RESUMO
OBJECTIVE: Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired B-cell response following treatment with anti-CD20 monoclonal antibodies (mAbs), mostly in those treated for haematological malignancies. We aimed to describe severe EV infections in patients receiving anti-CD20 mAbs for immune-mediated inflammatory diseases (IMIDs). METHODS: Patients were included following a screening of data collected through the routine surveillance of EV infections coordinated by the National Reference Center and a review of the literature. Additionally, neutralising antibodies were assessed in a patient with chronic EV-A71 meningoencephalitis. RESULTS: Nine original and 17 previously published cases were retrieved. Meningoencephalitis (n=21/26, 81%) associated with EV-positive cerebrospinal fluid (n=20/22, 91%) was the most common manifestation. The mortality rate was high (27%). EV was the only causal agents in all reported cases. Patients received multiple anti-CD20 mAbs infusions (median 8 (5-10)), resulting in complete B-cell depletion and moderate hypogammaglobulinemia (median 4.9 g/L (4.3-6.7)), and had limited concomitant immunosuppressive treatments. Finally, in a patient with EV-A71 meningoencephalitis, a lack of B-cell response to EV was shown. CONCLUSION: EV infection should be evoked in patients with IMIDs presenting with atypical organ involvement, especially meningoencephalitis. Anti-CD20 mAbs may lead to impaired B-cell response against EV, although an underlying primary immunodeficiency should systematically be discussed.
Assuntos
Anticorpos Monoclonais , Antígenos CD20 , Infecções por Enterovirus , Humanos , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/diagnóstico , Masculino , Feminino , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Pessoa de Meia-Idade , Adulto , Meningoencefalite/imunologia , Meningoencefalite/virologia , Meningoencefalite/etiologia , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Idoso , Rituximab/uso terapêutico , Linfócitos B/imunologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/complicações , Inflamação/imunologiaRESUMO
BACKGROUND: Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM. METHODS: The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility. RESULTS: This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036). LIMITATIONS: The study was limited by the lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME. CONCLUSIONS: The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM.
Assuntos
Autoanticorpos , Doenças do Cão , Proteína Glial Fibrilar Ácida , Meningoencefalite , Doenças da Medula Espinal , Animais , Cães , Doenças do Cão/genética , Doenças do Cão/imunologia , Meningoencefalite/veterinária , Meningoencefalite/genética , Meningoencefalite/imunologia , Autoanticorpos/sangue , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/imunologia , Masculino , Doenças da Medula Espinal/veterinária , Doenças da Medula Espinal/genética , Feminino , Genótipo , Predisposição Genética para DoençaRESUMO
Objective: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. Methods: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. Results: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. Conclusions: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.
Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Proteína Glial Fibrilar Ácida/imunologia , Imunoglobulina G/imunologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Encefalomielite/sangue , Encefalomielite/líquido cefalorraquidiano , Encefalomielite/imunologia , Encefalomielite/fisiopatologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Lactente , Masculino , Meningoencefalite/sangue , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/imunologia , Meningoencefalite/fisiopatologia , Mielite/sangue , Mielite/líquido cefalorraquidiano , Mielite/imunologia , Mielite/fisiopatologia , Estudos RetrospectivosRESUMO
Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently defined autoimmune meningoencephalomyelitis, associated with GFAP-IgG antibody. A pooled analysis of 324 cases from published literature and a retrospective single-center study were performed, firstly reveals the possibility that patients with myelitic lesions respond better to initial immunotherapy, but are prone to relapse, suggesting a more aggressive and long-term immunosuppressive medication for them. Moreover, our results showed using tacrolimus at maintenance stage exhibited a less tendency to relapse, providing a possibly new choice to future clinical treatments.
