Assuntos
Anticorpos Monoclonais/metabolismo , Membrana Celular/metabolismo , Endocitose/imunologia , Gangliosídeo G(M1)/metabolismo , Gangliosídeos/metabolismo , Fator 6 de Ribosilação do ADP , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/imunologia , Animais , Afinidade de Anticorpos , Autoantígenos/imunologia , Autoantígenos/metabolismo , Transporte Biológico , Células CHO , Linhagem Celular Tumoral , Membrana Celular/imunologia , Cricetulus , Endossomos/imunologia , Endossomos/metabolismo , Gangliosídeo G(M1)/imunologia , Gangliosídeos/imunologia , Expressão Gênica , Humanos , Cinética , Camundongos , Camundongos Knockout , Imagem Molecular , Neurônios/citologia , Neurônios/imunologia , Neurônios/metabolismo , Ligação Proteica , Imagem com Lapso de TempoRESUMO
Elevated titers of serum antibodies against GM1 ganglioside are associated with a variety of autoimmune neuropathies. Much evidence indicates these autoantibodies play a primary role in the disease processes, but the mechanism for their appearance is unclear. We studied the fine specificity of anti-GM1 antibodies of the IgG isotype present in sera from patients with Guillain-Barré syndrome (GBS), using thin-layer chromatogram-immunostaining of GM1, asialo-GM1 (GA1), GD1b and GM1-derivatives with small modifications on the oligosaccharide moiety. We were able to distinguish populations of antibodies with different fine specificity. Remarkably, individual patients presented only one or two of them, and different patients had different populations. This restriction in the variability of antibody populations suggests that the appearance of the anti-GM1 antibodies is a random process involving restricted populations of lymphocytes. With the origin of disease-associated anti-GM1 antibodies as a context, this finding could provide explanation for the "host susceptibility factor" observed in GBS following enteritis with GM1 oligosaccharide-carrying strains of Campylobacter jejuni.
Assuntos
Autoanticorpos/imunologia , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Idoso , Especificidade de Anticorpos/imunologia , Autoanticorpos/sangue , Autoimunidade , Criança , Reações Cruzadas/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Immunization of rabbits with bovine brain gangliosides induced an experimental neuropathy, with clinical signs resembling Guillain-Barré syndrome. All the immunized animals developed immunoglobulin G immunoreactivity to GM1 ganglioside. In a few (4 of 27) animals, an additional anti-ganglioside antibody population showing an unusual binding behavior was detected. Enzyme-linked immunosorbent assay and thin-layer chromatography immunostaining analyses showed that the binding of these unusual antibodies required the presence of two co-localized gangliosides. Maximal interaction was observed to a mixture of GM1 and GD1b, but the antibodies also showed "density-dependent" binding to GD1b. The antibodies were purified by affinity chromatography and displayed the ability to target antigens in biological membranes (rat synaptosomes).
Assuntos
Gangliosídeo G(M1)/imunologia , Gangliosídeos/imunologia , Imunoglobulina G/imunologia , Animais , Química Encefálica , Bovinos , Síndrome de Guillain-Barré/induzido quimicamente , Síndrome de Guillain-Barré/imunologia , Neurite Autoimune Experimental/induzido quimicamente , Neurite Autoimune Experimental/imunologia , Coelhos , RatosRESUMO
BACKGROUND: Clinical severity of Guillain-Barré syndrome (GBS) is highly variable, but the immunopathological reason is unknown. OBJECTIVE: The study was designed to show which antibody parameters are associated with disease severity in GBS patients with serum anti-GM1 IgG antibodies. METHODS: Thirty-four GBS patients with anti-GM(1) IgG antibodies were grouped into two categories according to disease severity at nadir: mild (grades 1-3 by Hughes functional scale, n=13) and severe (grades 4 and 5, n=21). Titre, affinity, fine specificity and cell binding of anti-GM(1) antibodies were obtained and compared between the two groups. RESULTS: No differences in antibody titre (GM(1)-ELISA) or affinity were found between the two patient groups. In contrast, the severe group showed a significantly higher frequency (95%, vs 46% in the mild group, p=0.002) of specific (not cross-reacting with GD(1b)) anti-GM(1) antibodies. In addition, the severe group also exhibited a higher antibody binding titre to cellular GM(1). CONCLUSIONS: Differences in fine specificity of antibodies are strong indications that different regions of the GM(1)-oligosaccharide are involved in antibody binding. High titres of specific anti-GM(1) antibody binding to cellular GM(1) can be explained by antigen exposure, that is, GM(1) exposes or forms mainly epitopes recognised by specific antibodies, and 'hides' those involved in binding of cross-reacting antibodies. Thus, the fine specificity of anti-GM(1) antibodies may influence disease severity by affecting antibody binding to cellular targets. Additionally, since antibody specificity studies are relatively easy to implement, fine specificity could be considered a useful predictor of disease severity.
