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1.
J Biol Chem ; 287(21): 17206-17213, 2012 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-22493449

RESUMO

It has become increasingly clear that only antibodies recognizing conformation-dependent epitopes of myelin oligodendrocyte glycoprotein (MOG) have a demyelinating potential in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Nevertheless, for the induction of EAE, most studies to date have used MOG peptides or bacterially expressed MOG, neither of which contain the tertiary structure of the native antigen. Non-refolded recombinant human MOG does not induce EAE in DA rats. Therefore, we refolded this protein in order to assess the influence of MOG conformation on its pathogenicity in DA rats. DA rats immunized with refolded human MOG developed severe acute EAE. As expected, rats immunized with the refolded protein had a higher amount of conformational MOG antibodies present in serum. But in addition, a striking effect of MOG refolding on the generation of T-cell responses was found. Indeed, T-cell responses against the encephalitogenic MOG 91-108 epitope were greatly enhanced after refolding. Therefore, we conclude that refolding of MOG increases its pathogenicity both by generating conformation-dependent MOG antibodies and by enhancing its processing or/and presentation on MHC molecules. These data are important in regard to investigations of the pathogenic potential of many (auto)antigens.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Proteínas da Mielina/imunologia , Dobramento de Proteína , Linfócitos T/imunologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Apresentação de Antígeno/imunologia , Autoanticorpos/farmacologia , Autoantígenos/imunologia , Linfócitos B/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Proteínas da Mielina/química , Proteínas da Mielina/farmacologia , Glicoproteína Mielina-Oligodendrócito , Estrutura Terciária de Proteína , Ratos , Linfócitos T/patologia
2.
J Immunol ; 185(6): 3574-82, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20696861

RESUMO

Congenital heart block develops in fetuses of anti-Ro52 Ab-positive women. A recurrence rate of 20%, despite the persistence of maternal autoantibodies, indicates that there are additional, yet unidentified, factors critical for development of congenital heart block. In this study, we demonstrate that besides the maternal MHC controlling Ab specificity, fetal MHC-encoded genes influence fetal susceptibility to congenital heart block. Using MHC congenic rat strains, we show that heart block develops in rat pups of three strains carrying MHC haplotype RT1(av1) (DA, PVG.AV1, and LEW.AV1) after maternal Ro52 immunization, but not in LEW rats (RT1(l)). Different anti-Ro52 Ab fine specificities were generated in RT1(av1) versus RT1(l) animals. Maternal and fetal influence was determined in an F(2) cross between LEW.AV1 and LEW strains, which revealed higher susceptibility in RT1(l) than RT1(av1) pups once pathogenic Ro52 Abs were present. This was further confirmed in that RT1(l) pups more frequently developed heart block than RT1(av1) pups after passive transfer of RT1(av1) anti-Ro52 sera. Our findings show that generation of pathogenic Ro52 Abs is restricted by maternal MHC, whereas the fetal MHC locus regulates susceptibility and determines the fetal disease outcome in anti-Ro52-positive pregnancies.


Assuntos
Bloqueio Atrioventricular/genética , Bloqueio Atrioventricular/imunologia , Autoanticorpos/biossíntese , Predisposição Genética para Doença , Antígenos de Histocompatibilidade/genética , Troca Materno-Fetal/imunologia , Ribonucleoproteínas/imunologia , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos/genética , Bloqueio Atrioventricular/congênito , Linhagem Celular , Modelos Animais de Doenças , Feminino , Antígenos de Histocompatibilidade/imunologia , Troca Materno-Fetal/genética , Dados de Sequência Molecular , Gravidez , Ratos , Ratos Endogâmicos Lew , Ribonucleoproteínas/administração & dosagem
3.
Mol Cell Proteomics ; 8(9): 2090-101, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19531498

RESUMO

Tandem mass spectrometry was used to identify naturally processed peptides bound to major histocompatibility complex (MHC) I and MHC II molecules in central nervous system (CNS) of eight patients with multiple sclerosis (MS). MHC molecules were purified from autopsy CNS material by immunoaffinity chromatography with monoclonal antibody directed against HLA-A, -B, -C, and -DR. Subsequently peptides were separated by reversed-phase HPLC and analyzed by mass spectrometry. Database searches revealed 118 amino acid sequences from self-proteins eluted from MHC I molecules and 191 from MHC II molecules, corresponding to 174 identified source proteins. These sequences define previously known and potentially novel autoantigens in MS possibly involved in disease induction and antigen spreading. Taken together, we have initiated the characterization of the CNS-expressed MHC ligandome in CNS diseases and were able to demonstrate the presentation of naturally processed myelin basic protein peptides in the brain of MS patients.


