g(m1)-ganglioside and Cytomegalovirus-Infections

Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain-Barré syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4-66%), cytomegalovirus (5-15%), Epstein-Barr virus (2-10%), and Mycoplasma pneumoniae (1-5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C. jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14-50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside-like epitopes exist in the bacterial wall of C. jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner 0:19 and 0:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of GBS to the fine specificity of anti-ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, P2, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up-regulate matrix metalloproteinases, cross the blood-nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is diffi

Topics: Animals; Campylobacter jejuni; Cytomegalovirus Infections; Demyelinating Diseases; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Mice; Miller Fisher Syndrome; Neuritis, Autoimmune, Experimental; Refsum Disease

The clinical spectrum of Guillain-Barré syndrome (GBS) is summarized in relation to antecedent infections and anti-ganglioside antibodies. Associations exist between a pure motor form of GBS, diarrhea, Campylobacter jejuni infection, and anti-GM1 antibodies; between cranial nerve involvement and Miller Fisher syndrome, C. jejuni infection, and anti-GQ1b antibodies; and between variants, such as severe sensory involvement and cytomegalovirus infection. These three clinical variants are suggested to form the extremes of a continuous spectrum; they are discussed in relation to the more pathologically defined patterns of acute motor axonal neuropathy and acute motor-sensory axonal neuropathy. In particular, patients with a clinically pure motor variant of GBS, diarrhea, anti-GM1 antibodies, or C. jejuni infection seem to respond better to early treatment with high-dose immunoglobulins than to plasma exchange.

Topics: Autoantibodies; Campylobacter Infections; Campylobacter jejuni; Cytomegalovirus Infections; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Infections; Plasma Exchange; Polyradiculoneuropathy

We herein present the case of a 38-year-old woman with left-sided oculomotor paralysis with ocular pain that developed after a respiratory infection. Her serum was positive for IgM against GM2 and GalNAc-GD1a gangliosides and cytomegalovirus. Thin-slice magnetic resonance imaging revealed enhanced abnormal tissue located primarily in the superolateral part of the left-sided cavernous sinus, which corticosteroids subsequently obscured with immediate resolution of the patient's ocular symptoms. These clinical features were consistent with those of Tolosa-Hunt syndrome (THS). Our findings in the present patient suggest that cytomegalovirus may provoke granuloma formation in the cavernous sinus, as reported in other various organs, thereby leading to the development of THS.

Topics: Adult; Antibodies, Viral; Autoantibodies; Cavernous Sinus; Cytomegalovirus; Cytomegalovirus Infections; Diplopia; Female; G(M1) Ganglioside; G(M2) Ganglioside; Granuloma; Humans; Imaging, Three-Dimensional; Immunocompetence; Immunoglobulin M; Macrophages; Magnetic Resonance Imaging; Prednisolone; Respiratory Tract Infections; Tolosa-Hunt Syndrome

To investigate whether anti-GM2 antibodies in patients with Guillain-Barré syndrome (GBS) are induced by molecular mimicry with cytomegalovirus (CMV).. Antibodies against ganglioside GM2 are frequently present in the serum from GBS patients with an antecedent infection with CMV.. The authors detected inhibition of anti-GM2 reactivity after incubation of GM2-reactive serum samples with fibroblasts infected with a GBS-associated CMV strain. Control sera consisted of GQ1b-reactive samples, and control antigens included uninfected fibroblasts and fibroblasts that were infected with other herpes viruses.. Serum immunoglobulin M reactivity with GM2 was decreased in a dose-dependent manner after incubation with CMV-infected fibroblasts. Incubation of anti-GM2-positive serum samples with uninfected fibroblasts and fibroblasts infected with varicella zoster virus did not inhibit anti-GM2 reactivity, whereas this reactivity was slightly decreased after incubation with herpes simplex virus type 1 in one patient. Antibodies against ganglioside GQ1b did not react with CMV-infected fibroblasts.. CMV-infected fibroblasts express gangliosidelike epitopes that recognize specifically anti-GM2 antibodies. These results support the hypothesis that antiganglioside antibodies in CMV-infected GBS patients are induced by molecular mimicry between GM2 and antigens that are induced by a CMV infection.

