Assuntos
Predisposição Genética para Doença/etnologia , Antígeno HLA-DR4/genética , Transtornos de Fotossensibilidade/epidemiologia , Dermatopatias Genéticas/epidemiologia , Luz Solar/efeitos adversos , Fatores Etários , Alelos , Criança , Feminino , Antígeno HLA-DR4/imunologia , Humanos , América Latina/epidemiologia , Masculino , Transtornos de Fotossensibilidade/etiologia , Fatores de Risco , Fatores Sexuais , Pele/efeitos da radiação , Dermatopatias Genéticas/etiologiaRESUMO
Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated T* was previously identified by screening T cells from volunteers immunized with irradiated P. falciparum sporozoites. The T* sequence spans twenty amino acids that contains multiple T cell epitopes restricted by various HLA alleles. Subunit malaria vaccines including T* are highly immunogenic in rodents, non-human primates and humans. In this study we characterized a highly conserved HLA-DRß1*04:01 (DR4) restricted T cell epitope (QNT-5) located at the C-terminus of T*. We found that a peptide containing QNT-5 was able to elicit long-term anti-CS Ab responses and prime CD4 T cells in HLA-DR4 transgenic mice despite forming relatively unstable MHC-peptide complexes highly susceptible to HLA-DM editing. We attempted to improve the immunogenicity of QNT-5 by replacing the P1 anchor position with an optimal tyrosine residue. The modified peptide QNT-Y formed stable MHC-peptide complexes highly resistant to HLA-DM editing. Contrary to expectations, a linear peptide containing QNT-Y elicited almost 10-fold lower long-term antibody and IFN-γ responses compared to the linear peptide containing the wild type QNT-5 sequence. Some possibilities regarding why QNT-5 is more effective than QNT-Y in inducing long-term T cell and anti-CS Ab when used as vaccine are discussed.
Assuntos
Anticorpos Antiprotozoários/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígeno HLA-DR4/imunologia , Memória Imunológica , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Animais , Epitopos de Linfócito T/genética , Feminino , Antígeno HLA-DR4/genética , Humanos , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Estabilidade Proteica , Proteínas de Protozoários/genéticaRESUMO
Interleukin (IL)-21 and protein tyrosine phosphatase non-receptor 22 (PTPN22) regulate lymphocyte function and have been implicated in the pathogenesis of autoimmune diabetes. We sequenced the proximal promoter of the IL-21 gene for the first time and analysed the PTPN22 1858T polymorphism in type 1A diabetes (T1AD) patients and healthy controls (HC). We correlated the frequencies of islet and extra-pancreatic autoantibodies with genotypes from both loci. The case series comprised 612 T1AD patients and 792 HC. Genotyping of PTPN22 C1858T was performed on 434 T1AD patients and 689 HC. The -448 to +83 base pairs (bp) region of the IL-21 gene was sequenced in 309 Brazilian T1AD and 189 HC subjects. We also evaluated human leucocyte antigen (HLA) DR3/DR4 alleles. The frequencies of glutamic acid decarboxylase (GAD65), tyrosine phosphatase-like protein (IA)-2, anti-nuclear antibody (ANA), thyroid peroxidase (TPO), thyroglobulin (TG), thyrotrophin receptor autoantibody (TRAb), anti-smooth muscle (ASM) and 21-hydroxylase (21-OH) autoantibodies were higher in T1AD patients than in HC. The PTPN22 1858T allele was associated with an increased risk for developing T1AD [odds ratio (OR) = 1·94; P < 0·001], particularly in patients of European ancestry, and with a higher frequency of GAD65 and TG autoantibodies. HLA-DR3/DR4 alleles predominated in T1AD patients. A heterozygous allelic IL-21 gene variant (g.-241 T > A) was found in only one patient. In conclusion, only PTPN22 C1858T polymorphism and HLA-DR3 and/or DR4 alleles, but not allelic variants in the 5'-proximal region of the IL-21 gene were associated with T1AD risk. Patients with T1AD had increased frequencies of anti-islet-cell, anti-thyroid, anti-nuclear, anti-smooth muscle and anti-21-OH autoantibodies. The C1858T PTPN22 polymorphism was also associated with a higher frequency of GAD65 and TG autoantibodies.
Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/genética , Interleucinas/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Alelos , Autoanticorpos/genética , Autoanticorpos/metabolismo , Biomarcadores/metabolismo , Brasil , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/imunologia , Antígeno HLA-DR3/genética , Antígeno HLA-DR3/imunologia , Antígeno HLA-DR4/genética , Antígeno HLA-DR4/imunologia , Humanos , Interleucinas/imunologia , Masculino , Regiões Promotoras Genéticas , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Risco , Análise de Sequência de DNA , População BrancaRESUMO
BACKGROUND: Liver transplantation is the only therapy for end-stage liver disease. Cirrhosis secondary to autoimmune hepatitis (AIH) is an indication in 4-6% of adult transplants. AIMS: To describe the outcomes and recurrence of AIH in liver transplant patients. MATERIAL AND METHODS: Twenty patients were retrospectively studied. RESULTS: The female/male ratio was 3:1, the median age was 36.7 years (range, 16 to 39 years), and the median MELD score was 18.5. According to serological analysis, 19 patients were AIH type 1 and one patient was AIH type 2. AIH was associated with human leukocyte antigen (HLA) DR13+ and DR4+. The overall 5-year patient and graft survival rates were 94 and 85%, respectively. Three (15.7%) cases of recurrent AIH were diagnosed based on histological evidence. Clinical and histological features of acute and chronic rejection were present in four (20%) and three (16.6%) patients, respectively. CONCLUSION: AIH frequently affected young women, was the most frequent indication for liver transplantation. Rejection and recurrence were commonly associated with AIH, but did not affect patient survival. No significant relationship between HLA-DR type and recurrence was found. Rapid progression to cirrhosis should be considered in severe recurrences.
Assuntos
Subtipos Sorológicos de HLA-DR/imunologia , Antígeno HLA-DR4/imunologia , Hepatite Autoimune/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepatite Autoimune/complicações , Hepatite Autoimune/imunologia , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Peru , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Vogt-Koyanagi-Harada (VKH) syndrome is associated with human leukocyte antigen (HLA)-B54, -DR4, -DR beta 1*0405, -DQ4, and -DR53 in Japanese patients. Disease-associated HLA specificities may differ among races. This study examined HLA associations with VKH syndrome in Hispanic patients living in southern California, a racial subgroup at increased risk for the disease. METHODS: Human leukocyte antigen specificities were determined on 25 Hispanic patients with VKH syndrome and compared with HLA specificities of 217 healthy Hispanic control subjects. Inclusion criteria for study patients were nontraumatic panuveitis with exudative retinal detachments, with or without extraocular manifestations. Tests were performed using standard cytotoxic assays. RESULTS: HLA-DR4 was present in 14 (56%) patients with VKH syndrome and in 62(29%) control subjects (relative risk = 1.96). HLA-DR1 was present in 9 (36%) patients with VKH syndrome and in 19 (9%) control subjects (relative risk = 4.11). HLA-DR1 and DR4 share a common epitope within the DR beta 1 gene. HLA-DR1 and/or DR4 were present in 21 (84%) patients with VKH syndrome and in 76 (35%) control subjects (relative risk = 2.40). CONCLUSIONS: HLA-DR1 and -DR4 were found in a significantly disproportionate number of Hispanic patients with VKH syndrome living in southern California. HLA-DR4, although not HLA-DR1, has been previously associated with VKH syndrome in other groups. These associations suggest a common immunogenic predisposition to VKH among different racial groups, and suggest that a common epitope shared by DR1 and DR4 may be involved in the pathogenesis of the disease.