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1.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614573

RESUMO

It has been reported Human Leukocyte Antigen (HLA) gene polymorphism is a risk factor for the development of Behçet's disease (BD). In this study, the association of HLA class II subtypes HLA-DP, DQ, DR, and T cell subsets in BD patients with arthritis was evaluated. Frequencies of HLA-DP, DQ, DR positive cells, and T cell subsets in peripheral blood leukocytes (PBL) were measured by flow cytometric analysis in BD, and compared to rheumatoid arthritis as disease controls and healthy controls. Frequencies of HLA-DQ were significantly decreased in whole PBL and granulocytes of BD active patients as compared to healthy controls. In monocytes populations, proportions of HLA-DR positive cells were significantly increased in BD active patients as compared to healthy controls. Proportions of CD4+CCR7+ and CD8+CCR7+ cells were significantly higher in BD active patients than in BD inactive in whole PBL. Frequencies of CD4+CD62L- and CD8+CD62L- cells in lymphocytes were significantly decreased in active BD than those in inactive BD. There were also correlations between disease activity markers and T cell subsets. Our results revealed HLA-DP, DQ, and DR expressing cell frequencies and several T cell subsets were significantly correlated with BD arthritis symptoms.


Assuntos
Artrite Reumatoide/imunologia , Síndrome de Behçet/imunologia , Antígenos HLA-D/metabolismo , Subpopulações de Linfócitos T/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade
2.
Immunity ; 51(4): 766-779.e17, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31495665

RESUMO

Increasing evidence indicates CD4+ T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/imunologia , Mapeamento de Epitopos/métodos , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Imunoterapia/métodos , Espectrometria de Massas/métodos , Neoplasias/terapia , Algoritmos , Alelos , Apresentação do Antígeno , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Conjuntos de Dados como Assunto , Antígenos HLA/genética , Antígenos HLA-D/metabolismo , Humanos , Neoplasias/imunologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/genética , Software
3.
AAPS PharmSciTech ; 20(7): 270, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363872

RESUMO

Currently, there is no specific treatment for acute lung injury (ALI). E-selectin-binding peptide (Esbp), a high-affinity peptide that delivers drugs targeting inflammatory vascular endothelial cells, can bind to E-selectin and act as a targeting ligand for selective drug delivery. In this study, we coupled the thiol groups of Esbp to the amino groups on the surface of bovine serum albumin (BSA) using succinimidyl iodoacetic acid to make Esbp-modified BSA nanoparticles (BSANPs) at the average ratio of 19.3 µg Esbp to 1 mg BSA. The Esbp-modified BSANPs were spherical in shape and had a particle size of 266.7 ± 2.7 nm, polydispersity index of 0.165 ± 0.02, zeta potential of - 33.64 ± 1.23 mV, encapsulation efficiency of 84.3 ± 2.3%, and drug loading of 6.7 ± 0.32%. The cumulative release rate of dexamethasone-loaded Esbp-modified BSANPs was 51.2% within 12 h, significantly lower than that of 88.2% of free drugs. Moreover, Esbp-modified BSANPs could be uptaken in vitro by activated human umbilical vein endothelial cells and in vivo by the lungs of the established ALI mouse model. These results indicated that our Esbp-modified BSANPs delivery system has characteristics of good targeting ability and biocompatibility and is able to inhibit inflammation. Overall, our Esbp-modified BSANPs delivery system has therapeutic potentials as a new targeting drug system for the treatment of ALI in the future.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Dexametasona/administração & dosagem , Selectina E/administração & dosagem , Antígenos HLA-D/administração & dosagem , Nanopartículas/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Lesão Pulmonar Aguda/metabolismo , Animais , Bovinos , Linhagem Celular Tumoral , Dexametasona/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Selectina E/metabolismo , Antígenos HLA-D/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Nanopartículas/metabolismo , Tamanho da Partícula , Soroalbumina Bovina/metabolismo , Resultado do Tratamento
4.
Am J Physiol Gastrointest Liver Physiol ; 317(2): G127-G140, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141391