Assuntos
Astrócitos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/epidemiologia , Proteína Glial Fibrilar Ácida/imunologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrócitos/patologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Criança , Pré-Escolar , China/epidemiologia , Encefalomielite/diagnóstico , Encefalomielite/tratamento farmacológico , Encefalomielite/epidemiologia , Encefalomielite/imunologia , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Quimioterapia de Manutenção , Masculino , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Meningoencefalite/epidemiologia , Meningoencefalite/imunologia , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: To describe the autopsy findings and neuropathologic evaluation of autoimmune meningoencephalomyelitis associated with glial fibrillary acidic protein (GFAP) antibody. METHODS: We reviewed the clinical course, imaging, laboratory, and autopsy findings of a patient with autoimmune meningoencephalomyelitis associated with GFAP antibody who had a refractory course to multiple immunosuppressive therapies. RESULTS: The patient was a 70-year-old man who was diagnosed as GFAP antibody-associated autoimmune meningoencephalomyelitis. MRI of the head showed linear perivascular enhancement in the midbrain and the basal ganglia. Despite treatment with high-dose corticosteroids, plasma exchange, IV immunoglobulins, and cyclophosphamide, he died with devastating neurologic complications. Autopsy revealed a coexistent neuroendocrine tumor in the small intestine and diffuse inflammation in the brain parenchyma, perivascular spaces, and leptomeninges, with predominant T-cells, macrophages, and activated microglia. B-cells and plasma cells were absent. There was no astrocyte involvement with change in GFAP immunostaining. DISCUSSION: This case illustrates autoimmune meningoencephalomyelitis associated with GFAP antibody in the CSF and coexistent neuroendocrine tumor. The autopsy findings were nonspecific and did not demonstrate astrocyte involvement. Further accumulation of cases is warranted to delineate the utility and pathogenic significance of the GFAP autoantibody.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Proteína Glial Fibrilar Ácida/imunologia , Meningoencefalite , Tumores Neuroendócrinos , Idoso , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Autopsia , Encefalomielite/diagnóstico , Encefalomielite/imunologia , Encefalomielite/patologia , Humanos , Masculino , Meningoencefalite/diagnóstico , Meningoencefalite/imunologia , Meningoencefalite/patologia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologiaRESUMO
Cryptococcal meningoencephalitis (CM) is a leading cause of central nervous system (CNS) infection-related mortality worldwide, with surviving patients often developing neurological deficiencies. While CNS inflammation has been implicated in the pathogenesis of CM, little is known about the relative contribution of the specific inflammatory/immune pathways to CNS pathology versus fungal clearance. Increased cerebrospinal fluid level of C-C chemokine receptor 2 (CCR2) ligand CCL2 is associated with disease deterioration in patients with CM. Using a murine model, we investigated the role of the CCR2 pathway in the development of CNS inflammation and pathology during CM. We found that CCR2-deficient mice exhibited improved 28-day survival and alleviated neurological disease scores despite a brain fungal burden higher than that of the WT mice. Reduced CM pathology in CCR2-deficient mice was accompanied by markedly decreased neuronal cell death around cryptococcal microcysts and restored expression of genes involved in neurotransmission, connectivity, and neuronal cell structure in the brains. Results show that CCR2 axis is the major pathway recruiting CD45hiCD11b+Ly6C+ inflammatory monocyte to the brain and indirectly modulates the accumulation of CD4+ T cells and CD8+ T cells. In particular, CCR2 axis promotes recruitment of interferon gamma (IFN-γ)-producing CD4+ T cells and classical activation of myeloid cells. In this context, CCR2 deletion limits the immune network dysregulation we see in CM and attenuates neuropathology. Thus, the CCR2 axis is a potential target for interventions aimed to limit inflammatory CNS pathology in CM patients. IMPORTANCE Cryptococcal meningoencephalitis (CM) causes nearly 200,000 deaths worldwide each year, and survivors frequently develop long-lasting neurological sequelae. The high rate of mortality and neurologic sequelae in CM patients indicate that antifungal therapies alone are often insufficient to control disease progression. Here, we reveal that CM disease progression in mice is accompanied by inflammatory monocytes infiltration at the periphery of the infected foci that overlap locally perturbed neuronal function and death. Importantly, we identified that CCR2 signaling is a critical pathway driving neuroinflammation, especially inflammatory monocyte recruitment, as well as CNS pathology and mortality in CM mice. Our results imply that targeting the CCR2 pathway may be beneficial as a therapy complementary to antifungal drug treatment, helping to reduce CNS damage and mortality in CM patients.
