RESUMO
Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.
Assuntos
Autoimunidade , Linfócitos T CD8-Positivos , Síndrome de Guillain-Barré , Nervos Periféricos , Doenças do Sistema Nervoso Periférico , Células Th1 , Humanos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/imunologia , Antígenos HLA-DR/imunologia , Epitopos Imunodominantes/imunologia , Bainha de Mielina/imunologia , Nervos Periféricos/imunologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/imunologia , Células Th1/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Memória ImunológicaRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.
Assuntos
Autoanticorpos/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Idoso , Animais , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Síndrome de Guillain-Barré/epidemiologia , Humanos , Macaca , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Ratos , Espanha/epidemiologiaAssuntos
Síndrome de Guillain-Barré/genética , Imunoglobulinas/metabolismo , Mediadores da Inflamação/metabolismo , MicroRNAs/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Síndrome de Guillain-Barré/sangue , Humanos , Imunoglobulinas/sangue , Interleucina-6/sangue , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is a common acute immune-mediated inflammatory disorder affecting the peripheral nervous system (PNS) of humans. Studies in humans and in animal models revealed that neuropeptide Y (NPY) levels are altered in some neurodegenerative and neuroimmune disorders. Herein, we investigated the levels of NPY and cytokines in the serum of GBS patients and explored the roles of NPY in the disease severity and its short-term prognosis. METHODS: Twenty patients with GBS (case group) and twenty healthy individuals (control group) were enrolled in this study. NPY levels were analyzed by enzyme-linked immunosorbent assay (ELISA). The levels of pro- and anti-inflammatory cytokines (including interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, IL-12p70, IL-17A, and tumor necrosis factor-α (TNF-α)) were analyzed using cytometric beads array (CBA). The clinical characteristics, disease severity, and short-term prognosis were compared between the two groups. RESULTS: Compared with the control group, the levels of NPY and cytokines were significantly increased in the serum of patients with GBS. NPY levels in the serum of GBS patients were correlated with the disease severity. CONCLUSION: Our results suggest that NPY and cytokines are involved in the pathogenesis of GBS. The levels of NPY can help to predict the severity of the disease.
Assuntos
Citocinas/sangue , Citocinas/efeitos dos fármacos , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/tratamento farmacológico , Imunoglobulinas Intravenosas/farmacologia , Neuropeptídeo Y/sangue , Neuropeptídeo Y/efeitos dos fármacos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Gangliosides are sialylated glycosphingolipids, highly abundant in our nervous system. Antibodies targeting gangliosides are usually developed as a consequence of molecular mimicry following infections. Antiganglioside antibodies are implicated in many neurological disorders such as acute and chronic polyradiculoneuropathies which includes different variants of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy. Presence of such antibodies in paraneoplastic peripheral neuropathy, neurodegenerative disorders, multiple sclerosis, myasthenia gravis and amyotrophic lateral sclerosis have also been reported. Recent evidence supports a role of antiganglioside antibodies in the pathogenesis of acute vestibular syndrome. Binding of antibodies to gangliosides on axonal membranes, nodes of Ranvier, myelin sheath components, Schwann cells, neuromuscular junctions or other neural cell surfaces may elicit inflammatory damage through complement-dependent and independent mechanisms, resulting in nerve conduction blocks and subsequent axonal degeneration. Gangliosides are essential for proper cell signaling, transduction and influences neuroplasticity, all of which are affected by autoimmune mediated damage. Better insight into the pathophysiological role of antiganglioside antibodies in different neurological diseases may improve their utility as diagnostic and prognostic biomarkers.
Assuntos
Autoanticorpos/sangue , Gangliosídeos/sangue , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/diagnóstico , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Humanos , Polineuropatias/sangue , Polineuropatias/diagnósticoRESUMO
OBJECTIVE: To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. METHODS: Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. RESULTS: Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti-NF-155 IgG4 were directed against the NF-155-specific Fn3Fn4 domain. The description of a second phenotype of anti-NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. CONCLUSIONS: Our results indicate that anti-pan-NF-associated neuropathy differs from anti-NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti-NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.