RESUMO

Hepatitis B virus (HBV) infection and alcoholism are major public health problems worldwide, contributing to the development of end-stage liver disease. Alcohol intake affects HBV infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-major histocompatibility complex (MHC) class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs. Hence, the focus of this study was to investigate the mechanisms by which ethanol metabolism affects the presentation of CTL epitope on HBV-infected hepatocytes. As demonstrated here, although continuous cell exposure to acetaldehyde-generating system (AGS) increased HBV load in HepG2.2.15 cells, it decreased the expression of HBV core peptide 18-27-human leukocyte antigen-A2complex (CTL epitope) on the cell surface. Moreover, we observed AGS-induced suppression of chymotrypsin- and trypsin-like proteasome activities necessary for peptide processing by proteasome as well as a decline in IFNγ-stimulated immunoproteasome (IPR) function and expression of PA28 activator and immunoproteasome subunits LMP7 and LMP2. Furthermore, IFNγ-induced activation of peptide-loading complex (PLC) components, such as transporter associated with antigen processing (TAP1) and tapasin, were suppressed by AGS. The attenuation of IPR and PLC activation was attributed to AGS-triggered impairment of IFNγ signaling in HepG2.2.15 cells. Collectively, all these downstream events reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, which may suppress CTL activation and the recognition of CTL epitopes on HBV-expressing hepatocytes by immune cells, thereby leading to persistence of liver inflammation.NEW & NOTEWORTHY Our study shows that in HBV-expressing HepG2.2.15 cells, acetaldehyde alters HBV peptide processing by suppressing chymotrypsin- and trypsin-like proteasome activities and decreases IFNγ-stimulated immunoproteasome function and expression of PA28 activator and immunoproteasome subunits. It also suppresses IFNγ-induced activation of peptide-loading complex (PLC) components due to impairment of IFNγ signaling via the JAK-STAT1 pathway. These acetaldehyde-induced dysfunctions reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, thereby leading to persistence of HBV infection.


Assuntos
Acetaldeído/metabolismo , Quimases/metabolismo , Etanol/metabolismo , Hepatite B , Complexo Principal de Histocompatibilidade/imunologia , Serina Endopeptidases/metabolismo , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apresentação do Antígeno , Antígenos HLA-D/imunologia , Células Hep G2 , Hepatite B/imunologia , Hepatite B/metabolismo , Vírus da Hepatite B/imunologia , Humanos , Interferon gama/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfócitos T Citotóxicos/imunologia
5.
Crit Care Med ; 47(7): e538-e546, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30985453

RESUMO

OBJECTIVES: After return of spontaneous circulation, patients who experienced out-of-hospital cardiac arrest present an impaired innate immune response that resembles sepsis. Presepsin, a new biomarker for sepsis, has not been studied in out-of-hospital cardiac arrest patients. This study explored the role of presepsin in evaluating the prognosis and early innate immune alteration of out-of-hospital cardiac arrest patients after return of spontaneous circulation by observing presepsin levels, CD14, and human leukocyte antigen-DR expression on monocytes. DESIGN: Retrospective analysis. SETTING: The emergency department of an urban university tertiary hospital. PARTICIPANTS: One hundred sixty-five out-of-hospital cardiac arrest patients with return of spontaneous circulation more than 12 hours, and 100 healthy individuals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma presepsin and procalcitonin levels were tested after resuscitation (day 0) and on days 1 and 3 after return of spontaneous circulation. Presepsin levels were higher in out-of-hospital cardiac arrest patients than in healthy individuals. In the first 3 days, presepsin and procalcitonin levels were persistently lower in 28-day survivors and patients with favorable neurologic outcome patients than in 28-day nonsurvivors and patients with unfavorable neurologic outcome. On days 0, 1, and 3, different cut-off values of presepsin showed prognostic value for 28-day mortality and favorable neurologic outcomes similar to procalcitonin. CD14 and human leukocyte antigen-DR expression on monocytes were analyzed by flow cytometry. Compared with controls, CD14 expression in out-of-hospital cardiac arrest patients increased on day 1 and began to decrease on day 3, whereas human leukocyte antigen-DR+ monocyte percentages decreased on days 1 and 3. Presepsin and procalcitonin had a low positive correlation with CD14 expression and a strong negative correlation with human leukocyte antigen-DR+ monocyte percentages on day 1. CONCLUSIONS: Plasma presepsin concentrations are independent prognostic factors for out-of-hospital cardiac arrest patients after return of spontaneous circulation and are correlated with abnormal CD14 and human leukocyte antigen-DR expression on monocytes. Monitoring presepsin levels may be helpful for evaluating the prognosis and impaired innate immune response in the early period after return of spontaneous circulation.