Assuntos
Encéfalo/imunologia , Encéfalo/patologia , Criptococose/imunologia , Cryptococcus/imunologia , Monócitos/imunologia , Receptores CCR2/metabolismo , Transdução de Sinais/imunologia , Animais , Encéfalo/microbiologia , Cryptococcus/patogenicidade , Feminino , Inflamação , Masculino , Meningoencefalite/imunologia , Meningoencefalite/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR2/genética , Receptores CCR2/imunologiaRESUMO
Data on the immune response to West Nile virus (WNV) are limited. We analyzed the antiviral cytokine response in serum and cerebrospinal fluid (CSF) samples of patients with WNV fever and WNV neuroinvasive disease using a multiplex bead-based assay for the simultaneous quantification of 13 human cytokines. The panel included cytokines associated with innate and early pro-inflammatory immune responses (TNF-α/IL-6), Th1 (IL-2/IFN-γ), Th2 (IL-4/IL-5/IL-9/IL-13), Th17 immune response (IL-17A/IL-17F/IL-21/IL-22) and the key anti-inflammatory cytokine IL-10. Elevated levels of IFN-γ were detected in 71.7% of CSF and 22.7% of serum samples (p = 0.003). Expression of IL-2/IL-4/TNF-α and Th1 17 cytokines (IL-17A/IL-17F/IL-21) was detected in the serum but not in the CSF (except one positive CSF sample for IL-17F/IL-4). While IL-6 levels were markedly higher in the CSF compared to serum (CSF median 2036.71, IQR 213.82-6190.50; serum median 24.48, IQR 11.93-49.81; p < 0.001), no difference in the IL-13/IL-9/IL-10/IFN-γ/IL-22 levels in serum/CSF was found. In conclusion, increased concentrations of the key cytokines associated with innate and early acute phase responses (IL-6) and Th1 type immune responses (IFN-γ) were found in the CNS of patients with WNV infection. In contrast, expression of the key T-cell growth factor IL-2, Th17 cytokines, a Th2 cytokine IL-4 and the proinflammatory cytokine TNF-α appear to be concentrated mainly in the periphery.
Assuntos
Citocinas/líquido cefalorraquidiano , Meningite/imunologia , Meningoencefalite/imunologia , Febre do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/imunologia , Idoso , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Interleucina-17/sangue , Interleucina-17/líquido cefalorraquidiano , Interleucina-17/imunologia , Interleucina-4/sangue , Interleucina-4/líquido cefalorraquidiano , Interleucina-4/imunologia , Masculino , Meningite/sangue , Meningite/líquido cefalorraquidiano , Meningite/virologia , Meningoencefalite/sangue , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/virologia , Pessoa de Meia-Idade , Células Th17/imunologia , Febre do Nilo Ocidental/genética , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Vírus do Nilo Ocidental/fisiologiaRESUMO
Myelin oligodendrocyte glycoprotein (MOG) antibodies have been found in a broad range of demyelination diseases. In the present study, we reported three cases of patients with anti-MOG antibodies associated disorders (MOG-ADs) who initially presented as intracranial infection like encephalomeningitis with no evidence of demyelination injury, but were subsequently found the expression of MOG antibodies and other demyelination presentations. Our findings suggested that MOG-ADs can start as an intracranial infection like prodromal symptoms prior to the lesions of optic nerve, spinal cord, and white matter. Therefore, clinicians should be cautious of MOG-ADs in cases of encephalomeningitis even without demyelination injury.
Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Meningoencefalite/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Autoantígenos/imunologia , Feminino , Humanos , Masculino , Meningoencefalite/patologia , Adulto JovemRESUMO
BACKGROUND: Manifestations of intractable hyponatremia and hypokalemia in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy have been rarely reported. CASE PRESENTATION: A 75-year-old male patient presented as the case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) and intractable hypokalemia, showed fever, fatigue, and mental disorders. Signs and symptoms of meningoencephalitis, ataxia, and cognitive abnormalities. Magnetic resonance imaging (MRI) revealed multiple white matter lesions of the central nervous system. He had GFAP-IgG in the cerebrospinal fluid (CSF). After treatment with corticosteroids, his symptoms were alleviated gradually, and the level of electrolytes was normal. However, head contrast-enhanced MRI + susceptibility-weighted imaging (SWI) showed a wide afflicted region, and the serum GFAP-IgG turned positive. Considering the relapse of the disease, ha was treated with immunoglobulin and mycophenolate mofetil (MMF) to stabilize his condition. CONCLUSION: This case showed a rare disease with uncommon manifestations, suggesting that careful examination and timely diagnosis are essential for disease management and satisfactory prognosis.