Assuntos
Apresentação de Antígeno/imunologia , Sistema Nervoso Central/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Esclerose Múltipla/imunologia , Peptídeos/imunologia , Sequência de Aminoácidos , Bases de Dados de Proteínas , Humanos , Ligantes , Espectrometria de Massas , Dados de Sequência Molecular , Proteína Básica da Mielina/metabolismo , Peptídeos/análise , Peptídeos/química , Ligação Proteica , Proteômica , Reprodutibilidade dos Testes
4.
J Immunol ; 182(7): 4432-8, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19299744

RESUMO

We here present the first genetic fine mapping of experimental autoimmune neuritis (EAN), the animal model of Guillain-Barré syndrome, in a rat advanced intercross line. We identified and refined a total of five quantitative trait loci on rat chromosomes 4, 10, and 12 (RNO4, RNO10, RNO12), showing linkage to splenic IFN-gamma secretion and disease severity. All quantitative trait loci were shared with other models of complex inflammatory diseases. The quantitative trait locus showing strongest linkage to clinical disease was Ean6 and spans 4.3 Mb on RNO12, harboring the neutrophil cytosolic factor 1 (Ncf1) among other genes. Polymorphisms in Ncf1, a member of the NADPH oxidase complex, have been associated with disease regulation in experimental arthritis and encephalomyelitis. We therefore tested the Ncf1 pathway by treating rats with a NADPH oxidase complex activator and ameliorated EAN compared the oil-treated control group. By proving the therapeutic effect of stimulating the NADPH oxidase complex, our data strongly suggest the first identification of a gene regulating peripheral nervous system inflammation. Taken together with previous reports, our findings suggest a general role of Ncf1 and oxidative burst in pathogenesis of experimental autoimmune animal models.


Assuntos
Mapeamento Cromossômico , NADPH Oxidases/genética , Neurite Autoimune Experimental/genética , Neurite Autoimune Experimental/patologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Ligação Genética , Genótipo , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/patologia , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/imunologia , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/imunologia , NADH NADPH Oxirredutases/metabolismo , Neurite Autoimune Experimental/imunologia , Fitol/farmacologia , Polimorfismo Genético , Locos de Características Quantitativas , Ratos , Explosão Respiratória/fisiologia
5.
Eur J Immunol ; 38(1): 299-308, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18050272

RESUMO

Experimental autoimmune encephalomyelitis (EAE) can be actively induced with the extracellular domain of myelin oligodendrocyte glycoprotein (MOG 1-125). MOG-EAE closely mimics multiple sclerosis (MS) especially as far as demyelination, lesion formation and axonal pathology are concerned. MOG 91-108 is the encephalitogenic stretch within MOG 1-125 in two EAE-susceptible MHC congenic LEW rat strains [LEW.1AV1 (RT1(av1)) and LEW.1N (RT1(n))] and DA (RT1(av1)) rats. In LEW.1AV1 rats, disease could be induced with MOG 96-104 and to a lesser extent with MOG 98-106, whereas in LEW.1N rats, only MOG 98-106 was pathogenic. Both peptides bound well to their restricting MHC class II molecules, i.e., RT1.D(n) in the LEW.1N rat and RT1.B(a) in the LEW.1AV1 rat. TCR spectratyping of MOG 91-108 immunized LEW.1N, LEW.1AV1 and DA rats revealed that MHC class II determined the TCRBV preference of CNS infiltrating T cells. The data demonstrate that the most critical factor in inducing MS like pathology is presentation of autoantigenic peptides on MHC class II molecules resulting in demyelination and axonal pathology.


