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1.
J Immunol ; 199(1): 97-106, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28526683

RESUMO

Invariant NKT (iNKT) cells are innate-like lymphocytes that recognize lipid Ags presented by CD1d. The prototypical Ag, α-galactosylceramide, strongly activates human and mouse iNKT cells, leading to the assumption that iNKT cell physiology in human and mouse is similar. In this article, we report the surprising finding that human, but not mouse, iNKT cells directly recognize myelin-derived sulfatide presented by CD1d. We propose that sulfatide is recognized only by human iNKT cells because of the unique positioning of the 3-O-sulfated ß-galactose headgroup. Surface plasmon resonance shows that the affinity of human CD1d-sulfatide for the iNKT cell receptor is relatively low compared with CD1d-α-galactosylceramide (KD of 19-26 µM versus 1 µM). Apolipoprotein E isolated from human cerebrospinal fluid carries sulfatide that can be captured by APCs and presented by CD1d to iNKT cells. APCs from patients with metachromatic leukodystrophy, who accumulate sulfatides due to a deficiency in arylsulfatase-A, directly activate iNKT cells. Thus, we have identified sulfatide as a self-lipid recognized by human iNKT cells and propose that sulfatide recognition by innate T cells may be an important pathologic feature of neuroinflammatory disease and that sulfatide in APCs may contribute to the endogenous pathway of iNKT cell activation.


Assuntos
Apresentação de Antígeno , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Sulfoglicoesfingolipídeos/imunologia , Animais , Antígenos CD1d/imunologia , Apolipoproteínas E/líquido cefalorraquidiano , Apolipoproteínas E/química , Apolipoproteínas E/imunologia , Linhagem Celular , Cerebrosídeo Sulfatase/deficiência , Cerebrosídeo Sulfatase/metabolismo , Galactosilceramidas/imunologia , Humanos , Leucodistrofia Metacromática/imunologia , Camundongos , Células T Matadoras Naturais/fisiologia , Receptores de Antígenos de Linfócitos T/imunologia , Ressonância de Plasmônio de Superfície , Subpopulações de Linfócitos T/imunologia
2.
Mol Ther ; 23(7): 1160-1168, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25896249

RESUMO

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of the lysosomal enzyme arylsulfatase A. The prevailing late-infantile variant of MLD is characterized by widespread and progressive demyelination of the central nervous system (CNS) causing death during childhood. In order to gain insight into the pathomechanism of the disease and to identify novel therapeutic targets, we analyzed neuroinflammation in two mouse models reproducing a mild, nondemyelinating, and a more severe, demyelinating, variant of MLD, respectively. Microgliosis and upregulation of cytokine/chemokine levels were clearly more pronounced in the demyelinating model. The analysis of the temporal cytokine/chemokine profiles revealed that the onset of demyelination is preceded by a sustained elevation of the macrophage inflammatory protein (MIP)-1α followed by an upregulation of MIP-1ß, monocyte chemotactic protein (MCP)-1, and several interleukins. The tumor necrosis factor (TNF)-α remains unchanged. Treatment of the demyelinating mouse model with the nonsteroidal anti-inflammatory drug simvastatin reduced neuroinflammation, improved the swimming performance and ataxic gait, and retarded demyelination of the spinal cord. Our data suggest that neuroinflammation is causative for demyelination in MLD mice and that anti-inflammatory treatment might be a novel therapeutic option to improve the CNS function of MLD patients.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Inflamação/tratamento farmacológico , Leucodistrofia Metacromática/tratamento farmacológico , Sinvastatina/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Sistema Nervoso Central/fisiopatologia , Quimiocina CCL2/biossíntese , Quimiocina CCL4/biossíntese , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Humanos , Inflamação/fisiopatologia , Leucodistrofia Metacromática/imunologia , Camundongos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Fator de Necrose Tumoral alfa/biossíntese
3.
Biol Chem ; 394(12): 1571-81, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23959664

RESUMO

Myelinating cells wrap axons with multi-layered myelin sheaths for rapid impulse propagation. Dysfunctions of oligodendrocytes or Schwann cells are often associated with neuroinflammation, as observed in animal models of leukodystrophies and peripheral neuropathies, respectively. The neuroinflammatory response modulates the pathological changes, including demyelination and axonal injury, but also remyelination and repair. Here we discuss different immune mechanisms as well as factors released or exposed by myelinating glia in disease conditions. The spectrum of inflammatory mediators varies with different myelin disorders and has a major impact on the beneficial or detrimental role of immune cells in keeping nervous system integrity.