Assuntos
Corticosteroides/uso terapêutico , Astrócitos/patologia , Proteína Glial Fibrilar Ácida/imunologia , Doenças do Sistema Nervoso/tratamento farmacológico , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/líquido cefalorraquidiano , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Masculino , Meningoencefalite/imunologia , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/patologia , Doenças RarasAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Integrina alfa4/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Meningoencefalite/tratamento farmacológico , Natalizumab/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Integrina alfa4/imunologia , Integrina alfa4/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Masculino , Meningoencefalite/induzido quimicamente , Meningoencefalite/imunologia , Meningoencefalite/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Resultado do TratamentoRESUMO
X-linked lymphoproliferative disease (XLP1) is a combined immunodeficiency characterized by severe immune dysregulation caused by mutations in the SH2D1A/SAP gene. Loss or dysfunction of SH2D1A is associated with the inability in clearing Epstein-Barr-Virus (EBV) infections. Clinical manifestation is diverse and ranges from life-threatening hemophagocytic lymphohistiocytosis (HLH) and fulminant infectious mononucleosis (FIM) to lymphoma and antibody deficiency. Rare manifestations include aplastic anemia, chronic gastritis and vasculitis. Herein, we describe the case of a previously healthy eight-year old boy diagnosed with XLP1 presenting with acute non-EBV acute meningoencephalitis with thrombotic occlusive vasculopathy. The patient developed multiple cerebral aneurysms leading to repeated intracerebral hemorrhage and severe cerebral damage. Immunological examination was initiated after development of a susceptibility to infections with recurrent bronchitis and one episode of severe pneumonia and showed antibody deficiency with pronounced IgG1-3-4 subclass deficiency. We could identify a novel hemizygous SH2D1A point mutation affecting the start codon. Basal levels of SAP protein seemed to be detectable in CD8+ and CD4+ T- and CD56+ NK-cells of the patient what indicated an incomplete absence of SAP. In conclusion, we could demonstrate a novel SH2D1A mutation leading to deficient SAP protein expression and a rare clinical phenotype of non-EBV associated acute meningoencephalitis with thrombotic occlusive vasculopathy.
Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Transtornos Linfoproliferativos/imunologia , Meningoencefalite/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/imunologia , Trombose/imunologia , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Humanos , Transtornos Linfoproliferativos/diagnóstico , Masculino , Meningoencefalite/diagnóstico , Mutação , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Trombose/diagnósticoRESUMO
BACKGROUND: Glial fibrillary acidic protein (GFAP) autoimmune astrocytopathy is characterized by GFAP autoantibody positive encephalitis, meningoencephalitis or meningoencephalomyelitis. The initial clinical presentation may be similar to central nervous system infections making early diagnosis challenging. CASE PRESENTATION: A Chinese female patient presented with subacute meningitis with symptoms of headache, vomiting, and fever. Cerebrospinal fluid (CSF) analysis showed monocytic pleocytosis, elevated protein level, low glucose level, and negative basic microbiological studies including Xpert MTB/RIF. Brain magnetic resonance imaging (MRI) showed bilateral cerebral cortical and white matter hyperintensities on FLAIR sequences. The patient was diagnosed with possible tuberculous meningitis and started on anti-tuberculosis therapy (ATT). Three months later, the patient developed cervical myelopathy and encephalopathy with persistent CSF pleocytosis. Five months later, tissue-based and cell-based assays demonstrated GFAP antibodies in blood and CSF. Her symptoms improved with repeated administration of intravenous immunoglobulin (IVIG) and corticosteroids. One-and-a-half -year follow-up showed neither clinical progression nor relapses. CONCLUSIONS: Anti-GFAP astrocytopathy should be included in the differential diagnosis of patients who present with subacute meningitis with negative microbiological studies and a progressive clinical course including encephalitis and/or myelitis.
