoimmune Disease Triggered by Infection or Vaccination

Abstract

Guillain-Barré syndrome (GBS) is a rare autoimmune disorder, the incidence of which is estimated to be 0.6-4/100,000 person/year worldwide. Often, GBS occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal microbial infection. The disorder is sub-acute developing over the course of hours or days up to 3 to 4 weeks. About a third of all cases of Guillain-Barré syndrome are preceded by Campylobacter jejuni infection. C. jejuni strains isolated from GBS patients have a lipooligosaccharide (LOS) with a GM1-like structure. Molecular mimicry between LOS and the peripheral nerves as a cause of GBS was demonstrated in animal models of human GBS. Following the "swine flu" virus vaccine program in the USA in 1976, an increase in incidence of GBS was observed and the calculated relative risk was 6.2. Later studies have found that influenza vaccines contained structures that can induce anti-GM1 (ganglioside) antibodies after inoculation into mice. More recent information has suggested that the occurrence of GBS after currently used influenza and other vaccines is rare. GBS involves genetic and environmental factors, may be triggered by infections or vaccinations, and predisposition can be predicted by analyzing some of these factors.

Full text

Guillain–Barré Syndrome—A Classical Autoimmune
Disease Triggered by Infection or Vaccination
Eitan Israeli &Nancy Agmon-Levin &Miri Blank &
Joab Chapman &Yehuda Shoenfeld
Published online: 5 October 2010
#Springer Science+Business Media, LLC 2010
Abstract Guillain–Barré syndrome (GBS) is a rare auto-
immune disorder, the incidence of which is estimated to be
0.6–4/100,000 person/year worldwide. Often, GBS occurs a
few days or weeks after the patient has had symptoms of a
respiratory or gastrointestinal microbial infection. The
disorder is sub-acute developing over the course of hours
or days up to 3 to 4 weeks. About a third of all cases of
Guillain–Barré syndrome are preceded by Campylobacter
jejuni infection. C. jejuni strains isolated from GBS patients
have a lipooligosaccharide (LOS) with a GM1-like struc-
ture. Molecular mimicry between LOS and the peripheral
nerves as a cause of GBS was demonstrated in animal
models of human GBS. Following the “swine flu”virus
vaccine program in the USA in 1976, an increase in
incidence of GBS was observed and the calculated relative
risk was 6.2. Later studies have found that influenza
vaccines contained structures that can induce anti-GM1
(ganglioside) antibodies after inoculation into mice. More
recent information has suggested that the occurrence of
GBS after currently used influenza and other vaccines is
rare. GBS involves genetic and environmental factors, may
be triggered by infections or vaccinations, and predisposi-
tion can be predicted by analyzing some of these factors.
Keywords Guillain–Barré syndrome .Infections .
Autoimmunity .Vaccines .C. jejuni .Influenza
Definition
Guillain–Barré syndrome is a disorder in which the immune
system attacks gangliosides on the peripheral nervous
system. The first symptoms of this disorder include varying
degrees of weakness or tingling sensations in the legs. In
many instances, the weakness and abnormal sensations
spread to the arms and upper body [1]. These symptoms
can increase in intensity until the muscles fail completely
and the patient is almost totally paralyzed or there is severe
dysfunction of the autonomic nervous system. In these
cases, the disease is life-threatening and is considered a
medical emergency. Most patients, however, recover from
even the most severe cases of Guillain–Barré syndrome,
although some continue to have some degree of weakness.
Guillain–Barré syndrome is rare, incidence worldwide is
estimated to be 0.6–4/100,000 person/year [1]. Often (in
around one third of cases), Guillain–Barré occurs a few
days or weeks after the patient has had symptoms of a
respiratory or gastrointestinal microbial infection. Occa-
sionally, surgery or vaccinations will trigger the syndrome.
The disorder can develop over the course of hours, days, or
it may take up to 3 to 4 weeks, and reflexes are usually lost.