Assuntos
Autoanticorpos/imunologia , Gangliosídeo G(M1)/análogos & derivados , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromatografia em Camada Fina , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática , Feminino , Gangliosídeos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
Gangliosides are glycolipids mainly present at the plasma membrane (PM). Antibodies to gangliosides have been associated with a wide range of neuropathy syndromes. Particularly, antibodies to GM1 ganglioside are present in patients with Guillain-Barré syndrome (GBS). We investigated the binding and intracellular fate of antibody to GM1 obtained from rabbits with experimental GBS in comparison with the transport of cholera toxin (CTx), which binds with high affinity to GM1. We demonstrated that antibody to GM1 is rapidly and specifically endocytosed in CHO-K1 cells. After internalization, the antibody transited sorting endosomes to accumulate at the recycling endosome. Endocytosed antibody to GM1 is recycled back to the PM and released into the culture medium. In CHO-K1 cells, antibody to GM1 colocalized with co-endocytosed CTx at early and recycling endosomes, but not in Golgi complex and endoplasmic reticulum, where CTx was also located. Antibody to GM1, in contraposition to CTx, showed a reduced internalization to recycling endosomes in COS-7 cells and neural cell lines SH-SY5Y and Neuro2A. Results from photobleaching studies revealed differences in the lateral mobility of antibody to GM1 in the PM of analyzed cell lines, suggesting a relationship between the efficiency of endocytosis and lateral mobility of GM1 at the PM. Taken together, results indicate that two different ligands of GM1 ganglioside (antibody and CTx) are differentially endocytosed and trafficked, providing the basis to gain further insight into the mechanisms that operate in the intracellular trafficking of glycosphingolipid-binding toxins and pathological effects of neuropathy-associated antibodies.
Assuntos
Autoanticorpos/metabolismo , Toxina da Cólera/metabolismo , Células Epiteliais/metabolismo , Gangliosídeo G(M1)/metabolismo , Síndrome de Guillain-Barré/metabolismo , Vesículas Transportadoras/metabolismo , Animais , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Células CHO , Células COS , Chlorocebus aethiops , Toxina da Cólera/imunologia , Toxina da Cólera/farmacologia , Cricetinae , Cricetulus , Endocitose/imunologia , Células Epiteliais/imunologia , Gangliosídeo G(M1)/imunologia , Gangliosídeo G(M1)/farmacologia , Síndrome de Guillain-Barré/imunologia , Humanos , Transporte Proteico/imunologia , Coelhos , Vesículas Transportadoras/imunologiaRESUMO
Glycans are a class of molecules with high structural variability, frequently found in the plasma membrane facing the extracellular space. Because of these characteristics, glycans are often considered as recognition molecules involved in cell social functions, and as targets of pathogenic factors. Induction of anti-glycan antibodies is one of the early events in immunological defense against bacteria that colonize the body. Because of this natural infection, antibodies recognizing a variety of bacterial glycans are found in sera of adult humans and animals. The immune response to glycans is restricted by self-tolerance, and no antibodies to self-glycans should exist in normal subjects. However, antibodies recognizing structures closely related to self-glycans do exist, and can lead to production of harmful anti-self antibodies. Normal human sera contain low-affinity anti-GM1 IgM-antibodies. Similar antibodies with higher affinity or different isotype are found in some neuropathy patients. Two hypotheses have been developed to explain the origin of disease-associated anti-GM1 antibodies. According to the "molecular mimicry" hypothesis, similarity between GM1 and Campylobacter jejuni lipopolysaccharide carrying a GM1-like glycan is the cause of Guillain-Barré syndrome associated with anti-GM1 IgG-antibodies. According to the "binding site drift" hypothesis, IgM-antibodies associated with disease originate through changes in the binding site of normally occurring anti-GM1 antibodies. We now present an "integrated" hypothesis, combining the "mimicry" and "drift" concepts, which satisfactorily explains most of the published data on anti-GM1 antibodies.