Assuntos
Imunidade Inata/imunologia , Receptores de Lipopolissacarídeos/biossíntese , Parada Cardíaca Extra-Hospitalar/imunologia , Parada Cardíaca Extra-Hospitalar/mortalidade , Fragmentos de Peptídeos/biossíntese , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Citometria de Fluxo , Antígenos HLA-D/biossíntese , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Parada Cardíaca Extra-Hospitalar/sangue , Pró-Calcitonina/biossíntese , Prognóstico , Estudos Retrospectivos
6.
Mult Scler Relat Disord ; 30: 57-62, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30738281

RESUMO

BACKGROUND: The aim of the current study was to examine intra-family phenotype variations in familial neuromyelitis optica (NMO) spectrum disorder. METHODS: The clinical presentation and neuroimaging features of two family members (mother and daughter) from a NMO spectrum disorder family (index family) were analyzed. Multiplex polymerase chain reaction was performed based on targeted re-sequencing on the AQP4 gene and the human leukocyte antigen (HLA) loci. The clinical and neuroimaging features of the members of six other previously reported NMO spectrum disorder families were also included for analysis. RESULTS: In the core family, the mother was aged 39 at disease onset and the initial presentation was spinal cord involvement, whereas the daughter was 22 years old at disease onset and the initial presentation was brainstem involvement. No coding pathogenic variants or single nucleotide polymorphisms of the AQP4 gene were identified in the mother, daughter or father. As for HLA genotyping, the HLA-DRB1*03 and HLA-DPB1*04 alleles were shared by the mother and daughter. The HLA-DPB1*05 was present in the affected daughter and was inherited from the unaffected father. As for the other six reported families with familial NMO spectrum disorder, four mother-daughter pairs had a different age at disease onset and/or a different initial presentation. The other two affected family groups were sister-sister pairs; they had a similar age of onset and similar initial presentations. CONCLUSION: The present study offers a preliminary view of the clinical and neuroimaging features of patients with familial NMO spectrum disorder. Clinical heterogeneities were found among the family members, especially the mother and daughter pairs. The presence of risk allele HLA-DR*03:01 may be an important genetic finding for familial NMO spectrum disorder patients. To the best of our knowledge, this clinical heterogeneity has not been previously examined or reported in the literature. For better delineation of the intra-familial phenotype variations in familial NMO spectrum disorder, further large-scale studies are needed.


Assuntos
Antígenos HLA-D/genética , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/genética , Neuromielite Óptica/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
7.
Diabetes Care ; 42(3): 406-415, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30659077

RESUMO

OBJECTIVE: Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS: We generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5). RESULTS: African-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS: Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Testes Genéticos , Antígenos HLA-D/genética , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Estudo de Associação Genômica Ampla , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Projetos de Pesquisa , Fatores de Risco
8.
Immunogenetics ; 71(3): 189-196, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30683973

