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May 10, 2005; 64 (9) Articles

Antecedent infections in Fisher syndrome

A common pathogenesis of molecular mimicry

M. Koga, M. Gilbert, J. Li, S. Koike, M. Takahashi, K. Furukawa, K. Hirata, N. Yuki
First published May 9, 2005, DOI: https://doi.org/10.1212/01.WNL.0000160399.08456.7C
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Abstract

Objective: To assess the production mechanism of anti-GQ1b autoantibody in Fisher syndrome (FS).

Methods: The authors conducted a prospective case-control serologic study of five antecedent infections (Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae) in 73 patients with FS and 73 sex- and age-matched hospital controls (HCs). Serologic evidence in FS patients of C. jejuni (21%) and H. influenzae (8%) infections was present significantly more often than in the HCs. None of the five pathogens examined was found in the 49 (67%) patients with FS. Anti-GQ1b IgG antibody was detected in most FS patients infected with C. jejuni or H. influenzae. Mass spectrometry analysis identified a C. jejuni strain (CF93-6) carrying a GT1a-like lipo-oligosaccharide (LOS) that had been isolated from an FS patient. Immunization of complex ganglioside-lacking knockout mice with the GT1a-like LOS generated IgG class monoclonal antibodies (mAbs) that reacted with GQ1b and GT1a. Thin-layer chromatography with immunostaining showed that anti-GQ1b mAb bound to the C. jejuni LOS (50% of the 20 FS-related strains) more commonly than in the Guillain–Barré syndrome (GBS)–related (7% of 70) or enteritis-related (20% of 65) strains. Anti-GM1 and anti-GD1a mAbs also reacted with the LOS from some FS-related strains (both 20%), but binding frequencies were higher in the GBS-related strains (74 and 57%). The GQ1b epitope was detected in 4 (40%) of the 10 FS-related H. influenzae strains but was absent in strains from patients with GBS (n = 4) and uncomplicated respiratory infections (n = 10).

Conclusions: C. jejuni and H. influenzae are related to Fisher syndrome (FS) development, and production of anti-GQ1b autoantibody is mediated by the GQ1b-mimicking lipo-oligosaccharides on those bacteria. The causative agents remain unclear in the majority of patients with FS.

Fisher syndrome (FS) is characterized by the acute onset of ophthalmoplegia, ataxia, and areflexia.1 Its pathogenesis has been actively investigated,2 and most patients with FS are found to have serum anti-GQ1b IgG autoantibodies during the acute phase of the illness that are cross-reactive with GT1a.3–6 FS occurs subsequent to a wide variety of infections, most of which have been described in case reports, but there has been no case-control study of the antecedent infections. Previously, we reported positive serology for recent Campylobacter jejuni infection of 18% of 65 FS patients,7 but no other Guillain–Barré syndrome (GBS)–related agent in FS has been investigated in a large number of patients. We also reported that in 7% of 70 FS retrospective cases, there was serologic evidence of recent Haemophilus influenzae infection.8 A case-control study is needed to confirm its association with FS because the incidence of this infection is relatively rare.

C. jejuni strains isolated from FS patients had lipo-oligosaccharides (LOSs) that bore a terminal trisaccharide epitope mimicking GQ1b, GT1a, or GD3.9–11 Immunization of mice with GT1a- or GD3-like LOS produced a monoclonal antibody (mAb) reactive against GQ1b and GT1a.12 This raised the possibility that anti-GQ1b IgG antibody production is mediated by the trisaccharide epitope on bacterial LOSs. To verify this, it is necessary to prove that in a large number of isolates, FS is related to C. jejuni strains bearing a GQ1b-, GT1a-, or GD3-like LOS. We also reported that an H. influenzae type b serostrain had a GT1a-like LOS and hypothesized that ganglioside mimicry is involved in the development of FS after H. influenzae infection as well,8 but whether such epitope is present in FS-related strains has yet to be determined.

