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Molecular Mimicry between Gangliosides and Lipopolysaccharides ofCampylobacter jejuni Isolated from Patients with Guillain-Barre Syndrome andMiller Fisher Syndrome

Nobuhiro Yuki Department of Neurology, Dokkyo University School of Medicine,Tochigi, Japan

Some patients developed Guillain-Barre syndrome (GBS) after being given bovine gangliosides.Patients with GBS subsequent to Campylobacter jejuni enteritis frequently have IgG antibody toGM1 ganglioside. Miller Fisher syndrome (MFS), a variant of GBS, is associated with IgG antibodyto GQ1b ganglioside. The existence of molecular mimicry between GM1 and lipopolysaccharide ofC. jejuni isolated from a GBS patient and that between GQ1b and C. jejuni lipopolysaccharidesfrom patients with MFS are shown herein. The molecular mimicry between infectious agents andgangliosides may function in the production of anti-ganglioside antibodies and the development ofGBS and MFS.

Guillain-Barre syndrome (GBS) is the most common cause that 2 patients with GBS following C. jejuni infection had highIgG anti-GM1 antibody titers in the acute phase of the illness.of acute neuromuscular paralysis in persons in developed coun-

tries. Two-thirds of GBS patients develop the syndrome follow- No anti-GM1 antibody was detected in patients who hadC. jejuni enteritis that was not followed by GBS. The associa-ing various infections. Infection due to gram-negative bacte-

rium Campylobacter jejuni, a leading cause of acute diarrheal tion of IgG anti-GM1 antibody with GBS subsequent toC. jejuni enteritis was established by others [6–8].illness, commonly precedes the development of GBS. The hy-

pothesis that anti-neural antibodies may function in the devel-opment of GBS is supported by the observation that plasma

Molecular Mimicry between GM1 and C. jejuniexchange elicits a beneficial response. The dependence of GBSLipopolysaccharide (LPS)on molecular mimicry between infectious agents and surface

components of peripheral nerves has been postulated. Herein, Ganglioside extracted from bovine brain tissue was pre-a possible mechanism of the autoantibody production after in- viously widely given to persons throughout Western Europefection by C. jejuni is described. and South America for several neurologic disorders. Since my

colleagues and I first reported on amyotrophic lateral sclerosis–like disorder following ganglioside therapy [9], there have beenPure Motor GBS and IgG Anti-GM1 Antibodyan increasing number of reports of patients who developed

Gangliosides are highly expressed in nervous tissues and GBS after receiving bovine brain gangliosides [10, 11]. Thisare considered as cell surface molecules implicated in various development suggests an antecedent infectious agent with abiologic cellular functions. There have been several reports of ganglioside-like structure as a cause of GBS. By the Pennermotor neuron disease and multifocal motor neuropathy associ- serotyping method, C. jejuni seems to be typed according toated with IgM antibody to GM1 ganglioside [1, 2]. Ilyas et al. the difference in the LPS. Kuroki et al. [12] and my colleagues[3] and Inuzuka et al. [4] reported that several GBS patients and I [13] showed that a specific Penner’s serotype (PEN),who showed sensory dysfunction had autoantibodies to gangli- PEN 19 was frequently isolated from GBS patients. Thus, theosides, except for GM1 ganglioside. current study included an investigation of whether GM1 epitope

GBS patients often have sensory impairment; however, pa- is present in the LPS from PEN 19 C. jejuni.tients with GBS subsequent to C. jejuni enteritis show no or LPS was extracted from PEN 19 C. jejuni that had beenminimal sensory disturbance. My colleagues and I [5] reported isolated from a GBS patient by use of the hot phenol-water

technique. Thin-layer chromatography with immunostainingshowed that cholera toxin, which specifically recognizes theGM1-oligosaccharide, reacted with the LPS fraction [14], indi-Presented: Workshop on the Development of Guillain-Barre Syndrome fol-

lowing Campylobacter Infection, National Institute of Allergy and Infectious cating that the LPS has the GM1 epitope. The LPS showingDisease, National Institutes of Health, Bethesda, Maryland, 26–27 August the binding activity of the cholera toxin was purified by silica-1996.