Assuntos
Autoanticorpos/sangue , Moléculas de Adesão Celular/sangue , Imunoglobulina G/sangue , Fatores de Crescimento Neural/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Autoanticorpos/imunologia , Biomarcadores/sangue , Moléculas de Adesão Celular/imunologia , Linhagem Celular Tumoral , Criança , Estudos de Coortes , Feminino , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/imunologia , Células HEK293 , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Ratos , Ratos Endogâmicos Lew , Adulto JovemRESUMO
Acetylcholine receptor antibodies are very specific for myasthenia. During a large prospective cohort study of myasthenia, we encountered five patients, positive for acetylcholine receptor (AChR) antibodies by radioimmunoprecipitation assay (RIA), whose clinical course revealed diagnoses other than myasthenia. Two patients had transiently raised AChR antibodies associated with Guillain-Barré syndrome. Antibodies to clustered AChRs, in a live cell-based assay, were negative in all five patients, suggesting that results from the RIAs were false-positives. It is possible that the AChR antibodies detected by RIA in these cases were non-pathogenic, and directed to intracellular epitopes of the AChR.
Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Miastenia Gravis/sangue , Receptores Nicotínicos/imunologia , Adulto , Idoso , Especificidade de Anticorpos , Autoanticorpos/imunologia , Erros de Diagnóstico , Epitopos/imunologia , Reações Falso-Positivas , Feminino , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/diagnóstico , Estudos Prospectivos , Ensaio de Radioimunoprecipitação , Avaliação de Sintomas , Adulto JovemRESUMO
Interactions among cytokines have important roles in the inflammatory processes underlying Guillain-Barré syndrome (GBS). Resistin and high mobility group box 1 (HMGB1) are involved in many inflammatory processes. This study examined 51 GBS patients, and found that serum resistin levels were elevated in 51 patients with GBS and correlated with HMGB1 levels. In vitro, resistin induced the release of HMGB1, interleukin (IL)-1ß, and IL-6 in THP-1 macrophages. This process was dependent on activation of p38 mitogen-activated protein kinase and NF-κB signaling pathways. These results suggest that signaling between resistin and HMGB1 might be a potential therapeutic target in GBS.
Assuntos
Síndrome de Guillain-Barré/sangue , Proteína HMGB1/sangue , Resistina/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/genética , Proteína HMGB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Resistina/farmacologia , Adulto JovemRESUMO
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.
Assuntos
Subpopulações de Linfócitos B/imunologia , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Leucócitos Mononucleares/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Síndrome de Guillain-Barré/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Guillain-Barré syndrome is an acute inflammatory demyelinating polyneuropathy that is characterized histologically by demyelination of peripheral nerves and nerve roots, infiltrates of T lymphocytes, and an inflammatory response that includes macrophage infiltrates. The aim of this study was to evaluate the effects of vasoactive intestinal peptide (VIP) in a rat model of experimental autoimmune neuritis (EAN). METHODS: Forty male Lewis rats were divided into a control group (N=10), an EAN group (N=10), an EAN group treated with 15 nmol of VIP (N=10), and an EAN group treated with 30 nmol of VIP (N=10). The rat model was created by subcutaneous injection of P2 polypeptide (200 µg P257-81) into the base of the tail. Intraperitoneal injection of VIP was given on day 7. Rats were weighed and functionally evaluated using an EAN score (0-10). On day 16, the rats were euthanized. The sciatic nerve was examined histologically and using immunohistochemistry with antibodies against CD8, CD68, and forkhead box p3 (Foxp3). Serum concentrations of IL-17 and interferon-α (IFN-α) were measured by ELISA on day 16 after creating the EAN model. RESULTS: The VIP-treated EAN groups had increased body weight and improved EAN scores compared with the untreated EAN group. CD8-positive and CD68-positive cells were significantly reduced in the EAN group treated with 30 nmol of VIP compared with 15 nmol of VIP. Foxp3-positive cells were significantly decreased in both EAN groups treated with VIP, and serum concentrations of IL-17 and IFN-α were significantly lower compared with the untreated EAN group (P<0.05). CONCLUSION: In a rat model of EAN, treatment with VIP resulted in functional improvement, reduced nerve inflammation, and decreased serum levels of inflammatory cytokines.