Assuntos
Astrócitos/patologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Proteína Glial Fibrilar Ácida/imunologia , Mielite/diagnóstico , Povo Asiático , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/imunologia , Diagnóstico Diferencial , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imageamento por Ressonância Magnética , Meningoencefalite/diagnóstico , Meningoencefalite/etiologia , Meningoencefalite/imunologia , Mielite/etiologia , Mielite/imunologiaRESUMO
Angiostrongylus cantonensis is the main causative agent of eosinophilic meningoencephalitis (EoM) in humans. Molecular diagnostic methods are essential since the identification of larvae in cerebrospinal fluid (CSF) is extremely rare. To date, the detection of a 31 kDa antigen by Western blotting has been the primary immunodiagnostic method for EoM caused by A. cantonensis. However, cross-reactivity with other parasites has been observed. Therefore, we conducted a comparative analysis using sera from individuals with angiostrongyliasis. We also characterized proteins isolated from different cellular sources of A. cantonensis, Toxocara canis, Schistosoma mansoni, and Strongyloides stercoralis with mass spectrometry. A total of 115 cross-reactive proteins were identified. Three of these proteins, heat shock protein, an intermediate filament protein, and galectin 1, represent potential markers for cross-reactivity. In addition, synthetic peptides were generated from previously identified diagnostic targets and tested against sera from individuals infected with several other parasites. As a result, two other markers of cross-reactivity were identified: peptide #4 derived from the 14-3-3 protein and peptide #12 derived from the Lec-5 protein. In contrast, 34 proteins were exclusively present in the Angiostrongylus extracts and represent promising diagnostic molecules for specific identification of A. cantonensis infection. In particular, cytochrome oxidase subunit I is of great interest as a possible immunodiagnostic target for angiostrongyliasis.
Assuntos
Angiostrongylus cantonensis/imunologia , Antígenos de Helmintos/imunologia , Proteínas de Helminto/imunologia , Meningoencefalite/diagnóstico , Meningoencefalite/parasitologia , Infecções por Strongylida/diagnóstico , Sequência de Aminoácidos , Angiostrongylus cantonensis/química , Animais , Antígenos de Helmintos/sangue , Antígenos de Helmintos/química , Antígenos de Helmintos/isolamento & purificação , Western Blotting , Sequência Conservada , Reações Cruzadas , Eletroforese , Eletroforese em Gel Bidimensional , Proteínas de Helminto/química , Proteínas de Helminto/isolamento & purificação , Humanos , Imunoensaio , Testes Imunológicos , Espectrometria de Massas , Meningoencefalite/imunologia , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologiaRESUMO
Angiostrongylus cantonensis is a metastrongyloid nematode that causes eosinophilic meningoencephalitis in humans. A high infestation of A. cantonensis can cause permanent brain damage or even death. The inflammasome is an oligomeric molecular platform that can detect microbial pathogens and activate inflammatory cytokines. The recognition of larval surface antigens by pattern recognition receptors (PRRs) can cause oligomerization of the NOD-like receptor (NLR) or absent in melanoma 2 (AIM2) with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to form a caspase-1-activating scaffold. Activated caspase-1 converts pro-inflammatory cytokines into their mature, active forms. Helminths infection has been shown to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes. In this study, we aimed to investigate the mechanism of inflammasome activation upon A. cantonensis infection in a mouse model. This study provides evidence that A. cantonensis infection can activate NLRP1B and NLRC4 inflammasomes and promote pyroptosis to cause meningoencephalitis.
Assuntos
Encéfalo/patologia , Inflamassomos/imunologia , Meningoencefalite/imunologia , Meningoencefalite/parasitologia , Infecções por Strongylida/imunologia , Angiostrongylus cantonensis , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Encéfalo/imunologia , Encéfalo/parasitologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Inflamassomos/genética , Camundongos , Camundongos Endogâmicos BALB C , Piroptose , Infecções por Strongylida/complicaçõesRESUMO
Many pathogenicity factors are involved in the development of primary amoebic meningoencephalitis (PAM) caused by N fowleri. However, most of them are not exclusive for N fowleri and they have not even been described in other nonpathogenic Naegleria species. Therefore, the objective of this work was to identify differential proteins and protein pattern recognition between Naegleria fowleri and Naegleria lovaniensis using antibodies anti-N fowleri as strategy to find vaccine candidates against meningoencephalitis. Electrophoresis and Western blots conventional and 2-DE were performed for the identification of antigenic proteins, and these were analysed by the mass spectrometry technique. The results obtained in 2-DE gels and Western blot showed very notable differences in spot intensity between these two species, specifically those with relative molecular weight of 100, 75, 50 and 19 kDa. Some spots corresponding to these molecular weights were identified as actin fragment, myosin II, heat shock protein, membrane protein Mp2CL5 among others, with differences in theoretical post-translational modifications. In this work, we found differences in antigenic proteins between both species, proteins that could be used for a further development of vaccines against N fowleri infection.
