RESUMEN
A non-pathogenic Mycoplasma pneumoniae-based chassis is leading the development of live biotherapeutic products (LBPs) for respiratory diseases. However, reports connecting Guillain-Barré syndrome (GBS) cases to prior M. pneumoniae infections represent a concern for exploiting such a chassis. Galactolipids, especially galactocerebroside (GalCer), are considered the most likely M. pneumoniae antigens triggering autoimmune responses associated with GBS development. In this work, we generated different strains lacking genes involved in galactolipids biosynthesis. Glycolipid profiling of the strains demonstrated that some mutants show a complete lack of galactolipids. Cross-reactivity assays with sera from GBS patients with prior M. pneumoniae infection showed that certain engineered strains exhibit reduced antibody recognition. However, correlation analyses of these results with the glycolipid profile of the engineered strains suggest that other factors different from GalCer contribute to sera recognition, including total ceramide levels, dihexosylceramide (DHCer), and diglycosyldiacylglycerol (DGDAG). Finally, we discuss the best candidate strains as potential GBS-free Mycoplasma chassis.
Asunto(s)
Glucolípidos , Síndrome de Guillain-Barré , Mycoplasma pneumoniae , Síndrome de Guillain-Barré/microbiología , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/inmunología , Humanos , Glucolípidos/metabolismo , Galactosilceramidas , Reacciones Cruzadas , Neumonía por Mycoplasma/microbiología , Neumonía por Mycoplasma/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunologíaRESUMEN
BACKGROUND: Increased prevalence of autoantibody Fab glycosylation has been demonstrated for several autoimmune diseases. OBJECTIVES: To study whether elevated Fab glycosylation is a common feature of autoimmunity, this study investigated Fab glycosylation levels on serum IgG and its subclasses for autoantibodies associated with a range of different B cell-mediated autoimmune diseases, including rheumatoid arthritis, myasthenia gravis subtypes, pemphigus vulgaris, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, anti-glomerular basement membrane glomerulonephritis, thrombotic thrombocytopenic purpura, and Guillain-Barré syndrome. METHODS: The level of Fab glycosylated IgG antibodies was assessed by lectin affinity chromatography and autoantigen-specific immunoassays. RESULTS: In 6 of 10 autoantibody responses, in 5 of 8 diseases, the investigators found increased levels of Fab glycosylation on IgG autoantibodies that varied from 86% in rheumatoid arthritis to 26% in systemic lupus erythematosus. Elevated autoantibody Fab glycosylation was not restricted to IgG4, which is known to be prone to Fab glycosylation, but was also present in IgG1. When autoimmune diseases with a chronic disease course were compared with more acute autoimmune illnesses, increased Fab glycosylation was restricted to the chronic diseases. As a proxy for chronic autoantigen exposure, the investigators determined Fab glycosylation levels on antibodies to common latent herpes viruses, as well as to glycoprotein 120 in individuals who are chronically HIV-1-infected. Immunity to these viral antigens was not associated with increased Fab glycosylation levels, indicating that chronic antigen-stimulation as such does not lead to increased Fab glycosylation levels. CONCLUSIONS: These data indicate that in chronic but not acute B cell-mediated autoimmune diseases, disease-specific autoantibodies are enriched for Fab glycans.
Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Miastenia Gravis , Humanos , Autoanticuerpos , Inmunoglobulina G , AutoantígenosRESUMEN
Objective: The Guillain-Barré syndrome (GBS) is an acute, immune-mediated disease of peripheral nerves. Plasmablasts and plasma cells play a central role in GBS by producing neurotoxic antibodies. The standard treatment for GBS is high-dose intravenous immunoglobulins (IVIg), however the working mechanism is unknown and the response to treatment is highly variable. We aimed to determine whether IVIg changes the frequency of B-cell subsets in patients with GBS. Methods: Peripheral blood mononuclear cells were isolated from 67 patients with GBS before and/or 1, 2, 4, and 12 weeks after treatment with high-dose IVIg. B-cell subset frequencies were determined by flow cytometry and related to serum immunoglobulin levels. Immunoglobulin transcripts before and after IVIg treatment were examined by next-generation sequencing. Antiglycolipid antibodies were determined by ELISA. Results: Patients treated with IVIg demonstrated a strong increase in plasmablasts, which peaked 1 week after treatment. Flow cytometry identified a relative increase in IgG2 plasmablasts posttreatment. Within IGG sequences, dominant clones were identified which were also IGG2 and had different immunoglobulin sequences compared to pretreatment samples. High plasmablast frequencies after treatment correlated with an increase in serum IgG and IgM, suggesting endogenous production. Patients with a high number of plasmablasts started to improve earlier (P = 0.015) and were treated with a higher dose of IVIg. Interpretation: High-dose IVIg treatment alters the distribution of B-cell subsets in the peripheral blood of GBS patients, suggesting de novo (oligo-)clonal B-cell activation. Very high numbers of plasmablasts after IVIg therapy may be a potential biomarker for fast clinical recovery.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Leucocitos Mononucleares/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Síndrome de Guillain-Barré/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Antibody responses to Mycoplasma pneumoniae correlate with pulmonary M. pneumoniae clearance. However, M. pneumoniae-specific IgG antibodies can cross-react with the myelin glycolipid galactocerebroside (GalC) and cause neurological disorders. We assessed whether antiglycolipid antibody formation is part of the physiological immune response to M. pneumoniae We show that antibodies against M. pneumoniae proteins and glycolipids arise in serum of M. pneumoniae-infected children and mice. Although antibodies to M. pneumoniae glycolipids were mainly IgG, anti-GalC antibodies were only IgM. B-1a cells, shown to aid in protection against pathogen-derived glycolipids, are lacking in Bruton tyrosine kinase (Btk)-deficient mice. M. pneumoniae-infected Btk-deficient mice developed M. pneumoniae-specific IgG responses to M. pneumoniae proteins but not to M. pneumoniae glycolipids, including GalC. The equal recovery from M. pneumoniae infection in Btk-deficient and wild-type mice suggests that pulmonary M. pneumoniae clearance is predominantly mediated by IgG reactive with M. pneumoniae proteins and that M. pneumoniae glycolipid-specific IgG or IgM is not essential. These data will guide the development of M. pneumoniae-targeting vaccines that avoid the induction of neurotoxic antibodies.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Proteínas Bacterianas/inmunología , Glucolípidos/inmunología , Mycoplasma pneumoniae/inmunología , Neumonía por Mycoplasma/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Niño , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , RatonesRESUMEN
We report the case of a 9 year-old boy, presenting with an acute encephalitis with cerebrospinal fluid pleiocytosis. MRI showed T2/FLAIR (fluid attenuated inversion recovery) hyperintense signals of basal ganglia and cortex, EEG (electro encephalogram) showed diffuse slowing with epileptic discharges. A repetitively elevated IgM/IgG serologic response against Mycoplasma pneumoniae was observed with polymerase chain reaction in serum and cerebrospinal fluid remaining negative. No other pathogen or antigen could be identified. High IgG and IgM levels against the glycolipid galactocerebroside were detected in serum but not in CSF. After treatment with corticosteroids, the patient fully recovered. Brain MRI and EEG investigation returned completely normal. Besides a primary infection of the central nervous system, M. pneumoniae is associated with a parainfectious encephalitis in children which may be mediated by antibodies to galactocerebroside.
Asunto(s)
Autoanticuerpos/sangre , Encefalitis/sangre , Galactosilceramidas/sangre , Mycoplasma pneumoniae , Neumonía por Mycoplasma/sangre , Niño , Encefalitis/diagnóstico por imagen , Humanos , Masculino , Neumonía por Mycoplasma/diagnóstico por imagenRESUMEN
Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.
Asunto(s)
Autoanticuerpos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Gangliósidos/inmunología , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Polineuropatía Paraneoplásica/inmunología , Adulto , Anciano , Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Síndrome de Miller Fisher/sangre , Síndrome de Miller Fisher/inmunología , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Polineuropatía Paraneoplásica/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Síndrome de Sjögren/sangre , Síndrome de Sjögren/inmunologíaRESUMEN
Mycoplasma pneumoniae (Mp) triggers Guillain-Barré syndrome (GBS) and elicits anti-galactocerebroside (GalC) antibodies. Specifically anti-GalC IgG is associated with Mp-GBS, possibly because of its better ability to cross the blood-nerve barrier (BNB). We here investigated CSF for the presence of anti-GalC in GBS. Intrathecal anti-GalC was found in 46% of Mp-GBS patients (n=6/13), in contrast to 16% of GBS controls (n=4/25) and 0% of non-GBS controls (n=0/7). The antibodies most likely originated from increased BNB permeability and/or intrathecal synthesis. Intrathecal anti-GalC IgG was specifically associated with Mp-GBS, further supporting that anti-GalC IgG contributes to the pathogenesis of GBS.