Assuntos
Modelos Animais de Doenças , Síndrome de Guillain-Barré/tratamento farmacológico , Neurite Autoimune Experimental/tratamento farmacológico , Peptídeo Intestinal Vasoativo/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/patologia , Interferon-alfa/sangue , Interleucina-17/sangue , Masculino , Neurite Autoimune Experimental/sangue , Neurite Autoimune Experimental/patologia , Ratos , Ratos Endogâmicos Lew , Peptídeo Intestinal Vasoativo/síntese química , Peptídeo Intestinal Vasoativo/química , Vasodilatadores/síntese química , Vasodilatadores/químicaRESUMO
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.
Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Gangliosídeos/imunologia , Gamopatia Monoclonal de Significância Indeterminada/imunologia , Polineuropatia Paraneoplásica/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/sangue , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Síndrome de Miller Fisher/sangue , Síndrome de Miller Fisher/imunologia , Gamopatia Monoclonal de Significância Indeterminada/sangue , Polineuropatia Paraneoplásica/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/sangue , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/imunologiaRESUMO
Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system triggered by molecular mimicry between pathogen lipopolysaccharides and host nerve gangliosides. Polymorphisms in the Fas receptor (FAS) and Fas ligand (FASL) genes may potentially alter the elimination of autoreactive immune cells and affect disease susceptibility or disease severity in GBS. We detected single nucleotide polymorphisms (SNPs) in FAS (-1377G/A and -670A/G) and FASL (-843C/T) in a prospective cohort of 300 patients with GBS and 300 healthy controls from the Bangladeshi population. Genotype distributions were not significantly different between patients with GBS and healthy controls. The FAS -670 AG heterozygous (P = 0.0005, OR = 2.5, 95% CI = 1.5-4.2) and GG homozygous (P = 0.0048, OR = 2.6, 95% CI = 1.3-5.0) genotypes were more common in patients with anti-GM1 antibodies than patients without anti-GM1 antibodies. The FAS -670 G allele was more prevalent in anti-GM1 antibody-positive than -negative patients (P = 0.0002, OR = 1.9, 95% CI = 1.4-2.7) and also in patients with the axonal subtype than demyelinating subtype (P < 0.0001, OR = 4.8, 95% CI = 2.3-10.1). The 1377G/-670G GG haplotype was significantly associated with the axonal subtype (P < 0.0001) and anti-ganglioside antibody-positivity (P = 0.0008) in GBS. Serum sFas (237.5 pg/mL vs. 159.5 pg/mL; P < 0.0001) and sFasL (225.1 pg/mL vs. 183.4 pg/mL; P = 0.0069) were elevated in patients with GBS compared to healthy controls, and among patients with high serum sFas was associated with severe GBS (P = 0.0406). In conclusion, this study indicates FAS-FASL promoter SNPs may promote the production of cross-reactive anti-ganglioside antibodies in GBS.