Topics: Adult; Aged; Antibody Specificity; Autoantibodies; Cross Reactions; Cytomegalovirus; Cytomegalovirus Infections; Dose-Response Relationship, Immunologic; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; G(M1) Ganglioside; G(M2) Ganglioside; Guillain-Barre Syndrome; Herpesvirus 1, Human; Herpesvirus 3, Human; Humans; Immunosorbent Techniques; Serologic Tests

The relationship between preceding infections and antibodies to glycolipids was investigated in 205 Japanese patients with Guillain-Barré syndrome (GBS). Serological evidence of recent Campylobacter jejuni (C. jejuni) infection was found in 45% of the patients, compared with 1% in healthy controls. In contrast, recent infection of cytomegalovirus (CMV), Mycoplasma pneumoniae (M. pneumoniae) and Epstein-Barr virus (EBV) was detected in only 5%, 2% and none of the patients, respectively. C. jejuni-associated GBS was more frequent in early spring than in other seasons. All stool specimens positive for C. jejuni isolation were obtained within 10 days after the onset of GBS symptoms. Of 13 C. jejuni isolates from GBS patients, 10 (77%) belonged to Penner serotype 19 (heat-stable, HS-19). Elevated titers of anti-GM1 antibody were found in 8 (80%) of 10 GBS patients whose C. jejuni isolates belonged to HS-19 and in none of those infected with non-HS-19 C. jejuni (P = 0.04), and in 49% of 92 patients with C. jejuni infection and 25% of patients without infection of C. jejuni, CMV, EBV, or M. pneumoniae (P = 0.0007). The frequencies of elevated antibody titers to GD1a, GD1b and GQ1b were also significantly higher in GBS patients associated with C. jejuni than those not associated with C. jejuni, CMV, EBV, and M. pneumoniae. GBS in Japan seems to be associated more frequently with C. jejuni and less frequently with CMV than in Europe and North America.

Topics: Adolescent; Adult; Aged; Antibodies, Bacterial; Antibodies, Viral; Antibody Specificity; Antigens, Bacterial; Autoantibodies; Autoimmune Diseases; Campylobacter Infections; Campylobacter jejuni; Child; Child, Preschool; Comorbidity; Cytomegalovirus Infections; Enteritis; Europe; Feces; Female; G(M1) Ganglioside; Galactosylceramides; Gangliosides; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Japan; Male; Middle Aged; Molecular Mimicry; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Polyradiculoneuropathy; United States

A 28-year-old housewife developed motor and sensory neuropathy in both limbs with facial nerve paralysis and decreased taste sensation, two weeks after cough and sore throat with slight fever. On laboratory examination, mild increase of transaminases was found. Enzyme-linked immunosorbent assay showed that the serum had markedly high titers of IgG antibodies to GM2 (1:3,200) and Ga1NAc-GD1a (1:1,600). Serum IgM-EIA index and CF titer of cytomegalovirus were markedly high. In cerebrospinal fluid examination, protein was increased (110 mg/dl). Blink reflex indicated involvement of bilateral facial nerves. In limb motor and sensory nerves, conduction studies revealed the presence of both axonal degeneration and segmental demyelination. The diagnosis of Guillain-Barré syndrome (GBS) with facial nerve paralysis, relatively unique to CMV infection, was made. In the fourth week following the initial neurologic symptom, weakness in facial and limb muscles and sensory disturbances in both limbs were gradually improved. In about three months, conduction studies of limb nerves and CSF protein were normalized. During the clinical course above, the titers of antibodies to GM2 and Ga1NAc-GD1a, IgM-EIA index and the titer of CF of CMV were significantly decreased. Anti-GM2 antibody was reported to be found in the sera from the patient of GBS associated with CMV infection. However, there is no report of GBS patient with CMV infection whose serum showed the presence of both anti-GM2 and anti-Ga1NAc-GD1a antibodies. In this patient, antibodies to CMV, GM2 and Ga1NAc-GD1a epitopes and other unexamined or/and unknown epitopes may be related to the neuropathy. The studies of the specific antibody to react with facial nerve in the serum from GBS patients with facial nerve paralysis and the molecular mimicry between the specific ganglioside and the structure of CMV are warranted in future.

Topics: Acetylgalactosamine; Adult; Antibodies, Viral; Autoantibodies; Biomarkers; Cytomegalovirus; Cytomegalovirus Infections; Facial Paralysis; Female; G(M1) Ganglioside; G(M2) Ganglioside; Hepatitis, Viral, Human; Humans; Immunoglobulin G; Immunoglobulin M; Polyradiculoneuropathy

A chemically synthesized lipid A subunit analogue, GLA-60 (2-deoxy-4-O-phosphono-2-[(3R)-3-hydroxytetradecanamido]-3-O-[(3R) - 3-tetradecanoyloxytetradecanoyl]-D-glucose), has many of the activities of endotoxins but little, if any, toxicity. We investigated the protective activity of GLA-60 against murine cytomegalovirus (MCMV) infection in NMRI mice. Intraperitoneal administration of GLA-60 at 1 day before MCMV infection at doses of 1, 10, or 100 micrograms per mouse significantly reduced mortality. GLA-60 stimulated peritoneal natural killer (NK) cell and macrophage activities, and these activities were abolished by in vitro treatment with anti-asialo GM1 antibody and anti-Mac1 antibody, respectively. GLA-60 proved also protective against MCMV infection in mice in which either NK cells or macrophages were depleted by in vivo treatment with anti-asialo GM1 or anti-Mac1 antibody. The anti-MCMV activity of GLA-60 can at least be partially attributed to activation of NK cells and macrophages.