Assuntos
Antígenos de Protozoários/imunologia , Infecções Protozoárias do Sistema Nervoso Central/imunologia , Meningoencefalite/imunologia , Naegleria fowleri/imunologia , Proteínas de Protozoários/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Proteínas de Membrana/imunologia , Meningoencefalite/parasitologiaRESUMO
OBJECTIVES: Recent studies suggest that the clinical presentation of tick-borne encephalitis (TBE) is determined by the host immune responses to the tick-borne encephalitis virus (TBEV). The aim of the study was to characterize immune responses in TBE to give a better insight into the immunopathogenesis of this disease. METHODS: Anti-TBEV antibody levels, cerebrospinal fluid (CSF) and blood lymphoid populations, and concentrations of CXCL13 (a potent B-cell and T-cell chemoattractant), were analyzed in 35 patients with TBE (20 adults and 15 children). RESULTS: When compared with the blood, the CSF lymphoid population was significantly enriched in CD4+ T-cells and relatively depleted in natural killer (NK) cells and B lymphocytes. In comparison with TBE meningitis, patients suffering from TBE meningoencephalitis (n = 11, 31%) had a 3.5-fold higher median CSF CXCL13 concentration, 1.8-fold higher CSF/serum ratio of anti-TBEV IgG antibodies, and 1.8-fold higher median CSF cell count. CSF CXCL13 levels did not change significantly in children with TBE meningitis receiving supportive treatment, but decreased in children with TBE meningoencephalitis who received intravenous steroids. CONCLUSIONS: CD4+ cells are abundant in the CSF of patients with TBE. CXCL13 may be involved in the neuropathology of TBE by attracting different subsets of lymphocytes to the CSF.
Assuntos
Quimiocina CXCL13/líquido cefalorraquidiano , Encefalite Transmitida por Carrapatos/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/líquido cefalorraquidiano , Linfócitos B , Líquido Cefalorraquidiano/imunologia , Criança , Pré-Escolar , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/sangue , Encefalite Transmitida por Carrapatos/líquido cefalorraquidiano , Feminino , Humanos , Células Matadoras Naturais , Contagem de Linfócitos , Subpopulações de Linfócitos , Masculino , Meningoencefalite/imunologia , Meningoencefalite/virologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
Autoimmune encephalitis is an important group of disease that can mimic infectious encephalitis, with one of the most severe forms being meningoencephalomyelitis. One of the recently identified biomarkers, glial fibillary acidic protein (GFAP), targets the cytosolic intermediate filament protein of astrocytes and causes a variety of clinical symptoms. Here, we report an adult Chinese woman presented with acute onset of confusion, CSF lymphocytosis, markedly elevated total protein mimicking tuberculosis meningitis with rapid deterioration resulted in coma and respiratory failure. She was diagnosed with anti-GFAP meningoencephalomyelitis, which later developed tetraplegia, sensorineural hearing loss, brainstem, bulbar and respiratory dysfunction. Intravenous immunoglobulin and methylprednisolone resulted in partial improvement. Further immunotherapy with plasma exchange and rituximab resulted in marked recovery.
Assuntos
Astrócitos/patologia , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Encefalomielite/diagnóstico , Proteína Glial Fibrilar Ácida/imunologia , Meningoencefalite/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Encefalomielite/imunologia , Encefalomielite/fisiopatologia , Feminino , Humanos , Meningoencefalite/imunologia , Meningoencefalite/fisiopatologia , Pessoa de Meia-IdadeRESUMO
To evaluate occurrence and extent of CSF CXCL13 elevations beyond Lyme neuroborreliosis, we investigated CXCL13 in an unselected patient cohort with neuroinflammatory disease. From March 2016 to March 2017, 180 in-patients with CSF pleocytosis were categorized into following groups: pyogenic CNS infections, aseptic meningoencephalitis, neuroimmunological diseases, and reactive pleocytosis. We provide evidence that CXCL13 elevation occurs at variable extent in the majority of neuroinflammatory diseases. The exact role of CXCL13 in CSF is elusive, but the broad occurrence in neuroinflammation points at CNS immune activation, which is not exclusive for LNB.