RESUMO

The main objective of antigen processing is to orchestrate the selection of immunodominant epitopes for recognition by CD4 T cells. To achieve this, MHC class II molecules have evolved with a flexible peptide-binding groove in need of a bound peptide. Newly synthesized MHC-II molecules bind a class II invariant chain (Ii) upon synthesis and are shuttled to a specialized compartment, where they encounter exogenous antigens. Ii serves multiple functions, one of which is to maintain the shape of the MHC-II groove so that it can readily bind exogenous antigens upon dissociation of the Ii peptide in MHC- II compartment. MIIC contains processing enzymes, one or both accessory molecules, HLA-DM/H2-M (DM) and HLA-DO/H2-O (DO), and optimal denaturing conditions. In a process known as "editing," DM facilitates the dissociation of the invariant chain peptide, CLIP, for exchange with exogenous antigens. Despite the availability of mechanistic insights into DM functions, understanding how DO contributes to epitope selection has proven to be more challenging. The current dogma assumes that DO inhibits DM, whereas an opposing model suggests that DO fine-tunes the epitope selection process. Understanding which of these, or potentially other models of DO function is important, as DO variants have been linked to autoimmunity, cancer, and the generation of broadly neutralizing antibodies to viruses. This review therefore attempts to evaluate experimental evidence in support of these hypotheses, with an emphasis on the less discussed model, and to explore intriguing questions about the importance of DO in biology.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos HLA-D/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ligação Proteica , Linfócitos T/metabolismo
9.
Mol Cell Proteomics ; 18(3): 490-503, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30573663

RESUMO

Presentation of antigenic peptides on MHC-II molecules is essential for tolerance to self and for initiation of immune responses against foreign antigens. DO (HLA-DO in humans, H2-O in mice) is a nonclassical MHC-II protein that has been implicated in control of autoimmunity and regulation of neutralizing antibody responses to viruses. These effects likely are related to a role of DO in selecting MHC-II epitopes, but previous studies examining the effect of DO on presentation of selected CD4 T cell epitopes have been contradictory. To understand how DO modulates MHC-II antigen presentation, we characterized the full spectrum of peptides presented by MHC-II molecules expressed by DO-sufficient and DO-deficient antigen-presenting cells in vivo and in vitro using quantitative mass spectrometry approaches. We found that DO controlled the diversity of the presented peptide repertoire, with a subset of peptides presented only when DO was expressed. Antigen-presenting cells express another nonclassical MHC-II protein, DM, which acts as a peptide editor by preferentially catalyzing the exchange of less stable MHC-II peptide complexes, and which is inhibited when bound to DO. Peptides presented uniquely in the presence of DO were sensitive to DM-mediated exchange, suggesting that decreased DM editing was responsible for the increased diversity. DO-deficient mice mounted CD4 T cell responses against wild-type antigen-presenting cells, but not vice versa, indicating that DO-dependent alterations in the MHC-II peptidome could be recognized by circulating T cells. These data suggest that cell-specific and regulated expression of HLA-DO serves to fine-tune MHC-II peptidomes, in order to enhance self-tolerance to a wide spectrum of epitopes while allowing focused presentation of immunodominant epitopes during an immune response.


Assuntos
Antígenos HLA-D/genética , Antígenos de Histocompatibilidade Classe II/química , Peptídeos/metabolismo , Animais , Apresentação do Antígeno , Linhagem Celular , Epitopos de Linfócito T/metabolismo , Antígenos HLA-D/química , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Epitopos Imunodominantes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
10.
Mult Scler ; 25(1): 23-30, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29111883