We conducted a prospective case-control study of antecedent infectious serology in FS and then chemically determined the terminal oligosaccharide structure of the LOS on isolates obtained from an FS patient. By immunizing complex ganglioside-lacking knockout mice with the bacterial LOS carrying a GT1a epitope, we could clone mAb with reactivities against GQ1b and GT1a for use in examining whether the GQ1b-like LOS on the isolate is associated with FS.

Methods.

Patients.

We receive many requests from physicians throughout Japan to test for serum antiganglioside antibodies in patients with various neurologic disorders. On receipt of serum samples from FS patients, we have requested the primary physicians to send hospital control (HC) serum from sex- and age-matched (±5 years) patients without an autoimmune disease who did not have a history of recent enteritis but were in hospital at that time. If no patients fulfilled these criteria, we accepted as HCs sex- and age-matched (±5 years) healthy persons working at the hospital. We also collected sera from family members if possible. Between February 2000 and November 2003, we received 367 serum samples from FS patients, of which 73 paired samples from FS patients (men/women, 45/28; median age 32) and HC subjects (45/28; age 33) were available. Twenty control (8/12; age 49) samples from 18 families also were available. During the same period, we received 1,814 serum samples from patients with GBS, of which 73 (men/women, 45/28; median age 49) were selected randomly to be the disease controls. FS and GBS diagnoses were based on published clinical criteria.13,14 Diagnosis of FS also was made for patients who initially presented with ophthalmoplegia, ataxia, and areflexia and then developed generalized muscle weakness. Although most had not been our patients, we collected their cases prospectively and asked the physicians whether diagnostic criteria had been fulfilled. One of the authors reviewed the medical records to verify the diagnoses.

Infectious serology.

Recent C. jejuni infection was detected by an ELISA, as reported previously,7 with altered criteria for seropositivity to increase its sensitivity and specificity (see appendix E-1 on the Neurology Web site at www.neurology.org). Under this condition, 43 of 47 GBS patients from whom C. jejuni had been isolated were judged positive within 4 weeks of GBS onset, whereas only 2 of 73 HC subjects with no history of recent enteritis were. Our assay therefore had a sensitivity of 91%, a specificity of 97%, and an efficiency of 95%. Evidence of recent H. influenzae infection was assayed serologically as reported elsewhere.8 Infections by cytomegalovirus (CMV), Epstein–Barr virus (EBV), and Mycoplasma pneumoniae were also tested because a case-control study showed that they are related to the GBS development.15 Serum IgM anti-CMV antibody and IgM anti-EBV capsid antigen antibody were tested using commercially available ELISA kits, Cytomegalo IgM(II)-EIA “SEIKEN” (Denka Seiken, Tokyo, Japan), and ETI-EBV-M reverse (DiaSorin, Stillwater, MN), according to the manufacturers’ instructions. Serum anti-M. pneumoniae antibody was detected by the particle agglutination test (Serodia-Mycon II test kit; Fujirebio, Tokyo, Japan) after heating sera to 56 °C to inactivate complement.

Antiganglioside antibodies.

We measured serum anti-GQ1b IgG/IgM/IgA and IgG antibodies against GT1a, GM1, and GD1a by ELISAs as described elsewhere.7,16 Serum was considered positive when the optical density was ≥0.1 at a dilution of 1:500 for the IgG and 1:100 for the IgM and IgA antibodies. The IgG subclasses of anti-GQ1b antibody were examined in an ELISA with peroxidase-conjugated mouse anti-human γ1-, γ2-, γ3-, and γ4-chain-specific mAbs (Southern Biotechnology Associates, Birmingham, AL) as the secondary antibodies, as reported elsewhere.17

Analysis of O-deacylated LOSs.