Assuntos
Anticorpos/imunologia , Autoimunidade/imunologia , Gangliosídeo G(M1)/imunologia , Polissacarídeos/imunologia , Animais , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , HumanosRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is an acute, immune-mediated flaccid paralysis frequently associated with Campylobacter infection. Of two predominant GBS subtypes, a demyelinating subtype (acute inflammatory demyelinative polyneuropathy [AIDP]) predominates in the United States and Europe, and axonal subtype (acute motor axonal neuropathy [AMAN]) is the predominant form in China. Previous clinical studies suggested that AMAN also occurs in Mexican children. The purpose of this study was to describe the subtypes of GBS in children from Mexico City. METHODS: We prospectively studied 121 children admitted to two pediatric hospitals in Mexico City from 1996 to 2002. Clinical histories were obtained, electrophysiologic studies were performed to determine GBS subtype, and microbiologic studies were performed. RESULTS: Of the 121 children, 46 had AMAN and 32 had AIDP. The male to female ratio was 1.3 for AMAN cases (mean age = 6.3) and 3.0 for AIDP cases (mean age = 7.0). There was a strong seasonal distribution of AMAN cases in July to September. Children with AMAN, but not AIDP, had worsening of illness during hospitalization as judged by peak severity scores. Vomiting was more likely in AIDP (28.1%) vs AMAN (6.5%) (p = 0.012) and diarrhea was more common in AMAN (32.6%) than AIDP (12.5%) (p = 0.06). IgG anti-GM1 antibody titers were higher in patients with AMAN vs AIDP (p = 0.067). Anti-GD1a antibodies were equally present in both groups. Anti GQ1b titers were higher in AMAN vs AIDP (p = 0.009). Campylobacter antibody responses were positive in 44.1% of patients with AMAN and 37.0% of patients with AIDP. Twenty patients (14 = AMAN, 6 = AIDP) had positive stool cultures for C jejuni. Two serotypes, HS:19 and HS:41, accounted for 6 of 10 Campylobacter isolates available for serotyping from these cases. CONCLUSIONS: This study confirms that acute motor axonal neuropathy is an important Guillain-Barré syndrome subtype in Mexican children, is associated with diarrhea, and occurs seasonally.
Assuntos
Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/fisiopatologia , Adolescente , Infecções por Campylobacter/epidemiologia , Criança , Pré-Escolar , Diarreia/etiologia , Feminino , Gangliosídeo G(M1)/análogos & derivados , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/microbiologia , Humanos , Imunoglobulina G/sangue , Lactente , Masculino , México/epidemiologia , Neurônios Motores/patologia , Estações do AnoRESUMO
High antibody affinity has been proposed as a disease determinant factor in neuropathies associated with anti-GM1 antibodies. An experimental model of Guillain-Barré syndrome, induced by immunization of rabbits with bovine brain gangliosides or GM1, was described recently (Yuki et al. [2001] Ann. Neurol. 49:712-720). We searched plasma from these rabbits, taken at disease onset and 1 or 2 weeks prior to onset, for the presence of high-affinity anti-GM1 IgG antibodies. Affinity was estimated by soluble antigen binding inhibition. High-affinity antibodies (binding inhibition by 10(-9) M GM1) were detected at disease onset but not before. No such difference was found for other antibody parameters such as titer, fine specificity, and population distribution. These findings support the proposed role of high affinity as an important factor in disease induction by anti-GM1 antibodies.