Assuntos
Proteína Ligante Fas/genética , Síndrome de Guillain-Barré/sangue , Sistema Nervoso Periférico/patologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptor fas/genética , Adolescente , Adulto , Bangladesh , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Gangliosídeo G(M1)/imunologia , Síndrome de Guillain-Barré/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem , Receptor fas/sangueRESUMO
Pazopanib, one of the antiangiogenic drugs, has recently become a first-line treatment for metastatic renal cell carcinoma. The most common adverse effects of pazopanib include diarrhea, fatigue, and nausea, but neuropathic complication has not been documented. Here, we report the first case of a patient with metastatic renal cell carcinoma who developed acute neuropathy mimicking Guillain-Barré syndrome following the first course of pazopanib therapy. A 75-year-old man with a metastatic renal cell carcinoma was admitted for rapidly progressive weakness and numbness in the extremities after the first course of pazopanib therapy. Neurological examination revealed symmetrical distal limb weakness, sensory disturbance, and areflexia. Based on the clinical pictures, conduction slowing on the nerve conduction studies of the extremities and albuminocytologic dissociation on the cerebrospinal fluid examination, a diagnosis of Guillain-Barré syndrome was made. After discontinuation of pazopanib and a subsequent high-dose intravenous immunoglobulin therapy, symptoms rapidly resolved and the patient became ambulatory with a cane. Serological and neuroradiological examinations failed to reveal any possible causes for the neuropathy other than pazopanib. While the benefits of pazopanib for metastatic renal cell carcinoma far outweigh this neurotoxic effect, physicians prescribing this drug should be aware of this rare complication of neuropathy.
Assuntos
Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Síndrome de Guillain-Barré/induzido quimicamente , Imunoglobulinas Intravenosas/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Administração Oral , Idoso , Carcinoma de Células Renais/secundário , Eletromiografia , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Humanos , Indazóis , Neoplasias Renais/patologia , Imageamento por Ressonância Magnética , Masculino , Testes SorológicosRESUMO
BACKGROUND: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. METHODS: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. RESULTS: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. CONCLUSION: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.
Assuntos
Síndrome de Guillain-Barré , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interleucina-33/sangue , Linfócitos T Reguladores/patologia , Idoso , Idoso de 80 Anos ou mais , Dinoprostona/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Seguimentos , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Estatísticas não ParamétricasRESUMO
INTRODUCTION: Voltage-gated Kv1 potassium channel complex (VGKC) autoantibodies subtyped for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated-proteinlike 2 (CASPR2), and Kv IgGs have a spectrum of neurological presentations. Painful polyneuropathy is seen in some patients, but nerve pathology descriptions are lacking. METHODS: Clinicopathologic features were studied in subtyped VGKC-autoantibody-seropositive patients who had undergone nerve biopsies. RESULTS: Five patients were identified, 1 LGI1 IgG positive and 1 CASPR2 IgG positive, but all negative for Kv1.1-, 1.2-, 1.6-subtyped IgG autoantibodies. Median symptom duration was 17 months. Pain was the predominant symptom; 3 had mild sensory loss and/or weakness. Histopathological abnormalities were limited to axonal loss in 3. None had mononuclear cellular infiltrates. Electron micrographs revealed no interstitial abnormalities. Three patients reported marked improvement in pain with immunotherapy. CONCLUSIONS: The nerve biopsy histopathology of patients subtyped for LGI1 and CASPR2 IgGs within the VGKC-complex spectrum disorders shows either normal density or axonal fiber loss without inflammatory infiltrates. A reversible neural hyperexcitable mechanism is considered to be the cause of this painful polyneuropathy. Muscle Nerve 55: 520-525, 2017.
Assuntos
Autoanticorpos/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/complicações , Canal de Potássio KCNQ1/imunologia , Dor/etiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Síndrome de Guillain-Barré/patologia , Síndrome de Guillain-Barré/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana/imunologia , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/imunologia , Condução Nervosa/fisiologia , Dor/sangue , Dor/tratamento farmacológico , Dor/patologia , Proteínas/imunologia , Índice de Gravidade de Doença , Nervo Sural/patologia , Nervo Sural/ultraestruturaRESUMO
ABSTRACT The purpose of this study was to investigate the prognostic value of the pretreatment and post-treatment albumin level, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) in subtypes of Guillain-Barré syndrome (GBS). A retrospective analysis of 62 patients with GBS treated between 2011 and 2015 in Dicle University Hospital, Turkey, was carried out. The pretreatment and post-treatment albumin, NLR, and PLR were documented, together with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy, motor sensory axonal neuropathy, and Hughes’ scores. Post-treatment albumin levels in GBS were significantly reduced, and albumin level was negatively correlated with the Hughes scores. Elevated pretreatment NLRs and PLRs were significantly associated with AIDP. There were no correlations between the Hughes scores, NLR, and PLR. The results point to a negative correlation between albumin levels and GBS disability and suggest that the NLR and PLR may be promising blood biomarkers of AIDP.