E. Israeli :N. Agmon-Levin :M. Blank :Y. Shoenfeld
The Chaim Zabludowicz Center for Autoimmune Diseases,
Sheba Medical Center, Tel-Hashomer,
Tel-Aviv, Israel
N. Agmon-Levin :Y. Shoenfeld (*)
Department of Medicine ‘B’& Center for Autoimmune Diseases,
Chaim Sheba Medical Center, Tel-Hashomer,
Tel-Aviv 52621, Israel
e-mail: shoenfel@post.tau.ac.il
Y. Shoenfeld
Sackler Faculty of Medicine,
Incumbent of the Laura Schwarz-Kip Chair for Research
of Autoimmune Diseases,
Tel-Aviv University,
Tel-Aviv, Israel
J. Chapman
Department of Neurology and Sagol Center for Neurosciences,
Sheba Medical Center, Tel-Hashomer,
Tel-Aviv, Israel
Clinic Rev Allerg Immunol (2012) 42:121–130
DOI 10.1007/s12016-010-8213-3

Due to slow down of signals travelling along the nerve,
nerve conduction velocity test can aid the diagnosis. The
cerebrospinal fluid contains more protein than usual, but
normal cell count, so a spinal tap is important for the
diagnosis.
Clinical Variants
Although ascending paralysis is the most common form of
spread in GBS, other variants also exist. Miller Fisher
Syndrome is a rare variant of GBS, proceeding in the
reverse order of the more common form of GBS. It usually
affects the ocular movements first and presents as oph-
thalmoplegia, ataxia, and areflexia. Anti-GQ1b (a ganglio-
side, see “Possible Mechanism that can Trigger GBS”in the
“Discussion”section) antibodies are present in 90% of
cases but not anti-GD3 antibodies [2]. Acute motor axonal
neuropathy (AMAN) [3] also termed Chinese paralytic
syndrome is prevalent in China and Mexico. The disease
may be seasonal and recovery can be rapid. Anti-GD1a
antibodies [4] are present. Anti-GD3 antibodies are found
more frequently in AMAN. Acute motor sensory axonal
neuropathy is similar to AMAN but also affects sensory
nerves with severe axonal damage. Recovery is slow and
often incomplete [5].
GBS as an Autoimmune Disease
To establish that a disease has an autoimmune etiology,
Witebsky–Rose postulates that an autoimmune response be
recognized in the form of an autoantibody or cell-mediated
immunity, that the corresponding antigen be identified, and
that an analogous autoimmune response be induced in
experimental animals. Finally, the immunized animals must
develop a similar disease [6].
How does GBS match the criteria for an autoimmune
disease? Shoenfeld et al. [7] addressed this question and
concluded that four major Witebsky–Rose criteria [6] are
fulfilled in GBS. (1) Autoantigens (i.e., myelin constitu-
ents) evoking an autoantibody response could be demon-
strated; (2) the presence of autoantibodies has been
confirmed and several pathogenic mechanisms by which
they may exert their influence have similarly demonstrated
in vitro; (3) active immunization with myelin constituents
has been shown to cause an autoimmune phenomena
resembling human GBS; (4) an adoptive transfer of
autoantibodies and or autoreactive T cells results in nerve
demyelination, clinical signs, and laboratory findings of
GBS [8]. Additionally, GBS is commonly seen in associ-
ation with other autoimmune diseases, changes in T cells
subclasses, and change in cytokine profile [7].
Willison [9] studied the motor nerve terminal as a model
site of injury, and through combined active and passive
immunization paradigms, have developed murine neuropa-
thy phenotypes mediated by anti-ganglioside antibodies.
This has been achieved through use of glycosyltransferase
and complement regulator knock-out mice, both for cloning
anti-ganglioside antibodies and inducing disease. Through
such studies, Willison and his group have proven “a
neuropathogenic role for murine anti-ganglioside antibodies
and human GBS-associated antisera and identified several
determinants that influence disease expression including (a)
the level of immunological tolerance to microbial glycans
that mimic self-gangliosides; (b) the ganglioside density in
target tissue; (c) the level of complement activation and the
neuroprotective effects of endogenous complement regu-
lators; and (d) the role of calcium influx in mediating
axonal injury”.
Environmental Factors Involved in GBS—Infection
and Vaccination
Infections and GBS
An infection can induce or trigger autoimmune disease via
two mechanisms—antigen-specific or antigen non-specific—
which can operate either independently or together. An
autoimmune disease will only arise, however, if the individual
is genetically predisposed to that particular condition. A
common explanation for how infectious agents stimulate
autoimmunity in an antigen-specific way is via molecular
mimicry. Antigenic determinants of microorganisms can thus
be recognized by the host immune system as being similar to
antigenic determinants of the host itself. Molecular mimicry
among sugar structures is common and leads to numerous
manifestations of infection-associated and antibody-mediated
neuropathies. About a third of all cases of Guillain–Barré
syndrome are preceded by Campylobacter jejuni infection
[10]. This bacterium expresses a lipooligosaccharide mole-
cule that mimics various gangliosides present in high
concentrations in peripheral nerves. Numerous viruses also
collect gangliosides as they incorporate plasma membrane
from the host cell. As a result, viral infections (i.e., influenza,
parainfluenza, polio, herpes) are often associated with
Guillain–Barré syndrome, and both bacterial and viral
vaccines have been linked with induction of the condition
[11].