Assuntos
Apresentação de Antígeno/imunologia , Autoantígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Mapeamento de Epitopos , Antígenos de Histocompatibilidade Classe II/imunologia , Glicoproteína Associada a Mielina/imunologia , Animais , Autoantígenos/química , Encefalomielite Autoimune Experimental/patologia , Feminino , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/química , Glicoproteína Mielina-Oligodendrócito , Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
6.
Am J Pathol ; 170(3): 1041-53, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17322387

RESUMO

To study the effect of enhanced glucocorticoid signaling on T cells, we generated transgenic rats overexpressing a mutant glucocorticoid receptor with increased ligand affinity in the thymus. We found that this caused massive thymocyte apoptosis at physiological hormone levels, which could be reversed by adrenalectomy. Due to homeostatic proliferation, a considerable number of mature T lymphocytes accumulated in the periphery, responding normally to costimulation but exhibiting a perturbed T-cell repertoire. Furthermore, the transgenic rats showed increased resistance to experimental autoimmune encephalomyelitis, which manifests in a delayed onset and milder disease course, impaired leukocyte infiltration into the central nervous system and a distinct cytokine profile. In contrast, the ability of the transgenic rats to mount an allergic airway response to ovalbumin was not compromised, although isotype switching of antigen-specific immunoglobulins was altered. Collectively, our findings suggest that endogenous glucocorticoids impact T-cell development and favor the selection of Th2- over Th1-dominated adaptive immune responses.


Assuntos
Apoptose/fisiologia , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Glândulas Suprarrenais/metabolismo , Animais , Animais Geneticamente Modificados , Autoimunidade , Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Células Jurkat , Ratos , Receptores de Glucocorticoides/genética , Transdução Genética
7.
J Neuroimmunol ; 166(1-2): 47-54, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15963573

RESUMO

To investigate the influence of antigen and restricting MHC class II molecule on the T cell repertoire, we varied the peptide source by immunizing either with myelin basic protein (MBP) (rat)63-88 or MBP(GUINEA PIG (GP))63-88, which differ in the core region of the peptide binding site at position 79 by a single exchange of threonine (T) to serine (S) and by altering the MHC by immunizing MHC congenic LEW (RT1(1)) and LEW.1W (RT1u) rats. In both MHC haplotypes both peptides lead to oligoclonal dominance of TCRBV8S2 expressing T cells within the central nervous system (CNS) as assessed by complementary determining region 3 (CDR3) spectratyping. In contrast cytofluorometric analysis indicated that only MBP(GP)63-88 in context with the RT1(l) haplotype of the LEW rat lead to strong expansions of TCRBV8S2 expressing T cells within the CNS. Importantly, the small conservative change from S to T at position 79 within MBP63-88 had a strong influence both on the encephalitogenic potential of the peptide and on the number of TCRBV8S2+ T cells infiltrating the CNS. These results demonstrate that even minor changes in only one side chain of an amino acid within an (auto)antigen can dramatically alter TCR avidity for certain MHC class II/peptide complexes.


Assuntos
Sistema Nervoso Central/metabolismo , Regiões Determinantes de Complementaridade , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Divisão Celular , Separação Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/imunologia , Citometria de Fluxo , Cobaias , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunização , Proteína Básica da Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew , Serina , Linfócitos T/patologia , Treonina
8.
Immunogenetics ; 57(1-2): 69-76, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15711804