Asunto(s)
Autoanticuerpos/líquido cefalorraquídeo , Galactosilceramidas/líquido cefalorraquídeo , Síndrome de Guillain-Barré/inmunología , Mycoplasma pneumoniae/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Femenino , Galactosilceramidas/inmunología , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Síndrome de Guillain-Barré/microbiología , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Neumonía por Mycoplasma/complicaciones , Adulto JovenRESUMEN
IMPORTANCE: There is an urgent need for biomarkers to monitor treatment efficacy and anticipate outcome in patients with Guillain-Barré syndrome (GBS). OBJECTIVE: To assess whether there is an association between serum albumin levels, a widely used and relatively easily measurable biomarker of health and inflammation, and the clinical course and outcome of GBS in patients treated with intravenous immunoglobulin (IVIG). DESIGN, SETTING, AND PARTICIPANTS: We used serum samples derived from a cohort of patients with GBS admitted to hospitals across the Netherlands participating in national GBS studies from May 5, 1986, through August 2, 2000. Serum albumin was measured from January 13 to 20, 2011. Analysis was performed from February 25, 2013, to September 6, 2016. All patients fulfilled the criteria for GBS and had severe disease (defined as not being able to walk unaided >10 m). Patients misdiagnosed as having GBS were retrospectively excluded from the study. Serum samples were obtained before and after IVIG treatment at 4 standardized time points from 174 patients. Albumin levels were determined by routine diagnostic turbidimetry and related to demographics and clinical course during a follow-up of 6 months. MAIN OUTCOMES AND MEASURES: Serum albumin concentration was determined before and after treatment with IVIG and related to clinical outcome: muscle weakness (measured by Medical Research Council sum score), respiratory failure (measured by requirement and duration of mechanical ventilation), and ability to walk (measured by GBS disability score). RESULTS: Serum albumin levels were determined in 174 patients with GBS (mean [SD] age, 49.6 [20.1] years; 99 males [56.9%]). Before treatment, the median serum albumin level was 4.2 g/dL (interquartile range, 3.8-4.5 g/dL), with hypoalbuminemia (albumin, <3.5 g/dL) in 20 (12.8%) of 156 patients. Two weeks after commencing treatment with IVIG (2 g/kg), the median serum albumin level decreased to 3.7 g/dL (interquartile range, 3.2-4.1 g/dL) (P < .001), and the number with hypoalbuminemia increased to 60 (34.5%) of 174 (P < .001). Hypoalbuminemia was associated with an increased chance of respiratory failure before (16 [36.4%] of 44, P = .001) or after (29 [54.7%] of 53, P < .001) IVIG treatment, inability to walk unaided (21 [35.0%] of 60 vs 6 [5.3%] of 114, P < .001), and severe muscle weakness at 4 weeks (Medical Research Council sum score, 31.8 vs 52.9, P < .001) and 6 months (Medical Research Council sum score, 49.4 vs 58.4, P < .001). CONCLUSIONS AND RELEVANCE: Patients with GBS may develop hypoalbuminemia after treatment with IVIG, which is related to a more severe clinical course and a poorer outcome. Further studies are required to confirm that serum albumin can be used as a biomarker to monitor disease activity and treatment response to IVIG in patients with GBS.
Asunto(s)
Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Albúmina Sérica/metabolismo , Estadística como Asunto , Adulto , Anciano , Análisis de Varianza , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study. METHODS: We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198). RESULTS: Anti-M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti-M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006). INTERPRETATION: M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566-580.
Asunto(s)
Anticuerpos Antibacterianos/inmunología , Autoanticuerpos/inmunología , Galactosilceramidas/inmunología , Síndrome de Guillain-Barré/inmunología , Infecciones por Mycoplasma/inmunología , Mycoplasma pneumoniae/inmunología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Reacciones Cruzadas , Femenino , Síndrome de Guillain-Barré/etiología , Humanos , Inmunoglobulina G , Inmunoglobulina M , Masculino , Persona de Mediana Edad , Infecciones por Mycoplasma/complicaciones , Adulto JovenRESUMEN
Treatment of Guillain-Barré syndrome with a standard course of high-dose intravenous immunoglobulin (IVIg) results in a variable clinical recovery which is associated with changes in serum IgG levels after treatment. The neonatal Fc-receptor protects IgG from degradation, and a genetic polymorphism in its promoter region that influences the expression of Fc-receptor, may in part explain the variation in IgG levels and outcome. This polymorphism was determined by polymerase chain reaction in a cohort of 257 patients with Guillain-Barré syndrome treated with IVIg. We could not demonstrate a relation between this polymorphism, the pharmacokinetics of IVIg, or the clinical course and outcome.