Numerous epidemiological studies and anecdotal cases
have established an association between infections and
Guillain–Barré syndrome (Table 1).
Kinnunen et al. [12] performed a retrospective analysis
of the incidence of Guillain–Barré syndrome (GBS) in
Finland in 1981–1986. Monthly rates showed an increased
122 Clinic Rev Allerg Immunol (2012) 42:121–130

incidence from baseline of GBS (8.2 per million) in March
1985, following by a few weeks of the onset of the
nationwide oral poliovirus vaccine campaign and partly
overlapping it. Analysis of the time series in depth
suggested, however, that a change point in the occurrence
of GBS had already taken place before the oral poliovirus
vaccine campaign. Widespread circulation of wild-type 3
poliovirus in the population immediately preceded the oral
poliovirus vaccine campaign and the peak occurrence of
GBS. These results demonstrate a temporal association
between poliovirus infections, caused by either wild virus
or live attenuated vaccine, and an episode of increased
occurrence of GBS.
Shoenfeld et al. [7], in a comprehensive review about
GBS as an autoimmune disease, cite numerous bacterial
and viral infections associated with the disease. Among the
viruses, echo, coxsackie, varicella, mumps, rubella, influ-
enza, and HIV are documented as infections preceding
episodes of GBS. Bacterial infections preceding GBS
included Borrelia,Mycoplasma pneumoniae, and C.jejuni.
A strong association between C.jejuni infection and
GBS, with an OR of 9.5, was also demonstrated in another
study, confirming a causal association [13].
Microbiological studies carried out on 84 patients resulted
in a probable diagnosis of infectious diseases etiology in 46
(55%). Coxsackieviruses (15%), Chlamydia pneumoniae
(8%), cytomegalovirus (7%), and M. pneumoniae (7%) were
the most frequently involved agents. Serological evidence of
aC.jejuni infection was found in six patients (7%). The
authors conclude that the etiology of antecedent diseases is
distributed over a wide spectrum of pediatric infectious
diseases. Most of the children who had been vaccinated
showed concomitant infectious diseases, thus obscuring the
causative role for GBS [14].
Another strong association between GBS and influenza
infections was documented by Stowe et al. [15]. The
authors used the self-controlled case series method to
investigate the relation of Guillain–Barré syndrome with
influenza vaccine and influenza-like illness using cases
recorded in the General Practice Research Database from
1990 to 2005 in the United Kingdom. The relative
incidence of Guillain–Barré syndrome within 90 days of
vaccination was 0.76 (95% confidence interval, 0.41–1.40).
In contrast, the relative incidence of Guillain–Barré
syndrome within 90 days of an influenza-like illness was
7.35 (95% confidence interval, 4.36–12.38), with the
greatest relative incidence (16.64, 95% confidence interval,
9.37–29.54) within 30 days. The relative incidence was
similar (0.89, 95% confidence interval, 0.42–1.89) when
the analysis was restricted to a subset of validated cases.
The authors found no evidence of an increased risk of
Guillain–Barré syndrome after seasonal influenza vaccine.
The finding of a greatly increased risk after influenza-
like illness is consistent with anecdotal reports of a
preceding respiratory illness in Guillain–Barré syndrome
and has important implications for the risk/benefit assess-
ment that would be carried out, should pandemic vaccines
be deployed in the future.