RESUMO O objetivo deste estudo foi investigar o valor prognóstico dos níveis pré e pós-tratamento de albumina , da relação neutrófilo/linfócito (RNL) e da relação plaqueta/linfócito (RPL) em subtipos de síndrome de Guillain-Barré (SGB). Realizou-se uma análise retrospectiva de 62 pacientes com GBS, tratados entre 2011 e 2015 no Hospital da Universidade Dicle, na Turquia. Os valores pré e pós-tratamento de albumina, RNL e RPL foram documentados, juntamente com polirradiculoneuropatia desmielinizante inflamatória aguda, (PDIA) neuropatia axonal motora aguda, neuropatia axonal sensorial motora e pontuações de Hughes. Os níveis de albumina reduziram significativamente pós-tratamento e correlacionaram-se negativamente com as pontuações de Hughes. RNLs e RPLs pré-tratamento elevados foram significativamente associados à PDIA. Não houve correlação entre as pontuações de Hughes, RNL e RPL. Os resultados apontam uma correlação negativa entre os níveis de albumina e a deficiência na SGB e sugerem que a RNL e a RPL possam ser promissores biomarcadores sanguíneos para PDIA.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Plaquetas , Albumina Sérica/análise , Linfócitos , Síndrome de Guillain-Barré/sangue , Neutrófilos , Prognóstico , Valores de Referência , Contagem de Células Sanguíneas , Biomarcadores/sangue , Estudos Retrospectivos , Análise de Variância , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
Multiple sclerosis (MS) is a complex, demyelinating disease of the central nervous system (CNS) with variable phenotypic presentations, while Guillain-Barre Syndrome (GBS) is the prototypic acute inflammatory disorder that affects the peripheral nervous system. Myasthenia gravis (MG) is a T cell dependent and antibody mediated autoimmune disease. Although it has been shown that complement plays a critical role in the pathogenesis of MS, GBS, and MG, the role of mannose-binding lectin (MBL) as a biomarker of immunopathogensis of these diseases and also its association with the severity of them have been poorly investigated. Therefore, in this study we aimed to measure plasma levels of MBL in patients with MS, GBS, and MG. In a case-control study, plasma was obtained from healthy controls (n=100) and also patients with MS (n=120), GBS (n=30), and MG (n=30). Plasma level measurement of MBL was performed using enzyme-linked immunosorbent assay (ELISA). The mean serum level of MBL was significantly different between groups of patients and healthy controls (p<0.001). We also found a positive correlation between plasma levels of MBL and severity scores of MS, MG, and GBS patients including: expanded disability status scale (EDSS) (r=+0.60 and p=<0.001), quantitative myasthenia gravis score (QMGS) (r=+0.56 and p=0.01), and GBS disability scale (GDS) (r=+0.37 and p=0.04). Taken together, our findings suggest that complement activation mediated by MBL contributes to the pathogenesis and also severity of MS, MG, and GBS. However, because the lectin pathway can be involved in several phases of the immune response, further evidence will be required to elucidate the underlying mechanism.