RESUMO

BACKGROUND: The strongest genetic determinant for multiple sclerosis (MS) is located at the human leukocyte antigen (HLA) class II DRB1 and DQB1 loci. OBJECTIVES: To investigate the possible role of predisposing HLA genotypes in determining brain atrophy. METHODS: HLA genotypes were categorized as high risk (two predisposing haplotypes) or medium/low risk (one or no predisposing haplotypes). Patients underwent a brain magnetic resonance imaging (MRI) study and volumes of white matter (WM), gray matter (GM), and whole brain (WB) were estimated with SIENAX. Longitudinal atrophy was also assessed with SIENA. RESULTS: The study included 240 MS patients. In 51/240 (21%) subjects, a high-risk HLA genotype was observed, while medium- and low-risk HLA genotypes were 109/240 (45%) and 80/240 (34%), respectively. Multiple regression analysis found that the high-risk HLA genotype was associated with significant reduction in WB ( p = 0.02) and GM ( p = 0.03) volumes compared with the medium-/low-risk HLA genotypes, independently from MS clinical features. The longitudinal study included 60 patients and showed a brain volume loss of -0.79% in high-risk HLA genotype group versus -0.56% in low-risk HLA genotype. CONCLUSION: Our results suggest an influence of HLA genotype on WB and GM atrophy. Further investigations are necessary to confirm these findings.


Assuntos
Substância Cinzenta/patologia , Antígenos HLA-D/genética , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Substância Branca/patologia , Adulto , Atrofia , Encéfalo , Feminino , Substância Cinzenta/diagnóstico por imagem , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Itália , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
11.
Biotechnol Adv ; 37(1): 145-153, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30508573

RESUMO

Assessing T-cell mediated immune status can help to understand the body's response to disease and also provide essential diagnostic information. However, detection and characterization of immune response are challenging due to the rarity of signature biomolecules in biological fluid and require highly sensitive and specific assay technique for the analysis. Until now, several techniques spanning from flow cytometry to microsensors have been developed or under investigation for T-cell mediated immune response monitoring. Most of the current assays are designed to estimate average immune responses, i.e., total functional protein analysis and detection of total T-cells irrespective of their antigen specificity. Although potential, immune response analysis without detecting and characterizing the rare subset of T-cell population could lead to over or underestimation of patient's immune status. Addressing this limitation, recently a number of technological advancements in biosensing have been developed for this. The potential of simple and precise micro-technologies including microarray and microfluidic platforms for assessing antigen-specific T-cells will be highlighted in this review, together with a discussion on existing challenges and future aspects of immune-sensor development.


Assuntos
Antígenos/imunologia , Antígenos HLA-D/genética , Imunidade Celular/genética , Linfócitos T/imunologia , Citometria de Fluxo , Humanos
12.
Genes Immun ; 20(1): 74-81, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29282355

RESUMO

Environmental factors and the major histocompatibility complex (MHC) are involved in the pathogenesis of atopic dermatitis (AD). However, MHC type (H2 haplotype) of AD model mice NC/Nga is poorly understood. Alloreactive CD8+ or CD4+ T cells in NC/Nga strongly responded to each antigen-presenting cells (A/J: H-2a, C57BL/6: H-2b, BALB/c: H-2d, or C3H/HeJ: H-2k), suggesting that NC/Nga has other H2 haplotype. Polymorphic microsatellite (CA)n repeats in TNF-α gene differ based on the H2 haplotype at present. NC/Nga's (CA)n repeats (n = 19) were different from other examined strains, A/J (n = 14), BALB/c (n = 14), C3H/HeJ (n = 16), and C57BL/6 (n = 20). Using flow cytometry and genotyping, we demonstrated the NC/Nga H2 haplotype had a unique phenotype (Kd, I-Ak, and I-Ek) in which Dd and Ld lacked as protein despite sensitive mRNA detection. The loss of Dd and Ld was caused by forming a unique Ddm7/Ldm7-hybrid mutant (D/Ldm7). We propose to call this novel H2 haplotype the "H-2nc," and provide the important information regarding the AD research using NC/Nga mice.


Assuntos
Dermatite Atópica/genética , Antígenos HLA-D/genética , Mutação , Animais , Células Cultivadas , Antígenos HLA-D/metabolismo , Haplótipos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
14.
Arq Neuropsiquiatr ; 76(10): 697-704, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30427510

RESUMO

OBJECTIVE: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). METHODS: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. RESULTS: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon ß-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon ß-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon ß-1b (DQB1*02:01). CONCLUSION: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.