Two recent reports (2009) document association of GBS
and relatively rare viral infections: Lebrun et al. [16] report
two cases of GBS after Chikungunya virus infection in
Réunion Island, which correlated with epidemiological data
conferring the association between the two. Chikungunya
virus is an RNA alphavirus (group A arbovirus) in the
family Togaviridae. Aedes aegypti and Aedes albopictus are
the known mosquito vectors. Anti-Chikungunya IgM was
found in serum and CSF, although genomic products in
serum and CSF were negative, which was not surprising,
given the brief period (4–5 days) of viremia. These findings
strongly supported a disseminated acute Chikungunya
infection and support the conclusion that Chikungunya
virus was probably responsible for the GBS. In 2006,
Table 1 Infectious agents associated with GBS
Infectious agent Year Incidence per 10
6
Time post
infection
Reference
Chikungunya virus 2009 Up 22% from
baseline (3.3)
2–3 weeks [16]
Influenza 1990–2005 7.3 90 days [15]
16.6 30 days
RI
Coxsackieviruses; Chlamydia CMV; M.pneumoniae;C.jejuni Prospective ? 6 weeks [14]
Echo/Coxackie; varicela; mumps; rubella; influenza; HIV; Borrelia;M.
pneumoniae;C.jejuni
90′? Weeks [7]
C.jejuni 2003 9.5 OR ? [13]
Polio (circulating type 3) 1981–1986 Increase from
(8.2) baseline
Weeks [12]
Hepatitis E 2009 1 case Weeks [17]
Clinic Rev Allerg Immunol (2012) 42:121–130 123

Chikungunya virus was found on Réunion Island; seropre-
valence on the island was estimated to be 38.2% among
785,000 inhabitants (95% confidence interval 35.9%–
40.6%).
Epidemiologic data also support a causal relationship
between Chikungunya infection and GBS: The incidence
rate of GBS increased 22% in 2006 (26/787,000, persons)
over the rate in 2005 (21/775,000 or 2.7/10,000 persons)
and then declined to a rate closer to baseline in 2007 (23/
800,000 or 2.87/100,000 persons).
Loly et al. [17] report a case of Guillain–Barré syndrome
in a patient sporadically contaminated in a Western
country. This is the third report of GBS in a patient with
hepatitis E, and the first occurring in a patient sporadically
contaminated in a Western country. The authors believe it
is the first description of the presence of anti-ganglioside
GM2 antibodies in GBS associated with a hepatotropic
virus, suggesting possible molecular mimicry involving
gangliosides.
In all the above reports, the time between the infection
disease and the onset of GBS was a few weeks, ranging
from 2 to 3 weeks to 3 months. This time period is in
agreement with a temporal association between an environ-
mental trigger and the onset of an autoimmune disease.
Adding the high odds ratio of association calculated for
some of these infections, (OR = 9.5 for C.jejuni) and
augmentation of the relative incidence following infection,
(RI=7.3–16.6 for influenza), the conclusion is quite
obvious, that these bacterial and viral infections, as well
as others are strong environmental agents involved with the
onset of GBS.
Most infectious agents, such as viruses, bacteria and
parasites, can induce autoimmunity via a number of
mechanisms. In many cases, it is not a single infection
but rather the “burden of infections”from childhood that is
responsible for the induction of autoimmunity in adulthood,
many years after the original infection [18].
Vaccinations and GBS
There are anecdotal reports of GBS occurring in a time
frame after immunizations that can indicate a temporal
association between the two events. The period between
vaccination and first symptoms of GBS, range from as short
as 3–5 days, to 6–10 weeks, and up to a few months and
even years (Table 2). The temporal association and lack of
infections in those individual cases can indicate a causal
association [19–23]. However, in the epidemiological
studies cited, no significant causal association was found.
Incidence observed for GBS following the vaccinations was
either “small”,“in the expected range”, same as “back-
ground”,“extremely rare”, or lower then “baseline”. Only
two studies with polio vaccination found an increase
incidence from a background of 8.2:10
6
and an OR of
7.27 (10, 11).
Influenza Vaccination
Following the “swine flu”) influenza A/New Jersey) virus
vaccine program in the USA in 1976, an increase in
incidence of GBS was observed [24](Table3). The
National Influenza Immunization Program was suspended
on December 16, 1976 and nationwide surveillance for
GBS was begun. This surveillance uncovered a total of
1,098 patients with onset of GBS from October 1, 1976, to
January 31, 1977, from all50 states. A total of 532 patients
had received an A/New Jersey influenza vaccination prior
to their onset of GBS (vaccinated cases), and 15 patients
received a vaccination after their onset of GBS. Epidemi-
ologic evidence indicated that many cases of GBS were
related to vaccination. When compared to the unvaccinated
population, the vaccinated population had a significantly
elevated attack rate in every adult age group. The estimated
attributable risk of vaccine-related GBS in the adult
population was just under one case per 100,000 vaccina-
tions. The period of increased risk was concentrated
primarily within the 5-week period after vaccination,
although it lasted for approximately 9 or 10 weeks. The
mean interval from vaccination to onset was 3.9 weeks. The
incidence rose from 2.6:10
6
for nonrecipients to 13.3:10
6
for vaccine recipients (corrected later by Breman and
Hayner [25] to be 11.7:10
6
), and the calculated relative
risk was 6.2. More recent information suggested that the
occurrence of GBS after currently used influenza and other
vaccines is extremely rare [26]. Case control studies have
shown no evidence of a significant increase in risk of
having received an immunization preceding GBS (i.e.,
measles, mumps, rubella) compared with contemporary
controls [27–29].