Assuntos
Doenças Desmielinizantes/imunologia , Doenças Neurodegenerativas/imunologia , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/imunologia , Doença de Charcot-Marie-Tooth/metabolismo , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/imunologia , Leucodistrofia Metacromática/metabolismo , Camundongos , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/imunologia , Doença de Pelizaeus-Merzbacher/metabolismo , Transtornos Peroxissômicos/genética , Transtornos Peroxissômicos/imunologia , Transtornos Peroxissômicos/metabolismo
4.
Eur J Immunol ; 39(10): 2748-54, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19637231

RESUMO

A defect in invariant NKT (iNKT) cell selection was hypothesized in lysosomal storage disorders (LSD). Accumulation of glycosphingolipids (GSL) in LSD could influence lipid loading and/or presentation causing entrapment of endogenous ligand(s) within storage bodies or competition of the selecting ligand(s) by stored lipids for CD1d binding. However, when we analyzed the iNKT cell compartment in newly tested LSD animal models that accumulate GSL, glycoaminoglycans or both, we observed a defective iNKT cell selection only in animals affected by multiple sulfatase deficiency, in which a generalized aberrant T-cell development, rather than a pure iNKT defect, was present. Mice with single lysosomal enzyme deficiencies had normal iNKT cell development. Thus, GSL/glycoaminoglycans storage and lysosomal engulfment are not sufficient for affecting iNKT cell development. Rather, lipid ligand(s) or storage compounds, which are affected in those LSD lacking mature iNKT cells, might indeed be relevant for iNKT cell selection.


Assuntos
Diferenciação Celular/imunologia , Doenças por Armazenamento dos Lisossomos/imunologia , Células T Matadoras Naturais/imunologia , Animais , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/imunologia , Leucodistrofia de Células Globoides/patologia , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/imunologia , Fígado/imunologia , Fígado/patologia , Linfócitos/patologia , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Mucopolissacaridose I/genética , Mucopolissacaridose I/imunologia , Doença da Deficiência de Múltiplas Sulfatases/genética , Doença da Deficiência de Múltiplas Sulfatases/imunologia , Doença da Deficiência de Múltiplas Sulfatases/patologia , Células T Matadoras Naturais/patologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Doença de Sandhoff/genética , Doença de Sandhoff/imunologia , Doença de Sandhoff/patologia , Baço/imunologia , Baço/patologia , Timo/imunologia , Timo/patologia
5.
Pediatr Neurol ; 37(4): 235-44, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17903666

RESUMO

Although the genetics and biochemistry of leukodystrophies have been extensively explored, the immune response in these disorders has received relatively little attention. Both the disease course and its response to treatment may be highly dependent on the immune system. In this review, we compare three common leukodystrophies, each with a different immune response: (1) X-linked adrenoleukodystrophy, which demonstrates a severe, lymphocytic inflammatory response; (2) metachromatic leukodystrophy, which yields a histiocytic response; and (3) vanishing white-matter disease, in which no inflammation is typically seen. We highlight the biochemical, pathologic, and clinical differences, while focusing on the immune response in each disease. We also review the response of leukodystrophies to immunomodulatory therapies and interventions such as hematopoietic stem-cell transplantation. Future studies may delineate specific inflammatory markers as possible candidates for therapeutic intervention.


