RESUMO
AIM: There is little information on the demographic and clinical characteristics of Behçet's disease in children in different parts of the world. We sought to provide this information through a questionnaire survey of specialist eye centres. METHODS: Descriptive questionnaires were collected from 25 eye centres in 14 countries. The questionnaire surveyed details of juvenile-onset Behçet's disease with uveitis. Ethnic groups, clinical features, treatments and prognosis of paediatric-age Behçet's disease were examined on a worldwide scale. RESULTS: The clinical data of 135 juvenile-onset and 1227 adult-onset patients with uveitis were collected. The average age of disease diagnosis in the children was 11.7 years old. Of the ethnic groups identified 54% were from Middle East, 43% from Europe, but only 2% from East/South Asian countries. By contrast, 19.2% of adult patients were from East or South Asia. The frequency of genital ulcers in juvenile patients was 38.7%, which was significantly lower than in adult cases (53.5%; p<0.01). CONCLUSIONS: Behçet's disease with uveitis was less common in children than in adults in East/South Asia. Although the clinical features of the systemic disease were similar in children and adults, there was a lower frequency of genital ulceration in children.
Assuntos
Síndrome de Behçet/etnologia , Adulto , Idade de Início , Sudeste Asiático/etnologia , Síndrome de Behçet/epidemiologia , Criança , Europa (Continente)/etnologia , Ásia Oriental/etnologia , Feminino , Humanos , Masculino , Oriente Médio/etnologia , PrevalênciaRESUMO
Behçet's disease (BD) is a chronic inflammatory disease characterized by oral aphthous ulcers, genital ulcers, uveitis and skin lesions. Etiology and pathogenesis of BD are not fully elucidated, but the association with human leukocyte antigen (HLA)-B51 or B*5101 has been repeatedly reported. Previous studies have shown that there are few sequence variations in the protein-coding region of B51, while there is a report on many variations in the 5'-flanking region and intron. In this study, HLA-B*5101 gene from 37 individuals including Japanese, Turkish, Jordanian and Iranian patients and healthy controls were fully sequenced to further clarify the B*5101 gene in association with BD. We found that all the patients and healthy controls carried B*510101 with no variation in the 5'-flanking region, exon and intron. However, seven polymorphisms were found in the 3'-flanking region. These polymorphisms composed of six haplotypes that were shared and stretched over the ethnic groups, suggesting that the susceptibility to BD was conferred by the B*510101 itself and not by any genes in linkage disequilibrium with B*510101. In addition, phylogenetic analyses of B*510101 showed that the 3'-flanking sequences followed an evolutional divergence differently from that of the other regions, implying that a unifying selection might operate to conserve B*510101.
Assuntos
Síndrome de Behçet/genética , Antígenos HLA-B/genética , Haplótipos/genética , Sequência de Bases , Éxons , Predisposição Genética para Doença , Antígeno HLA-B51 , Humanos , Íntrons , Dados de Sequência Molecular , Filogenia , Polimorfismo GenéticoRESUMO
CARD15 was first identified as a susceptibility gene for Crohn's disease. More recently, CARD15 mutations were shown to be associated with the pediatric granulomatous inflammatory diseases, Blau syndrome and early-onset sarcoidosis (EOS). The aim of the present study was to evaluate whether CARD15 variants also play a role in patients with ordinary sarcoidosis other than EOS. We enrolled 135 Japanese sarcoidosis patients with uveitis as well as 95 healthy individuals and performed mutation analysis by direct sequencing of CARD15 exon 4. Direct DNA sequencing in the sarcoidosis patients showed eight CARD15 variants, including five novel mutations (13402C>T, 13543C>T, 13775C>A, 13937G>A, and 14079C>T). Compared with healthy individuals, CARD15 mutations are not common in the Japanese patients with sarcoidosis. Based on the results, we examined the clinical manifestations in patients with sarcoidosis according to their CARD15 mutations. Sarcoidosis patients with these mutations have no specific clinical features with regard to course of the disease or disease severity. Our results indicate that in general, CARD15 mutations may not contribute to the risk of sarcoidosis.