Retrospective examination of the incidence of GBS for
the seasons of the 1992–3 and 1993–4 influenza vaccina-
tion programs in the USA suggested that influenza
vaccination only caused 1–2 extra cases of GBS per million
vaccines [30]. The calculated relative risk in different
studies from 1978 to 2005 produced RR values ranging
from 0.4 to 1.7. Only one study documenting the years
1991–1999 came up with higher RR values (4.3–8.5),
which may establish a significant causal association
between the influenza vaccination program and incidence
of GBS. Despite this evidence, GBS is an autoimmune
condition and the knowledge that immunizations are
designed to activate the immune system give rise to
continued unease about immunization following the disease
[31,32]. This unease is enhanced by a report of two cases
of GBS recurring following swine influenza vaccine [33].
In addition, recurrent attacks of chronic inflammatory
124 Clinic Rev Allerg Immunol (2012) 42:121–130

demyelinating polyradiculoneuropathy have followed teta-
nus toxoid immunization [31,34]. However, many patients
have received immunizations after the acute phase of their
disease, sometimes repeatedly [35], without suffering a
relapse. The number of such patients has, however, not
been monitored and the actual risk is not known. In the
absence of adequate evidence and the difficulty of
conducting an adequately powered randomized trial, it
would be appropriate to audit a recovered GBS patient
population to discover the proportion receiving immuniza-
tions and the corresponding outcome. Although the
experiment has never been done in GBS, patients with
multiple sclerosis have been randomized to receive or not
receive influenza vaccine, and no evidence emerged to
suggest that immunization stimulated relapse [36,37].
There are structural differences between nodes in the
central nervous system (CNS) and peripheral one (PNS)
that might explain the susceptibility of the PNS in GBS
[38]. In the PNS, specialized microvilli project from the
outer collar of Schwann cells and come very close to nodal
axolemma of large fibers. The projections of the Schwann
cells are perpendicular to the node and are radiating from
the central axons. However, in the CNS, one or more of the
astrocytic processes come in close vicinity of the nodes.
These processes may stem from multi-functional astrocytes,
as opposed to from a population of astrocytes dedicated to
contacting the node. On the other hand, in the PNS, the
basal lamina that surrounds the Schwann cells is continuous
across the node.
Discussion
An etiology for the 1976 increase in incidence of GBS
following the influenza vaccination program was suggested
by Nachamkin et al. [39]. The authors hypothesized that the
Table 2 Correlation between vaccinations and GBS
Vaccine Year Incidence Time post vaccination Reference
Hepatitis B 2004 1 case 10 weeks [73]
HBV 1983–2002 19 cases 3 days–9 months [73]
Measles; rubella 2003 Under baseline 6–10 weeks [74]
Live measles and rubella 1976 2 cases 1 week [75]
Meningococcal MCV4 2005–2006 Small 6 weeks [76]
Smallpox 2002–2004 Expected range 12 days [77]
Hepatitis A 2004 1 case 5 days [78]
Polio 2003 7.27 OR ? [13]
1981–1986 Increase from baseline 10 weeks [12]
Sabine strain 1996 38 cases Sabine strain isolated days–weeks of onset [79]
MMR 1982–1986 Background 80 days–years [80]
Tetanus 90′Extremely rare 6 weeks [81]
Tetanus-diphtheria 1997 1 case 4 days [19]
H influenza type B 1993 1 case (+4) 10 days [20]
Rabies (Semple vaccine) 90′5 cases ? [82]
(Diploid human cells) 1980 1 case 14 days [83]
Vaccination years/country Relative risk Significance Reference
1976/USA 6.2 Yes [84]
1978–1979 USA 1.4 No [85]
1980–1981 USA 1.4 No [86]
1976–1977 USA Attrib. risk 1:100,000 Yes [24]
1992–1994 England/Wales 1.7 No [29,31]
1991–1999 USA 4.3–8.5 Yes [87]
1993–1994 1.7 No [88]
2002–2003 USA 0.4
1992–2004 Canada 1.45 Small [89]
1990–2005/UK 0.76 No [15]
Table 3 Causal correlation
between influenza vaccination
and GBS
Clinic Rev Allerg Immunol (2012) 42:121–130 125

swine flu vaccine contained contaminating moieties (such
as C.jejuni antigens that mimic human gangliosides or
other vaccine components) that elicited an anti-GM1
antibody response in susceptible recipients. Surviving
samples of monovalent and bivalent 1976 vaccine, com-
prising those from 3 manufacturers and 11 lot numbers,
along with several contemporary vaccines were tested for
hemagglutinin (HA) activity, the presence of Campylobac-
ter DNA, and the ability to induce anti-Campylobacter and
anti-GM1 antibodies after inoculation into C3H/HeN mice.