Assuntos
Encefalopatias/imunologia , Adrenoleucodistrofia/imunologia , Formação de Anticorpos , Encefalopatias/metabolismo , Encefalopatias/patologia , Encefalopatias/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Fatores Imunológicos/uso terapêutico , Leucodistrofia Metacromática/imunologia
6.
Tissue Antigens ; 36(5): 194-202, 1990 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1982746

RESUMO

The major part of the proliferative response in primary mixed lymphocyte cultures (MLC) is caused by HLA-DRB1 incompatibilities. In DRB1-matched pairs the proliferation induced by HLA-DRB3, -DQ and -DP mismatches may be unmasked. In most previous studies the influence of HLA-DP incompatibilities in primary MLC has been investigated in homozygous typing cells representing only a few Dw specificities. We were interested in determining the stimulatory capacity of isolated HLA-DP mismatches, ascertained by RFLP analysis, in primary MLC in HLA-A, -B, -DR and -DQ compatible, unrelated heterozygous individuals of many different Dw specificities. Thirty-eight MLCs performed with cells from related pairs and 67 with cells from unrelated pairs were evaluated. All but nine of the MLCs were analyzed in both directions, giving a total of 201 investigated reactions. The relative responses (RR) in the three MLCs performed between DP incompatible, related pairs were all positive (RR greater than or equal to 8%). Eighty of 82 MLCs performed with cells from DP incompatible, unrelated individuals were positive, whereas 37 of 46 MLCs between DP compatible, unrelated pairs were negative (RR less than 8%) (p less than 10(-10)). The magnitude of the RR was influenced by the number of DP mismatches. Thus, the mean RR was approximately twice as high in MLCs in which responder and stimulator cells differed by two DP antigens (mean RR 60.5%) compared with reactions with only one DP mismatch (mean RR 35.4%) (p less than 10(-3)). RFLP-defined HLA-DP incompatibilities predict a positive primary MLC in HLA-A, -B, -DR and -DQ matched individuals with a high degree of accuracy (98%).(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Transplante de Medula Óssea/imunologia , Antígenos HLA-DP/imunologia , Teste de Histocompatibilidade , Teste de Cultura Mista de Linfócitos , Obtenção de Tecidos e Órgãos , Criança , Sondas de DNA , Feminino , Genes MHC da Classe II , Antígenos HLA/genética , Antígenos HLA/imunologia , Antígenos HLA-DP/genética , Histocompatibilidade , Teste de Histocompatibilidade/métodos , Humanos , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/imunologia , Leucodistrofia Metacromática/cirurgia , Ativação Linfocitária , Polimorfismo de Fragmento de Restrição , Doadores de Tecidos , Transplante Homólogo/imunologia
7.
J Neuroimmunol ; 18(3): 231-44, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2452830

RESUMO

Immunofluorescence studies of sural nerve demonstrated immune reactive C3d and IgM on the surface of myelin sheaths in seven patients with neuropathy and an anti-myelin-associated glycoprotein (MAG) IgM M-protein. Similar deposits of C3d and sometimes IgM were found in four of six patients with acute or chronic inflammatory demyelinating polyneuropathy and in three of six patients with vasculitic neuropathy (including one with acquired immunodeficiency syndrome (AIDS)). C3d was not found in 80 patients with other peripheral nerve disorders except for two with metachromatic leukodystrophy. None of the C3d deposits contained immune reactive C3c implying substantial degradation of C3b. C3d is a sensitive index of complement activation in nerve and may be useful in classification of neuropathies.