Assuntos
Afinidade de Anticorpos , Autoanticorpos/imunologia , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Animais , Especificidade de Anticorpos/fisiologia , Sítios de Ligação de Anticorpos , Bovinos , Cromatografia em Camada Fina/métodos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Coelhos , Fatores de TempoRESUMO
Anti-GM1 antibodies of the IgG isotype are found in serum from patients with Guillain-Barré syndrome. In normal human sera, anti-GM1 IgM-antibodies are commonly present, but their IgG counterpart has not been previously demonstrated. During routine screening, we found a normal human serum with a high titer of anti-GM1 IgG-antibodies (IgG1 subclass). Affinity estimation by soluble antigen-binding inhibition indicated that they are low-affinity antibodies with IC50 values between one and two orders of magnitude higher than those of anti-GM1 IgG-antibodies from Guillain-Barré patients. Various antibody parameters remained fairly constant for 1 year, in additional serum samples taken at 4-month intervals. Such anti-GM1 IgG1-antibodies were not detected in > 100 other normal serum samples tested, indicating a very low frequency in the general population. The low affinity of these unusually present antibodies could explain the absence of disease, despite their relatively high titer. The significance of this finding in the origin of disease-associated anti-GM1 antibodies is discussed.
Assuntos
Autoanticorpos/sangue , Autoanticorpos/imunologia , Gangliosídeo G(M1)/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Adulto , Afinidade de Anticorpos , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , HumanosRESUMO
Anti-GM(1) antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM(1) IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM(1) antibodies. Anti-GM(1) IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains.
Assuntos
Anticorpos Antibacterianos/sangue , Campylobacter jejuni/imunologia , Gangliosídeo G(M1)/imunologia , Imunoglobulina M/sangue , Adulto , Anticorpos Antibacterianos/imunologia , Infecções por Campylobacter/imunologia , Infecções por Campylobacter/microbiologia , Diarreia/imunologia , Diarreia/microbiologia , Escherichia coli/imunologia , Bactérias Gram-Negativas/imunologia , Humanos , Imunoglobulina M/imunologia , Lactente , Recém-Nascido , Veias Umbilicais/imunologiaRESUMO
Elevated titers of serum antibodies against GM1-ganglioside are associated with a variety of autoimmune neuropathies. The origin of these autoantibodies is still unknown, although there is evidence that they are produced by CD5+ B-lymphocytes and that antigen mimicry is involved. Anti-GM, IgM-antibodies in the normal human immunological repertoire are low affinity antibodies that cross-react with other glycoconjugates carrying Gal beta1-3GalNAc and probably do not have GM1-mediated biological activity. Other anti-GM1 IgM-antibodies with higher affinity and/or different fine specificity are present in patients with motor syndromes. Based on our studies of structural requirement for binding, we hypothesize that disease-associated anti-GM1 antibodies originate at random by mutations affecting the binding site of naturally-occurring ones. The hypothesis is conceptually similar to the established phenomenon of "genetic drift" in species evolutionary biology and is therefore termed "binding site drift".
Assuntos
Autoanticorpos/imunologia , Sítios de Ligação de Anticorpos , Gangliosídeo G(M1)/imunologia , HumanosRESUMO
Elevated titers of serum anti-GM(1) antibodies of IgG isotype are found frequently in patients with Guillain-Barré syndrome. Much evidence indicates that these autoantibodies are involved in disease progression, but their exact function and the mechanism of their appearance are still unclear. In an attempt to reproduce "ganglioside syndrome", the experimental model of neuropathy developed by Nagai et al. (Neurosci. Lett. 2 (1976) 107), rabbits were intensively immunized with GM(1) in complete Freund adjuvant (CFA). High titers of anti-GM(1) antibodies were produced, with class switch and affinity maturation indicating an elaborate immune response. Unexpectedly, the rabbits did not show any clinical symptoms of neuropathy. Relatively affinities of both IgM and IgG antibodies were significantly lower than those of similar antibodies from neuropathy patients. These results suggest the existence of a threshold value above which affinity of anti-GM(1) antibodies becomes an important factor in disease induction. The absence of neuropathy symptoms in rabbits may be explained by absence of these high-affinity anti-GM(1) antibodies.