RESUMO

Experimental autoimmune encephalomyelitis induced with myelin proteins in DA and LEW.1AV1 rats is a model of multiple sclerosis (MS). It reproduces major aspects of this detrimental disease of the central nervous system. MS is associated with the HLA-DRB1*1501, DRB5*0101, and DQB1*0602 haplotype. DA and LEW.1AV1 rats share the RT1av1 haplotype. So far, no MHC class II peptide motif of RT1.Da molecules has been described. Sequence alignment of the beta chain of the rat MHC class II molecule RT1.Da with human HLA class II molecules revealed strong similarity in the peptide-binding groove of RT1.Da and HLA-DRB1*1501. According to the putative peptide-binding pockets of RT1.Da, after comparison with the pockets of HLA-DRB1*1501, we predicted the peptide motif of RT1.Da. To verify the predicted motif, naturally processed peptides were eluted by acidic treatment from immunoaffinity-purified RT1.Da molecules of lymphoid tissue of DA rats and subsequently analyzed by ESI tandem mass spectrometry. In addition, we performed binding studies with combinatorial nonapeptide libraries to purified RT1.Da molecules. Based on these studies we could define a peptide-binding motif for RT1.Da characterized by aliphatic amino acid residues (L, I, V, M) and of F for the peptide pocket P1, aromatic residues (F, Y, W) for P4, basic residues (K, R) for P6, aliphatic residues (I, L, V) for P7, and aromatic residues (F, Y, W) and L for P9. Both methods revealed similar binding characteristics for peptides to RT1.Da. This data will allow epitope predictions for analysis of peptides, relevant for experimental autoimmune diseases.


Assuntos
Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade/química , Esclerose Múltipla/imunologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Biologia Computacional , Feminino , Antígenos HLA-DR/química , Antígenos HLA-DR/imunologia , Antígenos HLA-DR/metabolismo , Cadeias HLA-DRB1 , Antígenos de Histocompatibilidade/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Dados de Sequência Molecular , Esclerose Múltipla/genética , Biblioteca de Peptídeos , Peptídeos/imunologia , Peptídeos/metabolismo , Ratos , Alinhamento de Sequência
9.
Neurology ; 63(12): 2381-3, 2004 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-15623705

RESUMO

Antibodies against native glycosylated myelin-oligodendrocyte-glycoprotein (MOG) were measured by ELISA in patients with multiple sclerosis (MS) and controls. Anti-MOG IgM antibodies were elevated during the first demyelinating event. Higher MOG-specific IgG antibodies were found in patients during relapses and in secondary chronic progressive MS compared to patients in remission and healthy controls. Antibodies against native MOG may be a potential biomarker for MS.


Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Glicoproteína Associada a Mielina/imunologia , Processamento de Proteína Pós-Traducional , Adulto , Idoso , Animais , Especificidade de Anticorpos , Autoanticorpos/sangue , Doenças Desmielinizantes , Feminino , Glicosilação , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas da Mielina , Glicoproteína Associada a Mielina/química , Glicoproteína Associada a Mielina/isolamento & purificação , Glicoproteína Mielina-Oligodendrócito
10.
J Neuroimmunol ; 155(1-2): 73-84, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15342198

RESUMO

With a panel of rat strains, we demonstrate a strong impact of the MHC genotype on susceptibility and disease course in experimental autoimmune neuritis induced with peripheral nerve myelin or the P2 peptide 58-81 (KNTEISFKLGQEFEETTADNRKTK). Beside the MHC genotype, non-MHC genes determined disease susceptibility and resistance. The type of disease induced with P2 58-81 was strongly correlated to the strength of the MHC class II isotype interaction with P2 58-81. These findings suggest a link between susceptibility and acute versus chronic disease courses on one hand and the strength of the MHC class II molecule/peptide affinity on the other hand.


Assuntos
Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Síndrome de Guillain-Barré/genética , Antígenos de Histocompatibilidade/genética , Neurite Autoimune Experimental/genética , Doenças do Sistema Nervoso Periférico/genética , Animais , Doença Crônica , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Genótipo , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/fisiopatologia , Haplótipos/genética , Antígenos de Histocompatibilidade/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Masculino , Proteína P2 de Mielina/imunologia , Bainha de Mielina/imunologia , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/fisiopatologia , Fragmentos de Peptídeos/imunologia , Doenças do Sistema Nervoso Periférico/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos , Especificidade da Espécie
11.
J Immunol ; 173(4): 2792-802, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15294998