RESUMEN
OBJECTIVE: Guillain-Barré syndrome (GBS) is a postinfectious neuropathy most frequently caused by Campylobacter jejuni. Lipo-oligosaccharides (LOS), expressed by C. jejuni induce antibodies that cross-react with self-glycolipids in peripheral nerves, causing neuropathy. Less than 1 in 1,000 persons infected with C. jejuni develop GBS, and the factors that determine GBS susceptibility are poorly understood. We hypothesized that these persons have a high intrinsic dendritic cell (DC) response to C. jejuni LOS through Toll-like receptor 4 (TLR4) activation. METHODS: Intrinsic DC responsiveness to C. jejuni LOS was investigated first in 20 healthy controls at three time points with a 3-month interval, and second in patients, who previously developed GBS after a C. jejuni infection (n = 27) and controls (n = 26). RESULTS: The DC response to C. jejuni LOS was highly variable between, but not within, healthy individuals, suggesting that intrinsic factors determine the magnitude of TLR4-mediated innate response. High responsiveness to C. jejuni LOS by former GBS patients was evidenced by increased expression of CD38 and CD40. Frequency of CD38, CD40 and type I interferon high responders was significantly increased in the GBS group. INTERPRETATION: These results suggest that a strong response to TLR4 stimulation is a critical host condition for the development of GBS after an infection with C. jejuni.
Asunto(s)
Infecciones por Campylobacter/inmunología , Campylobacter jejuni/inmunología , Células Dendríticas/inmunología , Síndrome de Guillain-Barré/inmunología , Inmunidad Innata/inmunología , Receptor Toll-Like 4/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Infecciones por Campylobacter/diagnóstico , Infecciones por Campylobacter/epidemiología , Femenino , Estudios de Seguimiento , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/epidemiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Monoclonal gammopathy in patients with amyotrophic lateral sclerosis (ALS) and related disorders has been reported in small studies but the validity of the reported associations remains uncertain. Presence of monoclonal gammopathy may indicate specific pathogenic pathways and may facilitate the development of novel treatment strategies. The objective of this large case-control study was to determine the prevalence of monoclonal gammopathy in motor neuron diseases (MND) and multifocal motor neuropathy (MMN). Monoclonal gammopathy was determined by immunoelectrophoresis and immunofixation in serum from 445 patients with ALS, 158 patients with progressive muscular atrophy (PMA), 60 patients with primary lateral sclerosis (PLS), 88 patients with MMN and in 430 matched healthy controls. Anti-ganglioside antibody titers were determined in sera from patients with MMN and PMA, and in ALS and PLS patients with monoclonal gammopathy. Logistic regression analysis was used to investigate associations of monoclonal gammopathy with motor neuron diseases and clinical characteristics. Neither ALS nor PLS was associated with monoclonal gammopathy. IgM monoclonal gammopathy was more frequent in patients with PMA (8 %) (OR = 4.2; p = 0.001) and MMN (7 %) (OR = 5.8; p = 0.002) than in controls (2 %). High titers of anti-GM1 IgM antibodies were present in 43 % of MMN patients and 7 % of PMA patients. Patients with PMA and IgM monoclonal gammopathy or anti-GM1 antibodies had a higher age at onset, more often weakness of upper legs and more severe outcome than patients with MMN. PMA and MMN, but not ALS and PLS, are significantly associated with IgM monoclonal gammopathy and anti-GM1 antibodies. These results may indicate that a subset of patients presenting with PMA share pathogenic mechanisms with MMN.
Asunto(s)
Inmunoglobulina M/sangre , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/inmunología , Paraproteinemias/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: Multifocal motor neuropathy (MMN) and the Guillain-Barré syndrome (GBS) are immune-mediated motor neuropathies with antibodies against the ganglioside GM1. In GBS, these antibodies are induced by molecular mimicry, but in MMN their origin is elusive. METHODS: We compared the light-chain use of anti-GM1 IgM antibodies in serum from 42 patients with MMN and 23 patients with GBS by ELISA. RESULTS: Exclusive use of either κ or λ light chains was found in 38 (90%) patients with MMN and 9 (39%) with GBS (p<0.001). CONCLUSIONS: Anti-GM1 IgM antibodies in most patients with MMN are produced by only a single or very limited number of B-cell clones, whereas in most patients with GBS, anti-GM1 IgM antibodies are most likely polyclonal.