A C. jejuni strain, CF93-6, isolated from a patient with FS,10 was used. Overnight growth of the strain on an agar plate was done as described previously,18 except that we used 60 μg/mL proteinase K, 200 μg/mL RNAse A, and 100 μg/mL DNAse I. The O-deacylated LOS sample was analyzed by capillary electrophoresis–electrospray ionization–mass spectrometry (CE-ESI-MS), as described elsewhere.19

Generation of anti-GQ1b mAbs.

Mice lacking the functional gene for β-1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase; EC 2.4.1.92) were raised and their genotypes determined as described elsewhere.20 They expressed no complex gangliosides, including neither GQ1b nor GT1a and therefore are an immune naive host and show strong IgG response to ganglioside-like LOS, whereas wild mice do not.21 LOS was extracted from two C. jejuni strains (CF93-6 and CF90-26 [a GM1 epitope-bearing isolate from a GBS patient]22) by the hot phenol-water technique,23 after which the aqueous layer was dialyzed and centrifuged at 105,000 g for 16 hours. The mice were immunized intraperitoneally four times at 2-week intervals with 100 μg of LOS or 10 mg of a heat-killed lysate of C. jejuni dissolved in 50 μL of 2 mg/mL keyhole lympet hemocyanin solution (Sigma, St Louis, MO) that had been mixed with 50 μL of complete Freund adjuvant. Three days after final immunization with 50 μg of LOS in 50 μL of phosphate-buffered saline, mAbs were obtained as described elsewhere.24 This research was approved by the Animal Care and Use Committee, Dokkyo University School of Medicine (approval no. 00-22). Mice were treated according to the Guidelines for the Care and Use of Laboratory Animals, Dokkyo University School of Medicine.

Detection of ganglioside-like LOSs.

The presence of the GQ1b epitope was examined in C. jejuni and H. influenzae strains isolated from patients with FS (20 C. jejuni and 10 H. influenzae), GBS (70 C. jejuni and 4 H. influenzae), uncomplicated enteritis (65 C. jejuni), or a respiratory infection (10 H. influenzae). Anti-GQ1b IgG antibody was positive in patients from whom C. jejuni (FS, 18/20 [90%]; GBS, 3/70[4%]) or H. influenzae (FS, 10/10 [100%]; GBS, 0/4 [0%]) had been isolated. All the H. influenzae strains used were nontypable. Most of FS/GBS-related C. jejuni strains were isolated by one of the authors,25 and all H. influenzae strains were obtained from hospitals throughout Japan. Ganglioside epitopes (GQ1b, GM1, and GD1a) were examined by thin-layer chromatography with immunostaining (C. jejuni) and ELISA (H. influenzae), as shown in appendix E-2.

Statistical analysis.

Differences in the infectious serology frequencies of FS and HC were tested with the McNemar test, and frequency differences between groups were compared by the Fisher exact test. Differences in medians were examined by the Mann–Whitney U test. All calculations were done with SPSS 12.0J software (SPSS, Chicago, IL). A difference was considered significant when the two-sided p value was <0.05.

Results.

Infectious serology.

Recent infectious agents were identified in 24 (33%) of the patients with FS, serologic evidence of recent C. jejuni (21%) and H. influenzae (8%) infections being more common than in the HCs, whereas frequencies of the other agents did not differ (table 1). As compared with the patients with GBS, the frequency of antecedent C. jejuni infection was lower and that of H. influenzae infection higher in patients with FS, but the differences were not significant. One family member, the 80-year-old husband of a C. jejuni-negative patient with FS, who had no history of recent infectious symptoms, was seropositive for C. jejuni. No family members were positive for H. influenzae. Positive serology for CMV infection was found for 3 of 20 family members, of whom 2 (mother and daughter) had coughs and nasal discharges at the time of sampling. Positive serology for more than one infection was found for only three (4%) of the FS patients: C. jejuni and H. influenzae, C. jejuni and CMV, and C. jejuni and EBV.