Assuntos
Complemento C3/imunologia , Bainha de Mielina/imunologia , Doenças do Sistema Nervoso/imunologia , Anticorpos Monoclonais/análise , Complemento C3c , Complemento C3d , Humanos , Imunoglobulina M/imunologia , Imuno-Histoquímica , Leucodistrofia Metacromática/imunologia , Proteínas da Mielina/imunologia , Glicoproteína Associada a Mielina , Nervo Sural/imunologia
9.
Proc Natl Acad Sci U S A ; 80(10): 3074-7, 1983 May.
Artigo em Inglês | MEDLINE | ID: mdl-6134282

RESUMO

Cultured skin fibroblasts from the patient described by Shapiro and co-workers as having a variant form of metachromatic leukodystrophy (MLD) [Shapiro, L.J., Aleck, K. A., Kaback, M.M., Itabashi, H., Desnick, R.J., Brand, N., Stephens, R.L., Fluharty, A.L. & Kihara, H. (1979) Pediatr. Res. 13, 1179-1181] were confirmed to have a partial deficiency (25-40% of controls) of arylsulfatase A activity in vitro and a severe inability to metabolize [14C]stearic acid-labeled sulfatide presented in the medium. When 150 micrograms of purified activator protein for GM1 ganglioside beta-galactosidase and sulfatide sulfatase was added in 4 ml of medium with the 14C-labeled sulfatide, correction of the sulfatide metabolism to the normal range was found. Monospecific antibodies to this activator protein were prepared in rabbits, and they were used to examine cultured cells for the presence of crossreacting material by Ouchterlony double immunodiffusion and rocket immunoelectrophoresis. Cell extracts from controls and from patients with GM1 gangliosidosis and MLD were found to have a single line of identity. By comparison to known concentrations of purified activator protein, cell extracts from controls were found to have 0.76 +/- 0.32 micrograms of activator protein (mean +/- 1 SD, n = 10) per mg of solubilized protein, whereas those from patients with type 1 GM1 gangliosidosis and late infantile MLD had 1.53 and 1.41 micrograms/mg, respectively. Cell extracts from the patient with a variant form of MLD had no visible precipitin line by Ouchterlony double immunodiffusion and only a diffuse nonspecific region of staining by rocket immunoelectrophoresis. These immunologic studies provide evidence for a deficiency in the activator protein required for normal catabolism of sulfatide in the cells from this patient and possibly provide a method for diagnosis of similar patients.


Assuntos
Cerebrosídeo Sulfatase/deficiência , Leucodistrofia Metacromática/enzimologia , Deficiência de Proteína , Sulfatases/deficiência , Células Cultivadas , Ativação Enzimática , Gangliosídeo G(M1) , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/imunologia , Proteínas/imunologia , beta-Galactosidase/metabolismo
10.
J Inherit Metab Dis ; 6(1): 21-6, 1983.
Artigo em Inglês | MEDLINE | ID: mdl-6134864

RESUMO

Multiple sulphatase deficiency (MSD) and metachromatic leukodystrophy (MLD) are both characterized by a deficiency of arylsulphatase A (ARS A) activity, although they are inherited as separate autosomal recessive traits. However, it has been found that the immunologically active substance with anti-ARS A antibody is present in quite normal levels in MLD and in smaller quantities in MSD fibroblasts (Fiddler, 1979). Indirect immunofluorescence staining with anti-ARS A antibody displayed a coarse granular and diffuse distribution of ARS A or cross-reacting material (CRM) in the normal control and MLD fibroblasts, whereas very weak fluorescence staining was observed in MSD fibroblasts proportional to the decrease in the ARS A activity observed in the lysate enzyme assay. These results suggest that ARS A deficiency in MLD cells is due to an enzymatically deficient ARS A molecule, which is immunologically cross-reactive with anti-normal ARS A antibody. ARS A deficiency in MSD cells appears to be due to a reduced amount of normal ARS A.


Assuntos
Arilsulfatases/deficiência , Cerebrosídeo Sulfatase/imunologia , Aberrações Cromossômicas/enzimologia , Leucodistrofia Metacromática/imunologia , Sulfatases/deficiência , Sulfatases/imunologia , Anticorpos/análise , Células Cultivadas , Cerebrosídeo Sulfatase/deficiência , Transtornos Cromossômicos , Fibroblastos/enzimologia , Imunofluorescência , Humanos , Imunodifusão , Leucodistrofia Metacromática/enzimologia , Pele/enzimologia
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