Topics: Adjuvants, Immunologic; Animals; Cytomegalovirus Infections; Female; G(M1) Ganglioside; Injections, Intraperitoneal; Killer Cells, Natural; Lipid A; Macrophage Activation; Macrophage-1 Antigen; Mice; Phagocytosis

The purpose of this study was to determine the relationship between chemical suppression of natural killer (NK) cell activity in mice and chemical effects on susceptibility to murine cytomegalovirus (MCMV) infection. The goal was to provide a rational basis for applying MCMV as a host resistance model for immunotoxicity testing and to provide risk assessors some guidance in relating suppression of NK cell activity to enhanced risk of disease. Data from studies with eight chemicals administered in various doses and by various routes were evaluated, and a significant correlation was observed between chemical suppression of virus-augmented NK cell activity and increased mortality due to MCMV infection. In contrast, effects of the same chemical treatments on spontaneous NK cell activity (i.e., basal activity in uninfected mice) did not correlate with effects of these chemicals on mortality due to MCMV. Although chemicals that suppressed spontaneous NK cell activity enhanced infection, the converse was not always true--that is, increased susceptibility to infection and suppression of virus-augmented NK cell activity were observed on three occasions when spontaneous NK cell activity was unaffected. This latter phenomenon plus the fact that for two chemicals spontaneous NK was suppressed at concentrations twofold below that which affected mortality appear to account for the poor statistical correlation. Nevertheless, the data indicate that MCMV is a useful host resistance model to be applied in immunotoxicity testing when suppression of NK cell activity has been demonstrated. However, virus-augmented activity may be a better indicator than spontaneous activity. The data also indicated that suppression of NK cell activity is predictive of increased susceptibility to infection and hence provides qualitative guidance (hazard identification) to risk assessors.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzo(a)pyrene; Cadmium; Cadmium Chloride; Cells, Cultured; Chlorides; Cyclophosphamide; Cyclosporine; Cytomegalovirus Infections; Disease Susceptibility; Female; G(M1) Ganglioside; Immunity, Cellular; Immunosuppressive Agents; Killer Cells, Natural; Mice; Mice, Inbred C3H; Nickel; Polychlorinated Dibenzodioxins; Specific Pathogen-Free Organisms; Tetradecanoylphorbol Acetate

Studies were undertaken to assess the effect of murine cytomegalovirus (MCMV) in two different models involving injection of parental cells into F1 hosts. In both of these systems, MCMV-induced enhancement of hybrid resistance was found. In the first model, parent-into-F1 graft-vs-host reaction, MCMV infection of (C57BL/6 x C3H)F1 (B6C3F1) hosts was found to prevent the GVHR normally induced by injection of B6 parental splenocytes into the F1 hosts. The second model involved injection of parental bone marrow into lethally irradiated B6C3F1 and (C57BL/6 x DBA/2)F1 (B6D2F1) hosts. These irradiated hosts are known to exhibit resistance to engraftment by parental C57BL/6 (B6) bone marrow. This resistance was found to be markedly enhanced by injection of the hosts with MCMV 3 days before irradiation and bone marrow injection. In contrast, engraftment into B6C3F1 hosts of syngeneic marrow, or bone marrow from the C3H parent, was not affected by MCMV infection. Engraftment of DBA/2 marrow into B6D2F1 hosts was reduced at lower doses of injected marrow, suggesting enhanced resistance against the minor Hh Ag Hh-DBA. To test whether the MCMV-induced enhancement of resistance was mediated by NK cells, splenic NK activity (YAC-1 killing) and frequency (NK1.1 staining) were assessed. Both parameters were found to be elevated at 3 days after MCMV infection but to return to normal levels by 9 days. B6 bone marrow engraftment was in fact found to be normal when the marrow was administered to F1 mice 9 days after MCMV infection. Furthermore, anti-asialoGM1 administration prevented MCMV-induced enhancement of resistance to marrow engraftment. Thus, the NK enhancement resulting from MCMV infection appears to play a major role in the enhanced HR observed in the marrow engraftment model. This effect may be of importance in clinical bone marrow transplantation, a situation in which patients are susceptible to viral infection.

Topics: Animals; Bone Marrow Transplantation; Cytomegalovirus Infections; G(M1) Ganglioside; Glycosphingolipids; Graft Rejection; Graft vs Host Reaction; Killer Cells, Natural; Male; Mice; Mice, Inbred Strains