View this table:

Table 1 Infectious serology

C. jejuni-related FS.

Men predominated in the FS patients with C. jejuni infection (men/women, 11/4) as in patients without this infection (34/24). Teenagers and young adults (age <30) were proportionally higher in patients with C. jejuni-related FS (53%) than in the other patient groups (24%) (p = 0.06), but the median age did not differ significantly (28 vs 37 years old; p = 0.19). Patients with C. jejuni infection more often had a history of antecedent gastrointestinal symptoms (60 vs 35%; p = 0.03). The neurologic features of facial palsy (27%), bulbar palsy (27%), limb weakness (13%), sensory disturbance (33%), and autonomic disturbance (7%) did not differ markedly among the groups. Anti-GQ1b and anti-GT1a IgG antibodies were present in all the patients with C. jejuni infection, more frequently than in the other patients (p = 0.06 and 0.02), and anti-GM1 and anti-GD1a IgG antibodies also were detected more often (p = 0.01 and 0.11) (figure 1). The anti-GQ1b antibody IgG subclass distribution was similar to that for patients without this infection (table 2). IgA and IgM anti-GQ1b antibodies were more frequent in patients with C. jejuni infection (80 and 73%) than in those without it (55 and 51%), but the differences did not reach significance (p = 0.14 and 0.16).

Figure1

Figure 1. Frequency of positive antiganglioside IgG antibody in patients with Fisher syndrome. Black columns = Fisher syndrome after Campylobacter jejuni infection (n = 15); hatched columns = Fisher syndrome after Haemophilus influenzae infection (n = 6); white columns = Fisher syndrome without identified agents (n = 49).

View this table:

Table 2 IgG subclass classification of anti-GQ1b antibodies in patients with Fisher syndrome

H. influenzae-related FS.

The median age of the six patients with H. influenzae-related FS was 54 years (range 14 to 86 years), and four were women. Upper respiratory tract infection preceded FS onset in four (67%) and gastrointestinal symptoms in one (17%). Bulbar palsy tended to be more frequent in patients with H. influenzae infection (50%) than in those without it (18%) (p = 0.10), but the other neurologic features such as facial palsy (33%), limb weakness (17%), sensory disturbance (50%), and autonomic disturbance (0%) did not differ markedly. Five (83%) patients had anti-GQ1b and anti-GT1a IgG antibodies, but none had the anti-GM1 IgG antibody (see figure 1). The anti-GQ1b antibody IgG subclass distribution was similar to that found for the other patients (see table 2). A higher percentage of patients with H. influenzae infection had the IgM class of anti-GQ1b antibody (83 vs 54%; p = 0.22), but IgA antibody frequency did not differ between the two groups (67 vs 60%; p = 1.0).

FS with no identified infection.

None of the five infections examined was found in 49 of the FS patients. Their median age was 35 years (range 4 to 81 years), and 30 were men. An antecedent upper respiratory tract infection was more frequent in this (88%) than the other (63%) group (p = 0.03), whereas gastrointestinal symptom frequency did not differ (29 vs 42%; p = 0.30). The neurologic features of facial palsy (16%), bulbar palsy (18%), limb weakness (16%), sensory disturbance (49%), and autonomic disturbance (8%) did not differ markedly between the groups. Antiganglioside IgG antibodies were less common in patients without identified infectious agents than in those with them (anti-GQ1b, p = 0.12; anti-GT1a, p = 0.04; anti-GM1, p = 0.19; anti-GD1a, p = 0.19) (see figure 1). The anti-GQ1b antibody IgG subclass distribution was similar to that found for the other FS patients (see table 2). Patients in this group less commonly had IgA (53 vs 75%; p = 0.08) and IgM (49 vs 71%; p = 0.09), and anti-GQ1b antibodies were less common than in patients with identified infections.

LOS structures of C. jejuni CF93-6.