Asunto(s)
Gangliósido G(M1)/inmunología , Síndrome de Guillain-Barré/inmunología , Inmunoglobulina M/inmunología , Polineuropatías/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Linfocitos B/metabolismo , Estudios de Casos y Controles , Síndrome de Guillain-Barré/sangre , Humanos , Inmunoglobulina M/sangre , Cadenas kappa de Inmunoglobulina/sangre , Cadenas lambda de Inmunoglobulina/sangre , Polineuropatías/sangreRESUMEN
Intravenous immunoglobulin (IVIg) is the treatment of choice for Guillain-Barré syndrome (GBS), an immune-mediated peripheral neuropathy causing rapidly progressive limb weakness and respiratory failure. The working mechanism of IVIg in autoimmune diseases has not been elucidated, but previous studies indicate that some anti-inflammatory effects may be mediated by the N-glycosylation of the Fc-portion of IgG. GBS is a model disease to investigate these effects because GBS is an acute and monophasic disorder usually affecting healthy persons, which is treated with a standard course of IVIg, although the clinical response is highly variable. In the current study, the N-glycosylation of the Fc-portion of serum IgG was investigated in patients with GBS before and after treatment with IVIg in relation to clinical course and outcome. Glycoforms of serum IgG1 and IgG2 were determined separately by liquid chromatography mass spectrometry. These IgG subclasses were purified from the serum of 174 GBS patients before and in 150 patients 2 weeks after standard IVIg treatment regimen. Treatment-naive GBS patients compared with age- and sex-matched controls had lower levels of galactosylation of IgG1 and IgG2. IVIg preparations contained relatively high levels of galactosylated and sialylated IgG Fc glycoforms compared with serum IgG in patients. Treatment with IVIg resulted in an increase in serum of the Fc-galactosylation and -sialylation of both IgG1 and IgG2. The extent of normalization in serum IgG Fc glycosylation varied between patients. Multiple logistic regression analysis showed that patients with persistent low IgG galactosylation and sialylation despite IVIg treatment had the most severe forms of GBS and needed ventilator support more often. Kaplan-Meier analysis showed that these patients also needed more time to be able to walk again compared with patients with a normalized IgG Fc glycosylation profile. In conclusion, our results suggest that serum IgG Fc glycosylation in GBS is related to disease severity and clinical recovery after IVIg and may help to develop new measures to monitor the efficacy of treatment.
Asunto(s)
Síndrome de Guillain-Barré/sangre , Fragmentos Fc de Inmunoglobulinas/sangre , Inmunoglobulina G/sangre , Adulto , Anciano , Secuencia de Carbohidratos , Femenino , Galactosa/análisis , Galactosa/química , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamiento farmacológico , Síndrome de Guillain-Barré/patología , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Inmunoglobulina G/química , Inmunoglobulinas Intravenosas/uso terapéutico , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Pronóstico , Índice de Severidad de la Enfermedad , Ácidos Siálicos/análisis , Ácidos Siálicos/química , Resultado del TratamientoRESUMEN
IgM antibodies against gangliosides and their complexes were studied in sera from 54 patients with polyneuropathy and IgM monoclonal gammopathy (IgM-PNP) without anti-MAG antibodies. Anti-ganglioside antibodies were found in 19 (35%) patients. Five (9%) patients had antibodies against ganglioside complexes. IgM antibodies against gangliosides activated complement in vitro. Light chain usage was restricted to kappa or lambda in most, but not all patients. In conclusion, anti-ganglioside antibodies in IgM-PNP are common, display pathogenic properties and do not always arise from a monoclonal B cell proliferation.