Assuntos
Afinidade de Anticorpos/imunologia , Antígenos de Helmintos , Autoanticorpos/imunologia , Gangliosídeo G(M1)/análogos & derivados , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/imunologia , Animais , Autoanticorpos/sangue , Sítios de Ligação de Anticorpos/imunologia , Causalidade , Gangliosídeo G(M1)/sangue , Gangliosídeos , Glicoesfingolipídeos/sangue , Glicoesfingolipídeos/imunologia , Síndrome de Guillain-Barré/sangue , Proteínas de Helminto , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Proteínas de Membrana , Estrutura Molecular , Nervos Periféricos/imunologia , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia , Ligação Proteica/imunologia , CoelhosRESUMO
In order to evaluate the usefulness of liposomes as possible vaccine vehicles (oral and subcutaneous), the stability of liposomes in buffer, plasma and saliva at 25 and 37 degrees C was analyzed via fluorescence and enzymatic methodology. The tested mixtures included [EggPC/Chol] 1 : 1 (mixture I), [EggPC/Chol/SM] 1 : 1 : 1 (mixture II), [EggPC/Chol/SM/GM typeIII] 1 : 1 : 1 : 0.14 (mixture III), [EggPC/Chol/SM/GM1] 1 : 1 : 1 : 0.14 (mixture IV) and [DIAPC/DMPC] 1 : 1 non polymerized (mixture V) and polymerized (mixture VI); all mole ratio. Liposome mixtures I and II were more stable in buffer at 25 degrees C. On the other hand, mixtures III and IV were more stable in plasma at 37 degrees C; mixture VI was more stable in plasma at 37 degrees C than in buffer or saliva. Mixtures IV and V liposomes were both stable in saliva for at least one hour. Blood and feces anti-GM1 response to antigen associated liposomes after subcutaneous and oral administration was also examined. After mixture IV mice immunization, no detectable anti-ganglioside GM1 antibody response was detected. Negative stain transmission electron microscopy, shows that liposomes containing SM, GM1, GM typeIII and DIAPC : DMPC were twice the size of those made with EggPC/Chol. The hydrophobicity factor expressed as A(570/500) was obtained using the probe merocynine 540 (MC540). The order of fluidity increased from: mixture II < mixture I < mixture III < mixture IV < mixtureV < mixture VI. Although the high hydrophobicity factor for polymerizable lipids there are other factors like stability must be taken into account according to the administration via selected. Also, the hydrophilicity of the groups protruding from the membrane interphase into the solution in the case of subcutaneous inoculation is very relevant and for oral administration stability is the property to take into account, as long as they have to last through the different fluids of the gastrointestinal tract. The results obtained suggest that liposomes that showed stability in saliva and plasma at 37 degrees C containing GM1, GM typeIII or DIAPC/DMPC would serve effectively as a delivery vehicle for oral and subcutaneous non-viral vaccines.
Assuntos
Gangliosídeo G(M1)/metabolismo , Lipossomos/metabolismo , Animais , Antígenos/metabolismo , Sistemas de Liberação de Medicamentos , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Gangliosídeo G(M1)/imunologia , Glucose-6-Fosfato/metabolismo , Imunização , Cinética , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Microscopia de Fluorescência , Temperatura , Fatores de Tempo , VacinasRESUMO
Elevated titers of serum antibodies against GM(1)-ganglioside are associated with a variety of autoimmune neuropathies. Although much evidence indicates that these autoantibodies play a primary role in the disease processes, the mechanism of their appearance is unclear. Low-affinity anti-GM(1) antibodies of the IgM isotype are part of the normal human immunological repertoire. In patients with motor syndromes, we found that in addition to the usual anti-GM(1) antibodies, the sera contain IgM-antibodies that recognize GM(1) with higher affinity and/or different specificity. This latter type of antibodies was not detected in other autoimmune diseases. We studied the fine specificity of both normal and motor disease-associated antibodies using HPTLC-immunostaining of GM(1) and structurally related glycolipids, soluble antigen binding inhibition, and GM(1) affinity columns. Normal low-affinity anti-GM(1) antibodies cross-react with GA(1) and/or GD(1b). In the motor syndrome patients, different populations of antibodies characterized by their affinity and cross-reactivity were detected. Although one population is relatively common (low affinity, not cross-reacting with GA(1) and GD(1b)), there are remarkably few sera having the same set of populations. These results suggest that the appearance of the new antibody populations is a random process. When the different antibody populations were analyzed in relation to the three-dimensional structure of GM(1), a restricted area of the GM(1) oligosaccharide (the terminal Galbeta1-3GalNAc) was found to be involved in binding of normal anti-GM(1) antibodies. Patient antibodies recognize slightly different areas, including additional regions of the GM(1) molecule such as the NeuNAc residue. We hypothesize that disease-associated antibodies may originate by spontaneous mutation of normal occurring antibodies.