Because an LOS sample from C. jejuni CF93-6 was used to immunize mice to obtain mAbs against specific gangliosides (see Methods and Results), we performed various analyses to better define the ganglioside mimics present in the outer cores of that sample. CE-ESI-MS analysis of the O-deacylated LOS sample from C. jejuni CF93-6 yielded various masses, in which the major species was [M-4H]4− = (3,937 Da). Other variants, shown in table E-1, are due to lipid A variations as well as to the presence or absence of the terminal sialic acid. The presence of one terminal sialic acid produces a GD1a mimic, whereas the presence of two yields a GT1a mimic (figure 2). The presence of two sialic acids as a chain (diNeu5Ac) in some of the variants was confirmed by CE-MS-MS and looking for the precursor ion at 581 Da (data not shown).

Figure2

Figure 2. Proposed lipo-oligosaccharide (LOS) outer core structures based on capillary electrophoresis–electrospray ionization–mass spectrometry analysis of an O-deacylated LOS sample from Campylobacter jejuni CF93-6. Gal = galactose; NeuAc = N-acetylneuraminic acid; GalNAc = N-acetylgalactosamine; Hep = L-glycero-d-manno-heptose; Kdo = 3-deoxy-d-manno-2-octulosonic acid; PEA = phosphoethanolamine; Glc = glucose.

mAb characteristics.

A clone (FS1) with anti-GQ1b IgG activity (IgG2bκ) was obtained from a mouse inoculated with C. jejuni (CF93-6) LOS, and two clones (FS2 and FS3, IgG2bκ) were obtained from mice inoculated with the C. jejuni heat-killed lysate. An ELISA showed that FS1 reacted with GD3 as well as with GQ1b and GT1a and that FS2 and FS3 specifically reacted with GQ1b and GT1a (table 3). Two clones were obtained from a mouse inoculated with C. jejuni (CF90-26) LOS. One (GB2), as reported elsewhere,24 reacted strongly with GM1 and weakly with GD1a. The other (GB1) reacted strongly with GD1a but did not react with GM1.

View this table:

Table 3 Reactivity of monoclonal antibodies

Ganglioside-like LOS.

FS1 was used to detect the GQ1b epitope on C. jejuni LOS because FS2 and FS3 had not been cloned at that time. Although we used two reagents (mAb and the patient’s serum) in the detection of the ganglioside epitope, overall results were the same, except for some differences that probably were due to reagent sensitivities (table 4). The GQ1b epitope was more frequent in the FS-related C. jejuni strains than the GBS- and enteritis-related strains. In contrast, GM1 and GD1a epitope frequencies did not differ between the FS and enteritis strains. GBS-related strains more often had GM1- and GD1a-like LOSs than did the FS and enteritis ones.

View this table:

Table 4 Frequency of ganglioside epitopes on C. jejuni lipo-oligosaccharide

Ganglioside epitopes on the H. influenzae LOS were examined quantitatively in an ELISA with FS3, GB2, and GB1 mAbs. The cut-off value for the presence of a ganglioside epitope was defined as an optical density of 0.1 based on results found for strains from patients with uncomplicated upper respiratory tract infections. Four (40%) of the 10 FS strains had a GQ1b-like LOS, whereas none of the GBS and uncomplicated strains did (figure 3). Of the four strains bearing a GQ1b epitope, three had neither the GM1 nor the GD1a epitope and one had the GM1 epitope. GM1 reactivities were present in the three (30%) FS-related strains, one of which also had GD1a reactivity. Unexpectedly, none of the four GBS-related strains was judged to have GM1 and GD1a epitopes.

Figure3

Figure 3. Ganglioside epitopes on the Haemophilus influenzae lipo-oligosaccharide. Plots of individual antibody activities against ganglioside-like lipo-oligosaccharides on Haemophilus influenzae strains isolated from patients with Fisher syndrome (FS; n = 10), Guillain–Barré syndrome (GBS; n = 4), and uncomplicated upper respiratory tract infections (URTI; n = 10). Anti-GQ1b (FS3) (A), anti-GM1 (GB2) (B), and anti-GD1a (GB1) (C) were the monoclonal antibodies (mAbs).