The researchers found that, although C.jejuni was not
detected in 1976 swine flu vaccines, these vaccines induced
anti-GM1 antibodies in mice, as did vaccines from 1991 to
1992 and from 2004 to 2005. Preliminary studies suggest
that the influenza HA induces anti-GM1 antibodies. The
authors concluded that influenza vaccines contain structures
that can induce anti-GM1 antibodies after inoculation into
mice.
Possible Mechanism that can Trigger GBS
Molecular mimicry is one mechanism by which infectious
agents may trigger an immune response against autoan-
tigens. Although several examples of molecular mimicry
between microbial and self-components are known [40], in
most cases, the epidemiological relationship between
autoimmune disease and microbial infection has not been
established. In other cases, moreover, no replicas of human
autoimmune disease have been obtained by immunizing
with the mimic of an infectious agent. Replicas associated
with definite, epidemiological evidence of microbial infec-
tion are required to test the molecular mimicry theory of the
development of autoimmune diseases. Guillain–Barre´
syndrome, the prototype of postinfectious autoimmune
diseases, ranks as the most frequent cause of acute flaccid
paralysis, and C. jejuni is the most frequent antecedent
pathogen. Epidemiological studies, which established the
relationship between GBS and antecedent C. jejuni infec-
tion, showed that one fourth to one third of GBS patients
develop the syndrome after being infected. GBS was
considered a demyelinating disease of the peripheral
nerves, but the existence of primary “axonal GBS”has
been confirmed and is now widely recognized. Ganglioside
GM1 is an autoantigen for IgG Abs in patients with axonal
GBS subsequent to C. jejuni enteritis. C. jejuni strains
isolated from such patients have a lipooligosaccharide
(LOS) with a GM1-like structure. To verify that molecular
mimicry between an environmental agent and the peripheral
nerves causes GBS, Yuki et al. [41] sensitized animals with
C. jejuni LOS and produced a model of human GBS,
generated anti-GM1 mAb by immunization with the LOS,
and determined the distribution of GM1 in human spinal
nerve roots. As further proof that an autoimmune reaction
causes neuromuscular disease, the authors also showed that
anti-GM1 monoclonal antibody (mAb) blocked muscle
action potentials in a muscle–spinal cord co-culture. “On
sensitization with C. jejuni lipooligosaccharide, rabbits
developed anti-GM1 IgG antibody and flaccid limb
weakness. Paralyzed rabbits had pathological changes in
their peripheral nerves identical with those present in
Guillain–Barre´ syndrome. Immunization of mice with the
lipooligosaccharide produced mouse antibodies, from
which mAb were produced, that reacted with GM1 and
bound to human peripheral nerves. The mouse mAb and
anti-GM1 IgG from patients with Guillain–Barre´ syn-
drome did not induce paralysis but blocked muscle action
potentials in a muscle–spinal cord co-culture, indicating
that anti-GM1 antibody can cause muscle weakness”[41].
New tests were developed recently, for better detection
of antiganglioside-specific antibodies and antiganglioside
complexes [42]. The antibody specifically recognizes a
new conformational epitope formed by two gangliosides
(ganglioside complex) in the acute-phase sera of some
GBS patients. In particular, the antibodies against GD1a/
GD1b and/or GD1b/GT1b complexes are associated with
severe GBS requiring artificial ventilation. Some patients
with Miller Fisher syndrome also have antibodies against
ganglioside complexes including GQ1b; such as GQ1b/
GM1 and GQ1b/GD1a. The antibodies against ganglioside
complexes may therefore directly cause nerve conduction
failure and severe disability in GBS.