Assuntos
Antígenos HLA/genética , Esclerose Múltipla Recidivante-Remitente/genética , Adolescente , Adulto , Alelos , Criança , Progressão da Doença , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Antígenos HLA-D/genética , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
Sci Rep ; 8(1): 13296, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185867

RESUMO

Staphylococcus aureus is an opportunistic pathogen that causes a range of serious infections associated with significant morbidity, by strains increasingly resistant to antibiotics. However, to date all candidate vaccines have failed to induce protective immune responses in humans. We need a more comprehensive understanding of the antigenic targets important in the context of human infection. To investigate infection-associated immune responses, patients were sampled at initial presentation and during convalescence from three types of clinical infection; skin and soft tissue infection (SSTI), prosthetic joint infection (PJI) and pediatric hematogenous osteomyelitis (PHO). Reactivity of serum IgG was tested with an array of recombinant proteins, representing over 2,652 in-vitro-translated open reading frames (ORFs) from a community-acquired methicillin-resistant S. aureus USA300 strain. High-level reactivity was demonstrated for 104 proteins with serum IgG in all patient samples. Overall, high-level IgG-reactivity was most commonly directed against a subset of secreted proteins. Although based on limited surveys, we found subsets of S. aureus proteins with differential reactivity with serum samples from patients with different clinical syndromes. Together, our studies have revealed a hierarchy within the diverse proteins of the S. aureus "immunome", which will help to advance efforts to develop protective immunotherapeutic agents.


Assuntos
Imunoglobulina G/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Feminino , Antígenos HLA-D/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Masculino , Staphylococcus aureus Resistente à Meticilina/imunologia , Pessoa de Meia-Idade , Osteomielite/imunologia , Osteomielite/microbiologia , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/imunologia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/imunologia , Infecções Estafilocócicas/metabolismo , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidade
16.
Liver Transpl ; 24(12): 1726-1735, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30112820

RESUMO

Rejection is one of the most important drawbacks for graft and patient survival in intestinal and multivisceral transplantation. However, there is no consensus on the diagnostic criteria for humoral rejection, and the literature about the role of donor-specific antibodies (DSA) on allograft outcome and the risk factors that contribute to their development is scant with contradictory results. The present study analyzes the role of DSA exclusively in a pediatric cohort of 43 transplants. Among our patients, 11.6% showed preformed DSA, but they did not correlate with more rejection or less allograft survival. Having previous transplants was the main sensitization factor with an odds ratio (OR) = 44.85 (P = 0.001). In total, 16.3% of recipients developed de novo donor-specific antibodies (dnDSA), mostly directed against human leukocyte antigen (HLA) class II, polyspecific and complement fixing. Additionally, the presence of dnDSA had a deleterious effect on graft rejection (hazard ratio [HR] = 11.00; P = 0.01) and survival (HR = 66.52; P < 0.001) in an observational period of 5 years after transplantation. The inclusion of the liver emerged as the main protective factor against dnDSA development with an OR = 0.07 (P = 0.007). The analysis of HLA compatibility at the serological and epitope level with the computational tools HLAMatchmaker and PIRCHE revealed no association between HLA mismatching and dnDSA. In conclusion, this study performed in pediatric recipients shows the deleterious effect of dnDSA on intestinal transplantation supported by the complement-fixing activity observed. Additionally, the liver inclusion in the allografts showed to be a protective factor against dnDSA generation.


Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA-D/imunologia , Intestinos/transplante , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Síndromes de Malabsorção/cirurgia , Adolescente , Aloenxertos/imunologia , Criança , Pré-Escolar , Feminino , Seguimentos , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Imunidade Humoral , Lactente , Recém-Nascido , Fígado/imunologia , Transplante de Fígado/métodos , Masculino , Fatores de Risco , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
17.
J Neuroinflammation ; 15(1): 241, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30153843

RESUMO

BACKGROUND: Most of the animal models commonly used for preclinical research into Alzheimer's disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age. METHODS: The open field test was used as a measure of activity; and the Morris water maze was used to assess learning, memory, and strategy shift. Neuronal loss and microglia activation were also assessed throughout the brain. RESULTS: APP21 transgenic rats showed deficits in working memory from an early age, yet memory recall performance after 24 and 72 h was equal to that of wildtype rats and did not deteriorate with age. A deficit in strategy shift was observed at 19 months of age in APP21 transgenic rats compared to Fischer wildtype rats. Histologically, APP21 transgenic rats demonstrated accelerated white matter inflammation compared to wildtype rats, but interestingly no differences in neuron loss were observed. CONCLUSIONS: The combined presence of white matter pathology and executive function deficits mirrored what is often found in patients with mild cognitive impairment or early dementia, and suggests that this rat model will be useful for translationally meaningful studies into the development and prevention of sporadic AD. The presence of widespread white matter inflammation as the only observed pathological correlate for cognitive deficits raises new questions as to the role of neuroinflammation in cognitive decline.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Envelhecimento Cognitivo , Microglia/metabolismo , Substância Branca/patologia , Fatores Etários , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Antígenos HLA-D/metabolismo , Humanos , Aprendizagem em Labirinto/fisiologia , Rememoração Mental/fisiologia , Proteínas dos Microfilamentos/metabolismo , Microglia/patologia , Mutação/genética , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Natação/fisiologia
18.
Genome Med ; 10(1): 59, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053915

RESUMO

BACKGROUND: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines. METHODS: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~ 5 million genetic variants and antibody responses using single marker and gene burden tests. RESULTS: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRß1 and HLA-DPß1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations. CONCLUSIONS: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis. TRIALS REGISTRATION: ClinicalTrials.gov , NCT01699893.


Assuntos
Envelhecimento/imunologia , Antígenos HLA-D/genética , Imunidade Humoral/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Infecções Bacterianas/imunologia , Feminino , Antígenos HLA-D/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Vacinas/imunologia , Viroses/imunologia
19.
Sci Immunol ; 3(24)2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884618

RESUMO

Rare individuals, termed HIV controllers, spontaneously control HIV infection by mounting efficient T cell responses against the virus. Protective CD4+ T cell responses from HIV controllers involve high-affinity public T cell receptors (TCRs) recognizing an immunodominant capsid epitope (Gag293) presented by a remarkably broad array of human leukocyte antigen (HLA) class II molecules. Here, we determine the structures of a prototypical public TCR bound to HLA-DR1, HLA-DR11, and HLA-DR15 molecules presenting the Gag293 epitope. TCR recognition was driven by contacts with the Gag293 epitope, a feature that underpinned the extensive HLA cross-restriction. These high-affinity TCRs promoted mature immunological synapse formation and cytotoxic capacity in both CD4+ and CD8+ T cells. The public TCRs suppressed HIV replication in multiple genetic backgrounds ex vivo, emphasizing the functional advantage conferred by broad HLA class II cross-restriction.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-D/imunologia , Interações Hospedeiro-Patógeno/imunologia , Animais , Reações Cruzadas/imunologia , Fibroblastos , Células HEK293 , Voluntários Saudáveis , Humanos , Células Jurkat , Leucócitos Mononucleares , Ativação Linfocitária , Camundongos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/imunologia , Carga Viral/imunologia , Replicação Viral/imunologia
20.
Hum Mol Genet ; 27(15): 2762-2772, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29771307

RESUMO

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.


Assuntos
Rosácea/etiologia , Pigmentação da Pele/genética , Adulto , Cisteína Endopeptidases/genética , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Antígenos HLA-D/genética , Humanos , Fatores Reguladores de Interferon/genética , Interleucina-13/genética , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Rosácea/genética , Nexinas de Classificação/genética
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