Discussion.

Our study showed that C. jejuni and H. influenzae are causal agents of FS. No antecedent pathogens were identified in 67% of the FS patients studied, and no difference in the frequencies of CMV, EBV, and M. pneumoniae infections was found between FS and HC, whereas all were associated with GBS.15 Although we changed the definition of serologic evidence of antecedent C. jejuni infection, its frequency in FS was similar to that reported earlier (18%).7 It is noteworthy that most of the FS patients without identified infections had histories of antecedent upper respiratory infectious symptoms, indicative that respiratory infectious pathogens should be investigated as causal agents of FS. However, our results might merely reflect the low sensitivity of the infectious serology assays used. In spite of numerous infections reported as preceding FS onset,26 there are only a few clues as to the major antecedent agents. β-Hemolytic streptococcal infection is an attractive candidate27 because it may be followed by acute rheumatic fever and acute glomerulonephritis.28 One serologic study, however, has reported that this antecedent infection is not common in FS.29

We showed that FS-related C. jejuni strains had a GQ1b/GT1a-like LOS more often than GBS- and enteritis-related ones, confirmation of the results of a small study showing that all four FS-related C. jejuni strains had a GQ1b-like LOS.30 Moreover, for the first time, we determined that anti-GQ1b/GT1a mAb binds to LOSs from some FS-related H. influenzae strains. These findings indicate a common pathogenesis of molecular mimicry in the development of C. jejuni and H. influenzae-related FS. The IgG subclass of anti-GQ1b antibody was almost always IgG1, IgG3, or both, as reported elsewhere,31 IgG1 predominating irrespective of the antecedent infection identified. IgG2 was reported to be the main subclass of anti-GQ1b antibody in FS patients with an antecedent gastrointestinal infection (C. jejuni had been isolated from three of five patients),32 whereas other investigators reported IgG1 and IgG3 in an FS patient from whom C. jejuni had been isolated.33 Our and the other findings32 apparently conflict. The reason is not clear. Our results agree with those of other studies as to the frequent presence of anti-GM1 IgG1 antibody in GBS cases in which there was C. jejuni serology.17,33,34 We therefore believe that the IgG2 subclass of anti-GQ1b antibody is not associated with FS that develops subsequent to C. jejuni infection. Because the IgG subclass of antibody response is related closely to the types of antigens targeted and to T-cell dependency,35 the similar IgG subclassifications of the anti-GQ1b antibody present in FS after C. jejuni, H. influenzae, or unidentified infections suggest that the mechanism of autoantibody production, probably mediated by ganglioside-like molecules on the infectious agent, is common in FS populations other than C. jejuni- and H. influenzae-related ones.

Ganglioside epitopes were not detected in some C. jejuni strains isolated from FS patients, but this does not indicate that other mechanisms than the molecular mimicry principle are applied to the antiganglioside antibody production in these patients. Ganglioside-like structure on C. jejuni LOS would disappear during repeated culture owing to the phase variation in homopolymeric G tract in LOS biosynthesis genes.36 Another possibility is that FS patients were infected by several C. jejuni strains and the “causative” strain bearing ganglioside-like LOS had not been occasionally isolated. The presence of a GM1-mimicking epitope on the C. jejuni LOS9,22,37 and the development of acute motor axonal neuropathy with anti-GM1 antibody after inoculation of rabbits with the GM1-like LOS24 strongly suggest that anti-GM1 IgG antibody production is mediated by GM1 mimicry of C. jejuni LOS. To show that the principle of molecular mimicry provides a common pathogenesis of FS and GBS, it is necessary to establish the FS animal model by immunizing GQ1b-bearing LOSs of C. jejuni and H. influenzae.