C.jejuni infection also often precedes acute motor
axonal neuropathy (AMAN), a variant of GBS. Anti-
GM1, anti-GM1b, anti-GD1a, and anti-GalNAc-GD1a
IgG antibodies are associated with AMAN. Carbohydrate
mimicry (Galbeta1–3GalNAcbeta1–4(NeuAcalpha2–3)Gal-
beta1) was seen between the lipooligosaccharide of C.
jejuni isolated from an AMAN patient and human GM1
ganglioside. Sensitization with the lipooligosaccharide of
C.jejuni induces AMAN in rabbits as does sensitization
with GM1 ganglioside. Paralyzed rabbits have pathological
changes in their peripheral nerves identical to changes seen
in human GBS. C.jejuni infection may induce anti-
ganglioside antibodies by molecular mimicry, eliciting
AMAN. This is a verification of the causative mechanism
of molecular mimicry in an autoimmune disease. To
express ganglioside mimics, C.jejuni requires specific gene
combinations that function in sialic acid biosynthesis or
transfer. The knock-out mutants of these landmark genes of
GBS show reduced reactivity with GBS patients' sera, and
fail to induce an anti-ganglioside antibody response in
mice. These genes are crucial for the induction of neuro-
pathogenic cross-reactive antibodies [43].
Koga et al. [44] performed a comprehensive analysis of
bacterial risk factors for the development of GBS after C.
jejuni enteritis. C.jejuni strains carry a sialyltransferase
126 Clinic Rev Allerg Immunol (2012) 42:121–130

gene (cst-II), which is essential for the biosynthesis of
ganglioside-like lipooligosaccharides (LOSs). Strains of C.
jejuni from patients with GBS had LOS biosynthesis locus
class A more frequently (72/106; 68%) than did strains
from patients with enteritis (17/103; 17%). Class A strains
predominantly were serotype HS:19 and had the cstII
(Thr51) genotype; the latter is responsible for biosynthesis
of GM1-like and GD1a-like LOSs. Both anti-GM1 and
anti-GD1a monoclonal antibodies regularly bound to class
A LOSs, whereas no or either antibody bound to other LOS
locus classes. Mass-spectrometric analysis showed that a
class A strain carried GD1a-like LOS as well as GM1-like
LOS. Logistic regression analysis showed that serotype
HS:19 and the class A locus were predictive of the
development of GBS. The high frequency of the class A
locus in GBS-associated strains, which was recently
reported in Europe, provided the first GBS-related C. jejuni
characteristic that is common to strains from Asia and
Europe. The class A locus and serotype HS:19 seem to be
linked to cstII polymorphism, resulting in promotion of
both GM1-like and GD1a-like structure synthesis on LOS
and, consequently, an increase in the risk of producing
antiganglioside autoantibodies and developing GBS. The
sialyltransferase gene polymorphism may also direct the
clinical features of GBS.
The C.jejuni sialyltransferase (cst-II) consists of 291
amino acids, and the 51st determines its enzymatic activity.
Strains with cst-II (Thr51) expressed GM1-like and GD1a-
like LOS, whereas strains with cst-II (Asn51) expressed
GT1a-like and GD1c-like LOS. Patients infected with the
cst-II (Thr51) strains had anti-GM1 or anti-GD1a IgG
antibodies, and showed limb weakness. Patients infected
with the cst-II (Asn51) strains had anti-GQ1b IgG anti-
bodies and showed ophthalmoplegia and ataxia. The cst-II
gene is responsible for the development of Guillain–Barré
and Fisher syndromes, and the polymorphism (Thr/Asn51)
determines which syndrome develops after C.jejuni
enteritis [45].
The Role of the Nodes of Ranvier
Vucic et al. [1] reviewed the role of sodium channels in the
pathology of GBS. Specifically, the rapid improvement in
clinical deficits following immunomodulatory treatment
(such as IVIG) [46], often within hours, cannot be
explained by axonal remyelination, but possibly by removal
of antibodies or other circulating factors that may interfere
with Na
+
channel function. Inactivation of Na
+
channels
results in a conduction block and slowing of conduction
velocity. In GBS patients, Na
+
channel blocking factors
have been demonstrated in the CSF. GM1 gangliosides,
immunological targets in GBS, are localized to the nodes of
Ranvier where sodium and other targets are clustered. By
using binding assay of cholera and tetanus toxins, respec-
tively, it was established [47] that GM1 and G1b-series
gangliosides are predominantly localized to axonal and glial
structures of the nodes of Ranvier and to paranodal/
internodal axolemma, while polysialogangliosides not of
the G1b-series are present on the internodal Schwann cell
surface. Shavit and colleagues [48] have demonstrated also
a conduction block using protease-activated receptor 1
(PAR-1) on the nodes of Ranvier, implicating this structure
and PAR-1 activation in the pathogenesis of conduction
block in inflammatory and thrombotic nerve diseases. An
immune response to this structure may induce conduction
block which is one of the electrophysiological hallmarks of
GBS.