Asunto(s)
Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Gangliósidos/inmunología , Inmunoglobulina M/inmunología , Paraproteinemias/inmunología , Polineuropatías/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Especificidad de Anticuerpos/inmunología , Autoantígenos/inmunología , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Paraproteinemias/sangre , Paraproteinemias/epidemiología , Polineuropatías/sangre , PrevalenciaRESUMEN
OBJECTIVE: The aim of the study was to determine whether Guillain-Barré syndrome (GBS) is associated with preceding hepatitis E virus infection. METHODS: The frequency of hepatitis E virus (HEV) infections was determined by anti-HEV serology in a cohort of 201 patients with GBS and 201 healthy controls with a similar distribution in age, sex, and year of sampling. Blood samples from patients with GBS were obtained in the acute phase before treatment. In a subgroup of patients with GBS, blood, stool, and CSF samples were tested for HEV RNA. RESULTS: An increased ratio of anti-HEV immunoglobulin (Ig) M antibodies was found in 10 patients with GBS (5.0%) compared with 1 healthy control (0.5%, odds ratio 10.5, 95% confidence interval 1.3-82.6, p = 0.026). HEV RNA was detected in blood from 3 of these patients and additionally in feces from 1 patient. Seventy percent of anti-HEV IgM-positive patients had mildly increased liver function tests. All CSF samples tested negative for HEV RNA. The presence of anti-HEV IgM in patients with GBS was not related to age, sex, disease severity, or clinical outcome after 6 months. CONCLUSIONS: In the Netherlands, 5% of patients with GBS have an associated acute HEV infection. Further research is required to determine whether HEV infections also precede GBS in other geographical areas.
Asunto(s)
Síndrome de Guillain-Barré/epidemiología , Anticuerpos Antihepatitis/inmunología , Virus de la Hepatitis E/inmunología , Hepatitis E/epidemiología , ARN Viral/análisis , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Heces/virología , Femenino , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/virología , Hepatitis E/diagnóstico , Hepatitis E/inmunología , Virus de la Hepatitis E/genética , Humanos , Inmunoglobulina M/inmunología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Oportunidad Relativa , ARN Viral/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: All 25 CIDP patients had active but stable disease and were treated with individually optimised fixed dose IVIg regimens. IgG was measured by turbidimetry and variability was defined as coefficient of variation (CV). RESULTS: The intra-patient variability of the pre-treatment IgG levels, post-treatment levels and increase in serum IgG shortly after IVIg (ΔIgG) was low (mean CV=3%, 4%, 10%). The inter-patient variability between patients treated with the same dose and interval was low in pre-treatment, post-treatment and ΔIgG level (mean CV=13%, 11%, 20%). The ΔIgG levels were associated with IVIg dosage (rs=0.78, p<0.001). CONCLUSIONS: Clinically stable CIDP patients show a steady-state in serum IgG after serial IVIg infusions. The low intra- and inter-patient variability in IgG may indicate that constant levels are required to reach this stability.
Asunto(s)
Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/uso terapéutico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/sangre , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
BACKGROUND: Campylobacter jejuni is the predominant antecedent infection in Guillain-Barré syndrome (GBS). Molecular mimicry and cross-reactive immune responses to C. jejuni lipo-oligosaccharides (LOS) precipitate the development of GBS, although this mechanism has not been established in patients from developing countries. We determined the carbohydrate mimicry between C. jejuni LOS and gangliosides, and the cross-reactive antibody response in patients with GBS in Bangladesh. METHODOLOGY: Sera from 97 GBS patients, and 120 neurological and family controls were tested for antibody reactivity against LOS from C. jejuni isolates from GBS patients in Bangladesh (BD-07, BD-39, BD-10, BD-67 and BD-94) by enzyme-linked immunosorbent assay (ELISA). Cross-reactivity to LOS was determined by ELISA. The LOS outer core structures of C. jejuni strains associated with GBS/MFS were determined by mass spectrometry. PRINCIPLE FINDINGS: IgG antibodies to LOS from C. jejuni BD-07, BD-39, BD-10, and BD-67 IgG antibodies were found in serum from 56%, 58%, 14% and 15% of GBS patients respectively, as compared to very low frequency (<3%) in controls (p<0.001). Monoclonal antibodies specific for GM1 and GD1a reacted strongly with LOS from the C. jejuni strains (BD-07 and BD-39). Mass spectrometry analysis confirmed the presence of GM1 and GD1a carbohydrate mimics in the LOS from C. jejuni BD-07 and BD-39. Both BD-10 and BD-67 express the same LOS outer core, which appears to be a novel structure displaying GA2 and GD3 mimicry. Up to 90-100% of serum reactivity to gangliosides in two patients (DK-07 and DK-39) was inhibited by 50 µg/ml of LOS from the autologous C. jejuni isolates. However, patient DK-07 developed an anti-GD1a immune response while patient DK-39 developed an anti-GM1 immune response. CONCLUSION: Carbohydrate mimicry between C. jejuni LOS and gangliosides, and cross-reactive serum antibody precipitate the majority of GBS cases in Bangladesh.