Our serologic findings and the detection of GQ1b-like LOS in FS-related H. influenzae strains provide strong support for a relationship between FS and H. influenzae. This bacterium is classified as having capsulated (serotypes a to f) and uncapsulated (nontypable) strains. We determined the serotypes of the FS- and GBS-related H. influenzae strains and found all were nontypable. We cannot say that all the isolates were related to the development of FS and GBS because this bacterium is a major pathogen of respiratory infection, and patients with FS or GBS sometimes contract pneumonia after neuropathic onset, possibly owing to bulbar palsy. Our results, however, do indicate that uncapsulated strains are important in the development of H. influenzae-related FS and GBS, but whether H. influenzae is a major causative agent of GBS has still to be determined.8,15,38,39 In our study, there was serologic evidence of this infection in only 3% of the GBS patients, a frequency similar to findings of previous studies.8,15,39 Because all the studies, including the current one, used only serologic methods to test for antecedent H. influenzae infection, the seropositive frequency may have been underestimated owing to the low sensitivity of the assay.8 A standardized, highly sensitive serologic method and a culture survey are needed to establish the frequency of H. influenzae-related GBS.

The LOSs of C. jejuni and H. influenzae vary considerably in the oligosaccharide structures on their outer cores, and previous studies showed that both bacteria commonly have sialylated LOSs.40 Because ganglioside classification is based on the sialylation type, sialylation of a bacterial LOS may be the key to the development of FS and GBS after C. jejuni or H. influenzae infection. Three genes (cst-I, -II, and -III) in C. jejuni41,42 and three genes (lic3A, siaA, lsgB) in H. influenzae43,44 have been cloned for the sialylation enzyme. Whether the presence of the cst-II gene is a risk factor for developing GBS/FS after C. jejuni enteritis is not clear,45,46 but it seems to be essential for the biosynthesis of a GQ1b-like LOS and therefore is closely related to the anti-GQ1b antibody in FS.45 Variation in the LOS outer core could, however, be created not only by diverse gene contents.36,47 We sequenced the genes that encode the glycosyltransferases involved in synthesis of the outer core of the LOS in C. jejuni CF93-6 (GenBank accession no. AY644679). The DNA sequence is 99% identical (6,041 of 6,047 bp) to the corresponding region in C. jejuni OH4384 (GenBank accession no. AF130984), which had been isolated from a patient with GBS who showed ophthalmoplegia9,48 and expresses GT1a-like LOS similar to that of CF93-6.9 The amino acid sequences of these glycosyltransferases involved in the addition of the N-acetylgalactosamine residue (CgtA), terminal galactose residue (CgtB), and sialic acid residues (Cst-II) are 100% identical for C. jejuni CF93-6 and OH4384. This suggests that gene alleles also are critical for the biosynthesis of variable ganglioside mimics. To determine the critical factor in the development and characterization of FS after C. jejuni or H. influenzae infection, the presence and polymorphism of sialyltransferase-encoding genes need to be investigated.

Acknowledgment

The authors thank Denis Brochu, Scott Houliston, Frank St. Michael, and Evgeny Vinogradov for the lipo-oligosaccharide analyses, Marie-France Karwaski and Sonia Leclerc for help with the DNA sequencing, and Maki Okazaki for support with serologic assays.

Footnotes

  • Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the May 10 issue to find the title link for this article.

    Supported in part by grants-in-aid from the Ichiro Kanehara Foundation, the Kanae Foundation for Life and Socio-Medical Science, and the Japan Intractable Diseases Research Foundation; by a grant for Scientific Research (B) (KAKENHI 14370210 to N.Y.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a Research Grant for Neuroimmunological Diseases from the Ministry of Health, Labour, and Welfare of Japan; a Health Sciences Research Grant (Research on Psychiatric and Neurological Diseases and Mental Health) from the Ministry of Health, Labour, and Welfare of Japan; and a grant from the Human Frontier Science Program (RGP0038/2003-C).

    Received October 26, 2004. Accepted January 12, 2005.

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