Assuntos
Éxons/genética , Proteína Adaptadora de Sinalização NOD2/genética , Mutação Puntual , Sarcoidose/genética , Adolescente , Adulto , Idade de Início , Idoso , Povo Asiático , Criança , Doença de Crohn/genética , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The nervous system contributes to the mechanisms of ocular immune privilege by the constitutive presence of the immunosuppressive neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) in the eye. Alpha-MSH through the melanocortin 5 receptor (MC5r) mediates induction of CD4+ regulatory T cells that suppress in an antigen specific manner autoimmune disease. We investigated whether there was a role for MC5r expression in ocular immunity and the natural induction of regulatory T cells that emerged following resolution of experimental autoimmune uveoretinitis (EAU). Unlike wild type mice, EAU in MC5r-/- mice caused severe retinal damage, did mice expressed a not induce the emergence of ocular autoantigen regulatory immunity in the spleen, and the MC5r-/- classical memory immune response when reimmunized with ocular autoantigen. There was expression of MC5r in retinal pigment epithelial cells, in the ganglion cell and neural outer plexiform layers of healthy wild type mice retinas. The recovery of the ocular microenvironment from EAU was not dependent on the expression of MC5r, nor was the recovery dependent on the induction of CD4+ regulatory T cells (Treg cells) in the spleen. However, protection of the retina from the inflammatory damage of EAU and the induction of ocular autoantigen-responsive CD4+ Treg cells in the post EAU spleen requires expression of MC5r.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/fisiologia , Receptores da Corticotropina/fisiologia , Retinite/imunologia , Linfócitos T Reguladores/metabolismo , Uveíte/imunologia , Animais , Autoantígenos/imunologia , Autoantígenos/metabolismo , Doenças Autoimunes/metabolismo , Doenças Autoimunes/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Olho/imunologia , Olho/metabolismo , Olho/patologia , Feminino , Imunização/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Corticotropina/genética , Receptores da Corticotropina/metabolismo , Receptores de Melanocortina , Retina/metabolismo , Retinite/metabolismo , Retinite/fisiopatologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Fatores de Tempo , Uveíte/metabolismo , Uveíte/fisiopatologiaRESUMO
BACKGROUND/AIMS: Advanced glycation end products (AGEs) are considered to act as mediators of both age related pathologies and diabetic complications. It was recently reported that glyceraldehyde derived AGE (AGE-2) has a strong biological effect on various diseases. The aim of this study was to investigate the serum AGE-2 levels in Vogt-Koyanagi-Harada (VKH) disease. METHODS: Sera were obtained from 31 patients with active VKH. 20 of these 31 patients were treated with systemic corticosteroids. As controls, 33 healthy volunteers were also examined. The serum AGE-2 levels were determined with a competitive enzyme linked immunosorbent assay using AGE-2 polyclonal antibody. RESULTS: The mean AGE-2 level in the sera of patients with VKH disease was 4.91 (SD 2.23) U/ml, which was significantly lower than that of the healthy control subjects (8.32 (2.94), p<0.001). The average serum AGE-2 level significantly increased to 13.49 (2.17) U/ml after the patients were treated with systemic corticosteroids (p<0.001). CONCLUSIONS: These results suggest that AGE-2 may be involved in the onset of VKH disease.
Assuntos
Produtos Finais de Glicação Avançada/sangue , Síndrome Uveomeningoencefálica/sangue , Doença Aguda , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Glicemia/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gliceraldeído/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Uveomeningoencefálica/tratamento farmacológicoRESUMO
Lethally irradiated AKR mice received BMT from H-2D and minor lymphocyte stimulatory (Mls)-1 disparate B10.A mice. No GVHD signs were detected in AKR recipients of T cell-depleted BM cells (1 x 10(7)) alone ([B10.A --> AKR] T-). When B10.A splenic T cells (1 x 10(5)) were injected in addition to T cell-depleted BM cells ([B10.A --> AKR] T+), overt GVHD was observed. [B10.A --> AKR] T+ chimeras recovered from the GVHD 8 weeks after BMT. In T cells from these [B10.A --> AKR] T+ chimeras, a substantial population of Mls-1a-reactive Vbeta6+ T cells was present, whereas the Vbeta6+ cells were deleted in [B10.A --> AKR] T- chimeras. T cells from [B10.A --> AKR] T+ chimeras showed considerable MLR but no CTL response against AKR cells (split tolerance). Upon stimulation with AKR stimulators or anti-CD3 MoAb, T cells from [B10.A --> AKR] T+ chimeras produced significantly more IL-4 but significantly less IFN-gamma compared with those from [B10.A --> AKR] T- chimeras or unmanipulated B10.A mice. The serum level of IgG1 in [B10.A --> AKR] T+ chimeras was also significantly higher than that in [B10.A --> AKR] T- or B10.A mice. The present findings suggest that the split tolerance observed in BMT chimeras recovered from GVHD is attributable to the Th2 dominant state.