Assuntos
Quimiocina CXCL13/líquido cefalorraquidiano , Neuroborreliose de Lyme/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL13/fisiologia , Feminino , Humanos , Leucocitose/líquido cefalorraquidiano , Leucocitose/imunologia , Neuroborreliose de Lyme/imunologia , Masculino , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/imunologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Presumed autoimmune diseases affecting the central nervous system (CNS) of dogs are common. In people, antibodies against neuronal cell surface antigens that are associated with a wide variety of neurological syndromes have been identified. The presence of cerebrospinal fluid (CSF) autoantibodies that target neuronal cell surface proteins has not been reported in dogs with neurologic disorders. OBJECTIVES: Autoantibodies to neuronal cell surface antigens can be found in the CSF of dogs with inflammatory CNS disease. Our aim was to determine whether 6 neuronal cell surface autoantibodies were present in the CSF of dogs diagnosed with inflammatory and noninflammatory CNS disease. ANIMALS: Client-owned dogs with CNS disease and complete diagnostic evaluation including magnetic resonance imaging and CSF analysis were included. One healthy dog was included as a negative control. METHODS: Cerebrospinal fluid was tested for 6 antigenic targets with a commercially available indirect immunofluorescence assay test kit. RESULTS: There were 32 dogs with neurological disease, 19 diagnosed with inflammatory disease (encephalitis and meningitis), 10 with noninflammatory disease (neoplasia, intervertebral disk disease, degenerative myelopathy, and epilepsy), 2 with no diagnosis, and 1 with neoplasia and meningoencephalitis. Anti-N-methyl-d-aspartate receptor 1 (NMDAR1) antibodies were detected in 3 dogs (3/32; 9.38%). All 3 dogs responded to treatment of meningoencephalomyelitis of unknown etiology (MUE). CONCLUSIONS AND CLINICAL IMPORTANCE: Further evaluation of the prevalence and clinical relevance of CSF and serum antibodies to neuronal cell surface antigens is warranted. Defining antigenic targets associated with encephalitis in dogs might allow diagnostic categorization of MUE antemortem.
Assuntos
Autoanticorpos/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/veterinária , Doenças do Cão/líquido cefalorraquidiano , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/imunologia , Doenças do Cão/imunologia , Cães , Feminino , Técnica Indireta de Fluorescência para Anticorpo/veterinária , Humanos , Masculino , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/imunologia , Meningoencefalite/terapia , Neurônios/imunologiaRESUMO
The majority of invasive human fungal pathogens gain access to their human hosts via the inhalation of spores from the environment into the lung, but relatively little is known about this infectious process. Among human fungal pathogens the most frequent cause of inhaled fatal fungal disease is Cryptococcus, which can disseminate from the lungs to other tissues, including the brain, where it causes meningoencephalitis. To determine the mechanisms by which distinct infectious particles of Cryptococcus cause disseminated disease, we evaluated two developmental cell types (spores and yeast) in mouse models of infection. We discovered that while both yeast and spores from several strains cause fatal disease, there was a consistently higher fungal burden in the brains of spore-infected mice. To determine the basis for this difference, we compared the pathogenesis of avirulent yeast strains with their spore progeny derived from sexual crosses. Strikingly, we discovered that spores produced by avirulent yeast caused uniformly fatal disease in the murine inhalation model of infection. We determined that this difference in outcome is associated with the preferential dissemination of spores to the lymph system. Specifically, mice infected with spores harbored Cryptococcus in their lung draining lymph nodes as early as one day after infection, whereas mice infected with yeast did not. Furthermore, phagocyte depletion experiments revealed this dissemination to the lymph nodes to be dependent on CD11c+ phagocytes, indicating a critical role for host immune cells in preferential spore trafficking. Taken together, these data support a model in which spores capitalize on phagocytosis by immune cells to escape the lung and gain access to other tissues, such as the central nervous system, to cause fatal disease. These previously unrealized insights into early interactions between pathogenic fungal spores and lung phagocytes provide new opportunities for understanding cryptococcosis and other spore-mediated fungal diseases.