Assuntos
Lectina de Ligação a Manose da Via do Complemento/imunologia , Síndrome de Guillain-Barré/imunologia , Lectina de Ligação a Manose/imunologia , Esclerose Múltipla/imunologia , Miastenia Gravis/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Síndrome de Guillain-Barré/sangue , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Miastenia Gravis/sangueRESUMO
Normal autoimmune function is dependent on adequate levels of activated vitamin D, 25 hydroxy vitamin D [25(OH)D]. A recent study presented deficiency of 25(OH)D levels in Swedish MG patients. We aimed to study 25(OH)D levels in patients with MG and autoimmune polyneuropathies (PNP) at a southern latitude in Greece. Plasma levels of 25(OH)D were analyzed in Greek patients with MG (n = 19), immune-mediated PNP (N = 11) and in 30 Greek healthy age- and sex-matched controls. Ten MG patients received supplementation with vitamin D3. The MG Composite Score (MGC) and MG quality of life assessed disease severity in MG patients, whereas the INCAT Disability Scale assessed clinical features in the PNP patients. MG patients with and without vitamin D3 supplementation had higher 25(OH)D levels (mean 58.8 ± 16.3 and 62.0 ± 22.4 nmol/L, respectively) than PNP patients (mean 42.1 ± 11.5 nmol/L, p = 0.01) and healthy controls (mean 45.7 ± 13.8 nmol/L, p = 0.01). Plasma 25(OH)D levels was lower with age in all groups. There were no correlations between 25(OH)D and disease duration, MGC score, or INCAT score. Vitamin D deficiency was found in all Greek patient groups and healthy controls. Levels of 25(OH)D were higher in MG patients with as well as without vitamin D supplementation compared to healthy controls, whereas CIDP/GBS patients had levels similar to controls.
Assuntos
Miastenia Gravis/sangue , Miastenia Gravis/epidemiologia , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/epidemiologia , Vitamina D/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Anticorpos/sangue , Feminino , Grécia/epidemiologia , Síndrome de Guillain-Barré/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/sangue , Receptores Colinérgicos/sangue , Receptores Colinérgicos/imunologia , Estações do Ano , Índice de Gravidade de Doença , Adulto JovemRESUMO
Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system characterized by weakness in the limbs. To date, numerous hypotheses have been suggested to explain the pathogenesis of GBS; however, the pathogenesis of GBS remains to be elucidated. The aim of the present study was to investigate the association between Toll-like receptor (TLR) 2, TLR4 and GBS. Therefore, the mRNA of TLR2, TLR4, myeloid differentiation factor (MyD)88 and nuclear factor (NF)-κB of peripheral blood mononuclear cells (PBMCs) in patients with GBS and healthy controls was assessed. To confirm the function of TLR2 and TLR4 in the pathogenesis of GBS, PBMCs derived from patients with GBS and healthy controls were cultured with various TLR agonists. The levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were measured in the culture supernatant and fasting serum was obtained for the detection of anti-ganglioside antibodies. The results revealed that the mRNA levels of TLR2, TLR4, MyD88 and NF-κB were significantly increased in patients with GBS compared with those in healthy controls (P=0.003, 0.017, 0.032 and 0.015, respectively). PBMCs from patients with GBS secreted higher levels of TNF-α and IL-1ß than those from control subjects. The positive rate of immunoglobulin (Ig)G and IgM anti-ganglioside antibodies in patients with severe GBS was 42.86%, which was markedly higher than rates found in patients with mild GBS (9.09 and 18.18%, respectively). The results of the present study demonstrated that TLR2 and TLR4 are involved in the pathogenesis of GBS and that they and their associated signaling pathways may be targets for the treatment of GBS.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/patologia , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Estudos de Casos e Controles , Progressão da Doença , Regulação da Expressão Gênica , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Interleucina-1beta/biossíntese , Interleucina-1beta/sangue , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Índice de Gravidade de Doença , Transdução de Sinais , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/sangueRESUMO
Guillain-Barré Syndrome (GBS) is a demyelinating polyneuropathy resulting in sensory, motor and autonomic symptoms. The severity of the disease can range from mild to severe but it is classically described as an ascending demyelinating process. Initially thought to be the sequelae of a bacterial or viral infection, the clinical symptoms of post-infective GBS can present up to 4 weeks after sentinel injury. A rarely defined post-surgical GBS has been since described after major cranial, cardiothoracic and gastro-intestinal surgery. Post traumatic GBS is an even more unusual presentation with very few cases reported in contemporary academic literature. We present a case of GBS presenting two weeks after non-operative traumatic brain injury (TBI) and a review of the literature.