Assuntos
Antígenos/imunologia , Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/imunologia , Tolerância Imunológica , Teste de Cultura Mista de Linfócitos , Linfócitos T Citotóxicos/imunologia , Doença Aguda , Animais , Quimera , Citocinas/biossíntese , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/classificação , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BLRESUMO
AIMS: To determine whether macrophage migration inhibitory factor (MIF) levels were increased in sera of the patients with iridocyclitis. METHODS: Sera were obtained from 41 patients with acute iridocyclitis, 13 patients with chronic iridocyclitis, and 44 healthy control subjects. MIF levels were determined by a human MIF ELISA. RESULTS: The average levels of MIF in the sera of patients with both acute and chronic iridocyclitis were significantly higher than that of healthy subjects. CONCLUSION: Uveitis induces the elevation of serum MIF, which may affect various inflammatory symptoms in uveitis.
Assuntos
Iridociclite/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Doença Aguda , Doença Crônica , Feminino , Humanos , MasculinoRESUMO
Allogeneic bone marrow chimeras were prepared by donor and recipient combinations that differed in minor histocompatibility loci or H-2D locus alone. When 1 x 10(5) splenic T cells were inoculated in addition to T cell-depleted bone marrow cells (1 x 10(7)), clinically detectable GVHR was induced. In these GVHR chimeras, substantial numbers of T cells reactive to either donor or recipient antigens were both phenotypically and functionally detected. The mechanisms underlying the abrogation of intrathymic negative selection are discussed.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Antígenos H-2/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Animais , Antígenos/imunologia , Transplante de Células , Quimera , Antígeno de Histocompatibilidade H-2D , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologiaRESUMO
We have defined a peptide K2 (ADKDVVVLTSSRTGGV) that corresponds to residues 201-216 of bovine interphotoreceptor retinoid-binding protein and induces experimental autoimmune uveoretinitis (EAU)4 in H-2Ak-carrying mice (H-2Ak mice). In this study, we attempted to ameliorate EAU in the H-2Ak mice without nonspecific suppression of T cell responses. Preceding s.c. administration of liposomes including K2 (liposomal K2) specifically inhibited subsequent generation of T cell response to K2. The same result was obtained with a combination of OVA323-339 peptide and the OVA-specific TCR-transgenic T cells. It was suggested that the inhibition was mainly attributed to peripheral anergy induction of T cells specific for the peptide Ag, although specific cell death might also be involved in the inhibition. Pretreatment with liposomal K2 also considerably abolished IFN-gamma production but not IL-4 production. The specific inhibitory effect of the pretreatment with liposomal peptide was augmented by a simultaneous administration of anti-CD40 ligand (anti-CD40L) mAb. Moreover, it was shown that the pretreatment with liposomal K2 reduced both the incidence and severity of the subsequent K2-induced EAU, and the simultaneous administration of anti-CD40L mAb augmented this preventive effect by liposomal K2. Our findings demonstrate that the s.c. administration of liposomal pathogenic peptide and anti-CD40L mAb can be applied to preventing autoimmune diseases without detrimental nonspecific suppression of T cell responses.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Doenças Autoimunes/prevenção & controle , Proteínas do Olho , Glicoproteínas de Membrana/imunologia , Fragmentos de Peptídeos/administração & dosagem , Retinite/imunologia , Uveíte/imunologia , Sequência de Aminoácidos , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/patologia , Antígenos CD40/metabolismo , Ligante de CD40 , Bovinos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Portadores de Fármacos , Epitopos de Linfócito T/imunologia , Feminino , Imunossupressores/administração & dosagem , Injeções Subcutâneas , Ligantes , Lipossomos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Retinite/etiologia , Retinite/patologia , Retinite/prevenção & controle , Proteínas de Ligação ao Retinol/administração & dosagem , Linfócitos T/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Fatores de Tempo , Uveíte/etiologia , Uveíte/patologia , Uveíte/prevenção & controleRESUMO