Assuntos
Anticorpos/análise , Gangliosídeo G(M1)/imunologia , Imunoglobulina M/análise , Transtornos dos Movimentos/imunologia , Anticorpos/imunologia , Assialoglicoproteínas/imunologia , Ligação Competitiva , Reações Cruzadas , Gangliosídeos/imunologia , Humanos , Imunoglobulina M/imunologia , Valores de ReferênciaRESUMO
An 11-year-old girl had a painless oculomotor nerve palsy confined to the inferior division. Anti-galactocerebroside and anti-GM1 antibodies were elevated during the acute phase and decreased to normal limits with clinical improvement, suggesting a possible autoimmune basis for this mononeuropathy.
Assuntos
Gangliosídeo G(M1)/imunologia , Galactosilceramidas/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Doenças do Nervo Oculomotor/imunologia , Criança , Feminino , HumanosRESUMO
Intravenous immunoglobulin (IVIg) is used in the treatment of a variety of autoimmune diseases. The blocking of disease-associated antibodies by anti-idiotype antibodies present in IVIg has been proposed as an action mechanism. Anti-GM1 antibodies have been implicated in motor neuropathies. Although IVIg is frequently applied for these diseases, the presence in IVIg or in human plasma of anti-idiotype antibodies that recognize anti-GM1 antibodies has not been clearly demonstrated. Here we present evidence that normal human plasma contains antibodies that inhibit the binding of anti-GM1 IgG-antibodies from neuropathy patients but do not inhibit anti-GM1 IgG-antibodies of rabbit origin with the same fine specificity. The significance of these findings in the course of acute and chronic neuropathies is discussed.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Gangliosídeo G(M1)/imunologia , Imunoglobulina G/imunologia , Doença dos Neurônios Motores/imunologia , Adulto , Animais , Humanos , CoelhosRESUMO
A 68-year-old man, with Hairy Cell Leukemia developed a Guillain-Barré syndrome (G-B), 32 days after a single course of 2-Chlorodeoxyadenosine (CDA) at 0,14 mg/k/d, for five days in a two-hour-i.v. infusion and following a febrile neutropenia episode. In order to clarify whether this G-B case was related to an infection or to CDA neurotoxicity, we screened for infection-related autoimmune G-B and for antibodies (abs.) against gangliosides of peripheral nerves. Blood and urinary cultures were negative as well as serum anti-virus abs. However, serum anti-ganglioside abs. were positive for anti-asialo GM1 and anti-Gd1b. This latter finding was consistent with an autoimmune mechanism, not described until now as CDA neurotoxicity. In the present case, we do not have enough evidence to link CDA administration to the G-B syndrome. We think that it is necessary to exclude other causes of neurotoxicity before considering CDA adverse effect.
Assuntos
Cladribina/efeitos adversos , Síndrome de Guillain-Barré/induzido quimicamente , Leucemia de Células Pilosas/complicações , Idoso , Autoanticorpos/sangue , Cladribina/administração & dosagem , Gangliosídeo G(M1)/imunologia , Gangliosídeos/imunologia , Humanos , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/imunologia , MasculinoRESUMO
Chagas disease involves a cardiac impairment, being the first alterations of autonomic disorders which affect heart rate and blood pressure control. At this stage, diminished heart rate responses to atropine and propranolol are observed. Prior studies have shown that short term ganglioside treatment improves the responses to these agents, but there is no information about the long term effect of gangliosides and the evolution of antiGM1 titers. The effects of long term treatment with gangliosides on autonomic tests in patients with chagasic cardiodisautonomy and the evolution of antiGM1 titers were studied in 90 patients (57 men, 33 women, aged 25-60 years) with positive serology for Chagas disease and electrocardiogram showing sinusal bradycardia and incomplete right branch block, without cardiomegaly, with autonomic alterations by postural and Valsalva's tests. All patients were submitted to a test that consisted of intravenous injection of atropine 0.04 mg/kg followed 3 min later by intravenous injection of propranolol 0.2 mg/kg. During these tests heart rate and blood pressure were recorded continuously. Subsequently, 30 patients were treated with 100 mg/day of a mixture of gangliosides by intramuscular injection during 15 days in a row, followed by 40 mg/day during another 75 days. Another 30 patients received continuous treatment for 12 months. The remaining 30 patients were controls. The antiGM1 antibody circulating titers were determined before the treatment, at the third and 12th month. Seventy-four patients completed the study. Before treatment, the heart rate increased, though slightly, after the injection of atropine. After 3 months of ganglioside treatment a statistically significant increase in the response to atropine was recorded. In the controls at 12 months, the response to atropine remained increased without differences between the patients treated for 3 and 12 months. The control patients did not show any modification of the heart rate response during 12 months. Both ganglioside-treated groups showed an increase in the response to propranolol. The antiGM1 titer distribution was similar in both healthy subjects and chagasic patients. None of the patients had positive antiGM1 titers in basal conditions nor significant modifications after the ganglioside treatment. Chagasic cardioneuropathy was not associated in this study with high antiGM1 antibody titers. Chagasic patients showed a diminished heart rate response to atropine as well as to propranolol. Ganglioside treatment determined an increased heart rate response, particularly after atropine. Increased heart rate response was maintained until 1 year, without differences between the patients treated for 3 and 12 months. No changes in the antiGM1 titers were observed during the ganglioside treatment.
