Molecular genetics research of a Chinese family carrying triple HLA-A alleles / 中国输血杂志

【Objective】 To determine molecular basis of a rare HLA-A typing results carrying triple A alleles in potential allo-HSCT donor and her family. 【Methods】 HLA-A, -B, -C, -DRB1, -DQB1, -E, -F, -G of 5 members in the family were genotyped at a high-resolution level using next-generation sequencing (NGS). HLA-A of probosita was re-checked using polymerase chain reaction-sequence-based typing (PCR-SBT), and SNP oligonucleotide probes (SNP-array)were scanned with genomic DNA of probosita. 【Results】 There was 162.9Kb duplication in 6p22.1(29, 803, 377-29, 966, 301)of probosita who carried triple A alleles A*02∶01∶01, A*11∶01∶01, A*24∶02∶01. Other two family members were found to carry this haplotype: A*02∶01∶01, A*24∶02∶01, B*54∶01∶01, C*01∶02∶01, DRB1*04∶05∶01, DQB1*04∶01∶01, E*01∶01∶01∶03, F*01∶01∶01, G*01∶01∶01∶01, which as a Mendelian gene was segregated and stably transmitted through two generations. 【Conclusion】 Tiny gene duplication induces one haplotype carries two HLA-A alleles in a potential healthy donor for allo-transplantaion and stably transmits through two generations.Routine HLA typing laboratories should pay more attention to this situation and accurately report.

Retinocoroidopatía birdshot, reporte de un caso en Colombia / Birdshot retinochoroidopathy, case report in Colombia

Introducción: La retinocoroidopatía birdshot (RCB) es una uveítis posterior crónica, bilateral de origen autoinmune, con fuerte asociación al antígeno leucocitario humano HLA-A29. Objetivo: Describir un caso de RCB en Colombia. Material y métodos: Mujer caucásica de 57 años, con hallazgos clínicos y exámenes complementarios compatibles con RCB. Recibió terapia biológica durante 15 meses, con mejoría clínica significativa. Resultados y conclusiones: El tratamiento depende del estadio de la enfermedad y consiste en el uso solo de corticoesteroides o combinación con agentes inmunosupresores y biológicos, que han demostrado preservar la función visual y minimizar efectos adversos de los esteroides

Background: Birdshot Retinocoroidopathy (BRC) is a chronic, bilateral posterior uveitis of autoimmune origin, with a strong association with the human leukocyte antigen HLA-A29. Objective: To describe a BRC case in Colombia. Material and methods: A 57-year-old Caucasian woman with clinical findings and complementary tests compatible with BRC. She received biologic therapy for 15 months, with significant clinical improvement. Results and conclusions: Treatment depends on stage of disease and is about corticosteroid use, alone or combination with immunosuppressive and biological agents, which have been shown to preserve visual function and minimize adverse effects of steroids

Bioinformatics analysis of HLA-A2 restricted neoantigen epitopes in breast cancer / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To screen candidate epitopes of breast cancer HLA-A2 restrictive neoantigen and to identify high frequency mutation sites in breast cancer neoantigen by using bioinformatics method. Methods: NCBI and GDC databases were used to search missense mutation sites formed by single nucleotide mutation in breast cancer among reported literatures and sequencing data. The new antigen epitopes were predicted by HLA-A2 antigen epitope prediction website BIMAS, SYFPEITHI and artificial neural networkbased NetMHC4.0, and the epitopes with TAP binding power less than Intermediate were eliminated. The candidate epitopes were prioritized by mutation frequency and prediction results. Results: A total of 17 high-frequency mutation genes, including BTLA, ERBB2 and NBPF12 etc, were screened by the above-mentioned methods, and a total of 26 neoantigen epitopes were identified. The binding power of epitopes predicted using BIMAS and SYFPEITHI showed great difference (P<0.05), epitopes in high priority as GSTP1 (A114V , mutation frequency of 5.94%) and BRCA2 (N991H, mutation frequency of 5.40%) etc, were expected to be candidate neo-antigen epitopes; however, their mutation frequency was relatively too low to achieve“universal use” . The possibility of these epitopes used as general breast cancer neo-antigen epitopes is less likely. Conclusion: The common mutation frequency of breast cancer is lower than that of other tumors; it ’s difficult to find“universal”new antigen epitopes of breast cancer; the individualized neoantigen vaccine may be of more promise, which needs further research.