RESUMO

Most autoimmune diseases are associated with certain MHC class II haplotypes. Autoantigen-based specific immune therapy can lead either to beneficial or, in the context of inflammatory conditions, detrimental outcomes. Therefore, we designed a platform of peptides by combinatorial chemistry selected in a nonbiased Ag-independent approach for strong binding to the rat MHC class II isotype RT1.D(n) allelic product of the RT1(n) haplotype that is presenting autoantigen in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LEW.1N rats. Peptide p17 (Ac-FWFLDNAPL-NH(2)) was capable of suppressing the induction of and also ameliorated established experimental autoimmune encephalomyelitis. MHC class II isotype and allele specificity of the therapeutic principle were demonstrated in myelin basic protein-induced experimental autoimmune encephalomyelitis in LEW rats bearing the RT1(l) haplotype. A general immunosuppressive effect of the treatment was excluded by allogeneic heart transplantation studies. In vitro studies demonstrated the blocking effect of p17 on autoantigenic T cell responses. We thus demonstrate a rational design of strong MHC class II-binding peptides with absolute isotype and allele specificity able to compete for autoantigenic sequences presented on disease-associated MHC class II molecules.


Assuntos
Alelos , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Peptídeos/imunologia , Sequência de Aminoácidos , Animais , Autoantígenos/imunologia , Citocinas/imunologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Biblioteca de Peptídeos , Isoformas de Proteínas/imunologia , Ratos , Ratos Endogâmicos Lew , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
J Neuroimmunol ; 152(1-2): 44-56, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15223236

RESUMO

The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG) that is a T cell-dependent B cell-mediated autoimmune disorder. We tested the immunogenicity and myasthenogenicity of the extracellular and first transmembrane domain of the epsilon-chain(1-221) of the nAChR in inbred and MHC congenic rat strains. Immunodominant T and B cell determinants did not induce experimental autoimmune myasthenia gravis (EAMG), although immunization resulted in strong Th1 and B cell responses, which could be mapped with overlapping peptides of the nAChR epsilon-subunit in eight different rat strains. Our data underscores the concept that immunodominant autoantigen-specific T and B cell responses can lack pathogenicity in autoimmune disease and might be of relevance for the physiological integrity of the organism.


Assuntos
Linfócitos B/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Receptores Nicotínicos/imunologia , Células Th1/imunologia , Sequência de Aminoácidos , Animais , Animais Congênicos , Autoantígenos/imunologia , Modelos Animais de Doenças , Humanos , Masculino , Dados de Sequência Molecular , Miastenia Gravis Autoimune Experimental/imunologia , Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew
13.
Immunogenetics ; 56(1): 61-4, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15004728

RESUMO

The nicotinic acetylcholine receptor (nAChR) is the autoantigen in seropositive myasthenia gravis (MG), a T-cell-dependent B-cell-mediated autoimmune disease. The nAChR is a pentameric transmembrane receptor comprising alpha alpha beta gamma delta chains. During early postnatal development the nAChR gamma chain is replaced by the nAChR epsilon chain. We tested the myasthenogenicity in experimental autoimmune myasthenia gravis (EAMG) of the native nAChR derived from the electric ray Torpedo californica (T-nAChR) in various inbred and MHC -congenic rat strains. Differences in the disease course emerged dependent on the MHC haplotype and non-MHC genes. Interestingly, no tested rat strain was completely resistant to EAMG, but there were strong differences in disease severity mainly depending on the MHC haplotype. In the LEW non-MHC genome, the B-cell response and the severity of EAMG were dependent on the expressed MHC haplotype. This study underscores the influence of genetic factors on disease severity, disease course and on the degree of the emerging antibody responses in EAMG.