bead column chromatography. Gas-liquid chromatography–Reprints or correspondence: Dr. Nobuhiro Yuki, Dept. of Neurology, Dok-kyo University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, mass spectrometric analysis showed that the purified LPS con-Tochigi 321-02, Japan. tained galactose and N-acetylgalactosamine (GalNAc) and N-The Journal of Infectious Diseases 1997;176(Suppl 2):S150–3 acetylneuraminic acid (NeuAc), which are sugar componentsq 1997 by The University of Chicago. All rights reserved.0022–1899/97/76S2-0013$02.00 of GM1 ganglioside. 1H nuclear magnetic resonance methods

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36 C. jejuni have GM2-like structures. They concluded thatthese differences in sugar sequences and linkage types aresufficient to account for the serologic differences. In contrast,my colleagues and I [17] showed that monoclonal anti-GM1

and anti-GD1a antibodies reacted with PENs 1, 4, and 19 C.jejuni LPSs. We therefore proposed that Penner’s serotypingsystem is not dependent on differences in the ganglioside-likeoligosaccharide structures of the LPS. Aspinall et al. [18]reached the same conclusion when they noted that the LPSsof PEN 4 and 19 have the same ganglioside-like structures andthat there is structural variability among the low-molecular-weight LPSs from 3 PEN 19 strains.

Association of PEN 19 C. jejuni with IgG Anti-GM1

AntibodyFigure 1. Molecular mimicry between GM1 ganglioside and C. je-juni LPS. Terminal tetrasaccharide occupies nonreducing end of GM1 Kuroki et al. [19] reported that 10 (83%) of 12 isolates fromand LPS. Cer, ceramide; h, galactose; hatched symbol, N-acetylgalac- GBS patients were PEN 19, while this serotype accounts fortosamine; j, glucose; ., N-acetylneuraminic acid. õ2% of C. jejuni strains in Japan. The association of PEN 19

with GBS, however, is controversial [19, 20]. Therefore, mycolleagues and I [21] serotyped C. jejuni isolates from GBSrevealed that the oligosaccharide structure (Gal b1-3 GalNAcand enteritis patients: PEN 19 was more frequently isolatedb1-4 [NeuAc a2-3] Gal b) protruded from the LPS core. Myfrom the GBS patients (16/31 isolates, 52%) than from thecolleagues and I [15] showed that this terminal structure (Galenteritis patients (11/215 isolates, 5%). Next, we investigatedb1-3 GalNAc b1-4 [NeuAc a2-3] Gal b) is identical to thewhether PEN 19 C. jejuni is associated with IgG anti-GM1terminal tetrasaccharide of the GM1 ganglioside (figure 1), andantibody. The frequency of IgG anti-GM1 antibody titers§500the study was the first to demonstrate the existence of molecularamong GBS patients with PEN 19 C. jejuni was significantlymimicry between nerve tissue and the infectious agent isolatedhigher (12/14, 86%) than that among GBS and Miller Fisherfrom a GBS patient.syndrome (MFS) patients with non–PEN 19 C. jejuni (9/20,45%).

Penner’s Serotyping System Is Not Dependent onAspinall et al. [22] reported that a hyaluronic acid–like re-

Ganglioside-Like LPSpeat unit of LPS is an antigenic determinant of PEN 19. Glycos-aminoglycans, including hyaluronic acid, may play an im-Aspinall et al. [16] reported that LPS from PEN 4 C. jejuni

has a GD1a-like structure and that LPSs from PENs 1, 23, and portant role in the development of autoimmune diseases [23].

Figure 2. Pathogenesis of GBS associated with IgGanti-GM1 antibody subsequent to C. jejuni enteritis.Left, infection by C. jejuni bearing GM1-like LPSassociated with antigenic determinant of Penner’s(PEN) serotype 19 induces high production of IgGanti-GM1 antibodies with help of T helper cells (Th).B Å B cells. Right, IgG anti-GM1 antibodies bindto motor nerve terminal axons, inhibit motoneuronexcitability, and produce muscular weakness.

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Figure 3. Pathogenesis of Miller Fisher (Fisher)syndrome associated with IgG anti-GQ1b antibodysubsequent to C. jejuni enteritis. Left, infection by C.jejuni bearing GQ1b-like LPS associated with anti-genic determinant of Penner’s (PEN) serotype 2 in-duce high production of IgG anti-GQ1b antibodies withhelp of T cells (Th). B Å B cells. Right, IgG anti-GQ1b antibodies bind to oculomotor (III), trochlear(IV), and abducens (V) nerves and to deep cerebellarnuclei, causing external ophthalmoplegia and cerebel-lar ataxia.

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