Impact of HLA-A-B-DR matching in kidney transplantation: Graft and patient survival in 5-year experiences / Эрүүл мэндийн лаборатори

Background@#Kidney transplantation has being performed in Mongolia since 2006. However there is currently no published data available on long-term graft and patient survival. @*Objective@#Our aim was to assess the long-term graft and patient survival rate correlation with HLA-A-B-DR matching.@*Methods@#We retrospectively analyzed data from 70 adult kidney transplants performed at our hospital from August 2006 through January 2014. The data was retrospectively collected from patient files, including characteristics of the recipient and donor, post transplant features and HLA-A-B-DR DNA based typing results. The Kaplan-Meier method was used to analyze graft and patient survival. @*Results@#The mean patient follow-up period after kidney transplantation was 39,6±25.9 months, and the mean kidney graft follow-up period was 36.6±23.7 months for 70 cases. Overall graft and patient survivals were 52 (74.3%) and 60 (85.7%) respectively in 70 cases. Five-year graft and patient survivals were 23 (67.6%) and 29 (85.3%) respectively in 34 cases. The group with four to six mismatched were found to have a significantly lower 3 and 5-year graft and patient survival (71%; 35%); (80%; 40%) compared to 0 to 1 mismatched group (100%) (p=.030; p=.015). Furthermore we analyzed the association of HLA matching, immunosuppressive therapy and long-term graft survival. We selected CNI mono-therapy group for long-term survival analysis and observed a similar pattern. In mono-therapy group, the group with four to six mismatched were found to have a significantly lower 3 and 5-year graft and patient survival (75%; 30%); (65%; 30%) compared to 0 to 1 mismatched group (100%) (p=.037; p=.001). @*Conclusion@#The results showed that graft and patient survival rates were lower compared with results from established centers. Statistically highly significant effect of HLA matching on kidney graft and patient survival rates was found in our analysis. Five years after transplantation the graft survival rate of first adult kidney transplant with 4-6MM was 65-70% lower than that of grafts with 0-1MM. Longitudinal cohort study needed in the future to exhibit an improved transplantation outcome.

Identification of HLA-A3 restricted cytotoxic T-lymphocyte epitopes from cancer-testis antigen MAGEC2 / 中国病理生理杂志

AIM:To predict and identify an HLA-A3 supertype-restricted cytotoxic T-lymphocyte(CTL) epitope derived from MAGEC2,which is utility in epitope design for the development of HLA-based vaccines and immuno-therapeutics.METHODS:HLA-A3 epitopes from MAGEC2 protein were predicted by BIMAS, SYFPEITHI and IEDB. The binding affinity of the peptides to HLA-A*03 molecule was evaluated by T2A3 cell binding assay.ELISPOT assay was used to investigate the ability of the peptides inducing specific restricted CTLs to release interferon -γ(IFN-γ).The ability of the peptides to induce T-cell response was investigated by cytotoxicity assay in vitro.RESULTS:The candidate peptides P147,P167, P196, P229 and P251 showed moderate affinity toward HLA-A3 molecule.ELISPOT assay showed that P167,P196 and P251 were able to induce specific CTLs and higher levels of IFN-γwere released.The CTLs induced by P196 and P251 were able to lyse target cells.CONCLUSION:The peptides P196 and P251 have higher binding affinity with HLA-A3 and retain immunogenicity.They are excellent HLA-A3-restricted CTL epitopes from tumor antigen MA-GEC2,which could serve as new candidates towards antitumor peptide vaccines.

In vivo immunogenic characteristics of cytotoxic T lymphocyte epitopes from pancreatic tumor antigen MUC4 / 中国病理生理杂志

AIM:Peptide vaccines have been conceived as promising therapies for tumor-inflicted patients due to their easy production and capability of inducing specific immune response required for defending the tumor.During our previous research,4 HLA-A2-restricted peptides had been identified as immunogenic in vivo.In this study, we aimed to testify the in vivo immunogenicity of the 4 peptides.METHODS: BALB/c mice were vaccinated with HLA-A2 restricted peptides emulsified in incomplete Freund's adjuvant(IFA)subcutaneously in combination with the epitope at the adjacent location.After the 3rd peptide vaccination for 10 d,the peptide-specific immune response was evaluated by ELISPOT and ELISA.The ability to induce T cell response was investigated by using cytotoxicity assay in vivo and the presence of pep-tide-specific CD8+T cells capable of recognizing the MHC-peptide was detected by flow cytometry.RESULTS: Among the 4 candidate HLA-A2 restricted peptides,the immune response elicited by P2004-1Y9V was superior to that of the other 3 peptides.The CTLs induced by P2004 and P2004-1Y9V lysed CAPAN-2 cells.P2004-1Y9V peptide-specific CTLs showed higher cytotoxicity against pancreatic tumor cell lines of CAPAN-2 than the native peptide-specific CTLs.Intracellu-lar cytokine staining assay indicated the presence of P 2004-1Y9V specific CD8 +T cells in the P2004-1Y9V vaccinated mice.CONCLUSION:P2004-1Y9V is the most immunogenic peptide in vivo, and can be explored as potential tumor peptide vaccine in the future clinical study.