Recently it has been shown that modulation of CD40 molecules on antigen (Ag) carrying dendritic cells (DC) can bypass T cell help, resulting in priming cytotoxic T lymphocytes (CTL) specific for the Ag. In the present study we attempted to prime peptide Ag-specific CTL by a new method in which a peptide Ag in liposome (liposomal peptide), consisting of phosphatidylserine and phosphatidylcholine (3:7), was administrated subcutaneously with anti-CD40 and/or CTLA-4 monoclonal antibodies (mAb) to mice. We found that the subcutaneous administration of the liposomal peptide with both anti-CD40 and anti-CTLA-4 mAb enhanced CTL responses comparing with those induced by the liposomal peptide alone or the liposomal peptide plus each mAb. It was shown that liposomes were critical for induction of the CTL activity. Flow cytometry analysis of a peptide-bearing DC in lymph nodes (LN) and measurement of serum IL-12 indicated that anti-CD40 mAb promoted migration of DC to the LN, where DC might differentiate and acquire ability of priming CTL. These findings provide a possibility that our procedure is applicable to cancer patients.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação/imunologia , Antígenos CD40/imunologia , Imunoconjugados , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Abatacepte , Administração Cutânea , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD , Antígeno CTLA-4 , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Testes Imunológicos de Citotoxicidade , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Interleucina-2/sangue , Lipossomos , Linfonodos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Fosfatidilcolinas/imunologia , Fosfatidilcolinas/farmacologia , Fosfatidilserinas/imunologia , Fosfatidilserinas/farmacologia , Pele/imunologiaRESUMO
It has been shown that macrophage migration inhibitory factor (MIF) modulates not only macrophage functions, but also T cell functions. However, detailed analysis of the MIF function on responses of various T cell subpopulations remained to be elucidated. In this report, using a neutralizing anti-MIF monoclonal antibody (mAb) we examined MIF functions on various T cell lineages. It was shown that anti-MIF mAb inhibited antigen-specific responses of both IFN-gamma producing and IL-4 producing T cells. The inhibition appeared to be related to blockade of the signal pathway via T cell receptor (TCR) but not that via IL-2 receptor (IL-2R). However, the anti-MIF mAb showed no inhibitory effect on NK-T cell responses stimulated through TCR. These results suggest that MIF is involved in the signal pathway via TCR in mainstream T cells but not in NK-T cells.
Assuntos
Fatores Inibidores da Migração de Macrófagos/imunologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos/imunologia , Antígenos/imunologia , Antígenos de Superfície , Divisão Celular , Linhagem Celular , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Lectinas Tipo C , Ativação Linfocitária , Fatores Inibidores da Migração de Macrófagos/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Proteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Interleucina-2/imunologiaRESUMO
PURPOSE: The role of macrophage migration inhibitory factor (MIF) in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) in rats following immunization with a retinal antigen (Ag), interphotoreceptor retinoid-binding protein (IRBP). METHODS: LEW rats were immunized with a single injection of IRBP derived peptide, R16(ADGSSWEGVGVVPDV). A neutralizing monoclonal antibody (mAb, IgM) to MIF was injected intraperitoneally every second day from day 0 to day 6 (group A), or from day 8 to day 14 (group B). Control rats were treated with unrelated mouse IgM or PBS. T cell proliferative responses were measured 12 days after immunization. The occurrence and severity of EAU were observed and compared among experimental and control groups. RESULTS: T cell proliferative responses against R16 were inhibited in rats treated with anti-MIF mAb compared with the control rats. The development of EAU was delayed in the rats of group A in comparison with those of group B and the control group. The mean histological EAU score on day 18 in group A was 1.11 +/- 0. 11 and significantly lower than those of the group B (1.29 +/- 0.19) and the control (1.67 +/- 0.19). CONCLUSIONS: The present result suggests that MIF plays an important role in induction of EAU.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/prevenção & controle , Proteínas do Olho , Fatores Inibidores da Migração de Macrófagos/imunologia , Retinite/prevenção & controle , Uveíte/prevenção & controle , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Doenças Autoimunes/induzido quimicamente , Olho/efeitos dos fármacos , Olho/patologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/química , Ratos , Ratos Endogâmicos Lew , Retinite/induzido quimicamente , Proteínas de Ligação ao Retinol/química , Índice de Gravidade de Doença , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Uveíte/induzido quimicamenteRESUMO
To investigate the influence of corticosteroid administration on the serum level of macrophage migration inhibitory factor (MIF), sera obtained from 9 patients with Vogt-Koyanagi-Harada's disease who had been treated with high-dose corticosteroid were analyzed. The serum MIF levels of most patients were prominently increased on day 7 and/or day 14 after corticosteroid treatment. No TNF-alpha was detected in the sera. The average serum MIF level of nine patients at the highest stages after corticosteroid administration was significantly higher than that before the corticosteroid treatment. It seems that MIF is a unique cytokine and acts together with corticosteroid to regulate inflammation and immunity.