Assuntos
Autoanticorpos/sangue , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Cardiomiopatia Chagásica/tratamento farmacológico , Gangliosídeo G(M1)/imunologia , Gangliosídeos/administração & dosagem , Adulto , Atropina/uso terapêutico , Doenças do Sistema Nervoso Autônomo/imunologia , Cardiomiopatia Chagásica/imunologia , Doença Crônica , Feminino , Gangliosídeos/efeitos adversos , Frequência Cardíaca , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Propranolol/uso terapêutico , Fatores de TempoRESUMO
Antibodies reactive with the core glycan of asialoganglioside (GA1), monosialoganglioside (GM1), and disialoganglioside (GD1a) were studied in human sera. In healthy individuals, GA1-, GM1-, and GD1a-reactive antibodies were mainly of the IgM class, but also of the IgA and IgG classes, and were present at low titers in the serum of 68%, 79%, and 91% of the individuals studied, respectively. Levels of anti-GA1 and anti-GM1 antibodies, mainly of the IgA and IgG classes, were significantly elevated (P < 0.001) in 62% and 72% of subjects, respectively, chronically infected with Trypanosoma cruzi, with no association found with the degree of myocardial damage. No significant increase in anti-GA1 and anti-GM1 antibodies was found in dilated cardiomyopathy patients. The level of anti-GD1a antibody was not significantly different between healthy controls and chronic chagasic or dilatatory cardiomyopathy patients. Since the peripheral nervous system is very rich in gangliosides, it is possible that the increases in GA1- and GM1-specific antibodies that develop during chronic T. cruzi infection are involved in the pathology of peripheral neuropathy in Chagas' disease.
Assuntos
Autoanticorpos/biossíntese , Doença de Chagas/imunologia , Gangliosídeo G(M1)/imunologia , Glicoesfingolipídeos/imunologia , Imunoglobulinas/biossíntese , Animais , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/sangue , Autoanticorpos/sangue , Bovinos , Doença de Chagas/complicações , Doença Crônica , Ensaio de Imunoadsorção Enzimática , Gangliosídeos/imunologia , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/classificação , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/imunologiaRESUMO
Low affinity anti-GM1 IgM-antibodies are part of the normal repertoire of human plasma antibodies (Mizutamari et al.: J Neuroimmunol 50:215-220, 1994), a fact that is against the pathological role proposed for them in autoimmune diseases. Here we present evidence that these low affinity IgM-antibodies are devoid of complement-mediated lytic activity to GM1-liposomes, suggesting that they should not be considered harmful. In contrast to the absence in normal individuals, in the plasma of a patient with sensory polyneuropathy we detected high affinity anti-GM1 IgM-antibodies. Concomitant with the presence of these high affinity anti-GM1 IgM-antibodies, the patient plasma is capable of producing complement-mediated lysis of GM1-liposomes. These results suggest that an increase in the affinity of the naturally existing anti-GM1 antibodies could be the trigger that switches them from non-harmful to pathological.