Assuntos
Genes MHC da Classe II , Miastenia Gravis Autoimune Experimental/genética , Miastenia Gravis Autoimune Experimental/imunologia , Receptores Nicotínicos/imunologia , Animais , Animais Congênicos , Feminino , Genoma , Haplótipos , Humanos , Imunização , Miastenia Gravis Autoimune Experimental/etiologia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos , Torpedo
14.
J Immunol ; 170(4): 1806-13, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12574345

RESUMO

Vaccination with DNA encoding a myelin basic protein peptide suppresses Lewis rat experimental autoimmune encephalomyelitis (EAE) induced with the same peptide. Additional myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG), may be important in multiple sclerosis. Here we demonstrate that DNA vaccination also suppresses MOG peptide-induced EAE. MOG(91-108) is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1(av1)) and LEW.1N (RT1(n)) rats. We examined the effects of DNA vaccines encoding MOG(91-108) in tandem, with or without targeting of the hybrid gene product to IgG. In all investigated rat strains DNA vaccination suppressed clinical signs of EAE. There was no requirement for targeting the gene product to IgG, but T1-promoting CpG DNA motifs in the plasmid backbone of the construct were necessary for efficient DNA vaccination, similar to the case in DNA vaccination in myelin basic protein-induced EAE. We failed to detect any effects on ex vivo MOG-peptide-induced IFN-gamma, TNF-alpha, IL-6, IL-4, IL-10, and brain-derived neurotropic factor expression in splenocytes or CNS-derived lymphocytes. In CNS-derived lymphocytes, Fas ligand expression was down-regulated in DNA-vaccinated rats compared with controls. However, MOG-specific IgG2b responses were enhanced after DNA vaccination. The enhanced IgG2b responses together with the requirement for CpG DNA motifs in the vaccine suggest a protective mechanism involving induction of a T1-biased immune response.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Imunossupressores/imunologia , Glicoproteína Associada a Mielina/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Células Th1/imunologia , Vacinas de DNA/imunologia , Sequência de Aminoácidos , Animais , Subpopulações de Linfócitos B/imunologia , Células Cultivadas , Ilhas de CpG/imunologia , DNA Bacteriano/imunologia , Encefalomielite Autoimune Experimental/mortalidade , Encefalomielite Autoimune Experimental/patologia , Feminino , Cobaias , Imunossupressores/administração & dosagem , Injeções Intramusculares , Camundongos , Dados de Sequência Molecular , Glicoproteína Associada a Mielina/genética , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew , Subpopulações de Linfócitos T/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética
15.
J Immunol ; 169(1): 548-56, 2002 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12077287

RESUMO

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS with associated axonal loss. There is strong evidence for an autoimmune pathogenesis driven by myelin-specific T cells. Myelin oligodendrocyte glycoprotein (MOG) induces a type of experimental autoimmune encephalomyelitis in animals which is very MS-like since there are demyelinating CNS lesions and axonal loss. This underscores the potential role of MOG in MS pathogenesis. We performed a T cell reactivity pattern analysis of MS patients at the onset of relapse or progression of neurological deficits and controls that were stratified for the genetic risk factor HLA-DRB1*1501. For the first time, we show that there is an HLA-DR-restricted promiscuous dominant epitope for CD4(+) T cells within the transmembrane/intracellular part of MOG comprising aa 146-154 (FLCLQYRLR). Surprisingly, controls had broader T cell reactivity patterns toward MOG peptides compared with MS patients, and the transmembrane and intracellular parts of MOG were much more immunogenic compared with the extracellular part. Measurements of in vitro binding affinities revealed that HLA-DRB1*1501 molecules bound MOG 146-154 with intermediate and HLA-DRB1*0401 molecules with weak affinities. The binding of MOG 146-154 was comparable or better than myelin basic protein 85-99, which is the dominant myelin basic protein epitope in context with HLA-DRB1*1501 molecules in MS patients. This is the first study in which the data underscore the need to investigate the pathogenic or regulatory role of the transmembrane and intracellular part of MOG for MS in more detail.


Assuntos
Epitopos de Linfócito T/imunologia , Epitopos Imunodominantes/imunologia , Líquido Intracelular/imunologia , Glicoproteína Associada a Mielina/imunologia , Adulto , Membrana Celular/imunologia , Epitopos de Linfócito T/metabolismo , Espaço Extracelular/imunologia , Feminino , Antígenos HLA-DR/isolamento & purificação , Antígenos HLA-DR/metabolismo , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Humanos , Epitopos Imunodominantes/metabolismo , Imunofenotipagem , Vírus da Influenza A/imunologia , Líquido Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
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