Assuntos
Anti-Inflamatórios/uso terapêutico , Glucocorticoides/uso terapêutico , Fatores Inibidores da Migração de Macrófagos/sangue , Prednisolona/uso terapêutico , Síndrome Uveomeningoencefálica/tratamento farmacológico , Administração Oral , Anti-Inflamatórios/administração & dosagem , Relação Dose-Resposta a Droga , Glucocorticoides/administração & dosagem , Humanos , Injeções Intravenosas , Prednisolona/administração & dosagem , Fator de Necrose Tumoral alfa/análise , Síndrome Uveomeningoencefálica/sangueRESUMO
PURPOSE: To investigate pathogenesis underlying endogenous uveitis, macrophage migration inhibitory factor (MIF) was quantified in sera of patients. METHODS: Sera were obtained from the 55 patients with uveitis (24 with Behçet's disease; 9 with Vogt-Koyanagi-Harada's [VKH] disease; 22 with sarcoidosis) and 58 healthy control subjects. MIF levels were determined by a human MIF enzyme-linked immunosorbent assay. RESULTS: The mean MIF levels in the sera of the patients with Behçet's disease, VKH disease, and sarcoidosis and of healthy control subjects were 60.4+/-9.0 (mean+/-SE) ng/ml, 16.5+/-2.9 ng/ml, 27.1+/-5.6 ng/ml, and 5.4+/-0.04 ng/ml, respectively. The average levels of MIF in the sera of uveitis patients were significantly higher (P < 0.0001) than those of healthy control subjects. The high levels of MIF were especially noted in patients with Behçet's disease at the ocular exacerbation stage and patients with sarcoidosis at the severe uveitis stage. CONCLUSIONS: Significant increase of MIF in sera was characteristic of uveitis, and MIF may be a usefull laboratory parameter to use to comprehend the clinical course of uveitis.
Assuntos
Fatores Inibidores da Migração de Macrófagos/sangue , Uveíte/sangue , Síndrome de Behçet/sangue , Ensaio de Imunoadsorção Enzimática , Oftalmopatias/sangue , Humanos , Sarcoidose/sangue , Síndrome Uveomeningoencefálica/sangueRESUMO
When certain strains of mice bearing H-2Ak are immunized with the interphotoreceptor retinoid-binding protein (IRBP), EAU is induced. Thus far uveitogenic determinant(s) has not been determined in the H-2Ak mouse system. In addition it is hard to prepare purified IRBP. In the present study, to circumvent these problems we attempted to identify uveitogenic peptides derived from bovine IRBP in H-2Ak haplotype mice. Six peptides which had been selected according to the H-2Ak binding motif (Dxxxxxxxx[A, R, T]) were synthesized. We report here that all the peptides are immunogenic but only one peptide, K2, which consisted of IRBP201-216 residues, induces EAU in various mice carrying H-2Ak. Amino acid substitution of K2 revealed that the core region interacted with both H-2Ak and T cell antigen receptor (TCR). The amino acid sequence of the core region derived from bovine IRBP was identical to the corresponding region of mouse IRBP. In addition, K2 appeared to be a natural peptide antigen processed from bovine IRBP. Altogether, we concluded that K2 is one of the natural autoantigens involved in induction of EAU in H-2Ak mice.