As mentioned above, antecedent infections, particularly
infections with C.jejuni, are associated with production of
IgG antibodies against gangliosides, especially GQ1b.
GQ1b gangliosides are abundantly expressed in the para-
nodal myelin sheets of extraoculomotor nerves, the neuro-
muscular junction, and dorsal root ganglia. Anti-GQ1b IgG
antibodies are strongly associated with Fisher syndrome
and correlate with clinical features of ophthalmoplegia and
ataxia. The neurological effects of anti-GQ1b antibodies are
induced by complement-mediated destruction of both
perisynaptic Schwann cells and axonal terminals, resulting
in neuromuscular junction blockade. Patch clamp techni-
ques have shown that anti-GQ1b antibodies inhibit presyn-
aptic Ca2
+
inflow and interact with proteins of the
exocytotic apparatus, thereby interfering with neurotrans-
mitter release, which prevents activation of postsynaptic
neurons and ultimately results in muscle weakness.
Conclusion
Judging by the evidence presented here, the etiology of
GBS can be multifactorial, as in other autoimmune
diseases. It involves genetic and environmental factors,
may be triggered by infections or vaccinations, and
predisposition can be predicted by analyzing some of these
factors. Shoenfeld et al., in a series of three enlightening
reviews, depict the Mosaic of Autoimmunity. The authors
present the multifactorial character of autoimmune diseases,
including GBS, and concentrate on genetic factors, hor-
monal and environmental ones, and focus also on predic-
tion and therapy of these disorders [49–51]. GBS is unique
in the aspect that it can be triggered both by infection (C.
jejuni) or vaccination (influenza, polio), and in this respect,
it can serve as a model for the linkage between exposure to
environmental agents and autoimmune diseases. Many
other autoimmune diseases may be triggered by infections
and/or vaccinations, the pathologic mechanism may involve
molecular mimicry, and they can be treated by IVIG [52–
Clinic Rev Allerg Immunol (2012) 42:121–130 127

71]. However, GBS is still a classical example of an
autoimmune disease triggered by either infection or
vaccination.
The Global Advisory Committee on Vaccine safety
considers that investigation of a possible causal relationship
could best be achieved by large-scale studies of the
incidence of GBS before and after an immunization
program. All incident cases would need to be carefully
ascertained and documented to ensure as accurate a
diagnosis as possible and to identify the form of GBS
(principally AIDP or AMAN). Improved understanding of
the pathogenesis of all forms of GBS will assist the
investigation of possible associations between GBS and
immunization. In this context, the collection of serum
samples from incident cases of GBS would contribute to
the identification of the different forms of the disease and of
understanding their possible relationship with vaccines.
Such studies would be particularly helpful in investigating
neurological adverse events following immunization that
occur in association with pandemic or prepandemic
influenza vaccines [72]. On August 31, 2009, the Centers
for Disease Control and Prevention (CDC) and the
American Academy of Neurology (AAN) started a cam-
paign, requesting neurologists to report any possible new
cases of Guillain–Barré syndrome (GBS) following 2009
H1N1 flu vaccination using the CDC and U. S. Food and
Drug Administration Vaccine Adverse Event Reporting
System. Although they do not anticipate that the 2009
H1N1 vaccine will have an increased risk of GBS, out of an
abundance of caution, and given that GBS may be of
greater concern with any pandemic vaccine because of the
association of GBS with the 1976 swine flu vaccine, the
CDC and AAN asked neurologists to report any potential
new cases of GBS after-vaccination as part of the CDC's
national vaccine safety monitoring campaign (http://www.
aan.com/press/?fuseaction=release.view&release=757).
This campaign is now in progress.
Competing interests Y. Shoenfeld declares an association with the
following organizations: the US National Vaccine Injury Compensa-
tion Program. The other authors declare no competing interests.
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