Identificaiton of Novel Immunogenic Human Papillomavirus Type 16 E7-Specific Epitopes Restricted to HLA-A*33;03 for Cervical Cancer Immunotherapy

PURPOSE: To identify new immunogenic HLA-A*33;03-restricted epitopes from the human papillomavirus (HPV) 16 E7 protein for immunotherapy against cervical cancer. MATERIALS AND METHODS: We synthesized fourteen overlapping 15-amino acid peptides and measured intracellular interferon-γ (IFN-γ) production in PBMC and CD8+ cytotoxic T lymphocytes (CTLs) after sensitization with these peptides using flow cytometry and ELISpot assay. The immunogenicity of epitopes was verified using a ⁵¹Cr release assay with SNU1299 cells. RESULTS: Among the fourteen 15-amino acid peptides, E7₄₉₋₆₃ (RAHYNIVTFCCKCDS) demonstrated the highest IFN-γ production from peripheral blood mononuclear cells (PBMCs), and CD8+ CTLs sensitized with E7₄₉₋₆₃ showed higher cytotoxic effect against SNU1299 cells than did CD8+ CTLs sensitized with other peptides or a negative control group. Thirteen 9- or 10-amino acid overlapping peptides spanning E7₄₉₋₆₃, E7₅₀₋₅₉ (AHYNIVTFCC), and E7₅₂₋₆₁ (YNIVTFCCKC) induced significantly higher IFN-γ production and cytotoxic effects against SNU1299 cells than the other peptides and negative controls, and the cytotoxicity of E7₅₀₋₅₉- and E7₅₂₋₆₁-sensitized PBMCs was induced via the cytolytic effect of CD8+ CTLs. CONCLUSION: We identified E7₅₀₋₅₉ and E7₅₂₋₆₁ as novel HPV 16 E7 epitopes for HLA-A*33;03. CD8+ CTL sensitized with these peptides result in an antitumor effect against cervical cancer cells. These epitopes could be useful for immune monitoring and immunotherapy for cervical cancer and HPV 16-related diseases including anal cancer and oropharyngeal cancer.

Human leucocyte antigen Class I and II alleles associated with anti‑hepatitis C virus‑positive patients of North India.

Purpose: Humans are the only known natural hosts of hepatitis C virus (HCV). This study was undertaken to examine the frequencies of human leucocyte antigens (HLAs) Class I and Class II genotype profiles in anti‑HCV‑infected patients of Northern India. Materials and Methods: From a period of January 2013 to August 2014, 148 anti‑HCV‑positive patients of North India referred to the Department of Molecular Biology and Transplant Immunology, Indraprastha Apollo Hospitals, New Delhi, for performing HLA typing were included in the study. Results: A*02, A*31 allele frequency decreased significantly in anti‑HCV‑positive patients. Frequencies for HLA‑B loci did not reach any statistical significance. Among the Class II alleles, HLA‑DRB1*03 and HLA‑DRB1*10 were significantly higher in the patient population, and HLA‑DRB1*15 was significantly decreased in the patient population as compared to the controls. Conclusion: HLA‑A*33 was significantly increased as compared to control population and showed geographic variation in HCV‑infected individuals of India.

Perfil genético hla en familias venezolanas: útil herramienta biomédica / Hla genetic profile in venezuelan families: biomedical useful tool

El sistema de antígenos leucocitarios Humano (Human Leukocyte Antigen, HLA) regula la respuesta inmune mediante su unión a moléculas como el receptor de células T, participando en la presentación de antígenos y el reconocimiento de lo propio en el organismo. La caracterización genética del sistema HLA en determinada población es de gran utilidad para la comprensión de mecanismos asociados a susceptibilidad o resistencia a enfermedades y en la selección de donantes/receptores en trasplantes de órganos. En este estudio se planteó determinar la frecuencia de los Haplotipos HLA de clase I presentes en individuos sanos, relacionados familiarmente y venezolanos de tercera generación y su correspondiente desequilibrio de ligamiento. Se incluyeron 765 individuos pertenecientes a 218 familias a los cuales se les realizó tipificación HLA A y HLA B por PCR-SSOP (polymerase chain reaction-sequence specific oligonucleotide probe) en baja resolución. Se identificaron 265 haplotipos de los cuales los más frecuentes fueron HLA A*24 B*35 (11,98 %), A*02 B*51 (9,7%) y A*02 B*35 (8,6 %).Para los cálculos de desequilibrio de ligamiento se consideraron las frecuencias mayores al 1% (28,7%) y no arrojaron valores estadísticamente significativos el 6,78% de estos haplotipos. Los resultados obtenidos corroboran la composición triétnica históricamente conocida de nuestra población, en la cual predominan genes caucásicos, amerindios y afrodescendientes; y su porcentaje marca la diferencia con otras poblaciones americanas estudiadas. Estos resultados representan una aproximación de la conformación genética establecida en Venezuela y aporta datos que podrán ser usados como referencia en programas de salud para la población.

The system of Human leukocyte antigens (HLA) is the most polymorphic in humans. Its function is performed by regulating the immune response by binding to molecules such as T-cell receptor, involved in antigen presentation and recognition of the same in the body. Genetic characterization of HLA system in a given population is useful for understanding the mechanisms associated with susceptibility or resistance to various diseases and selection of donors and recipients in organ transplants, among others. The objective of the present study is to determine the frequency of HLA Class I Haplotypes present in healthy individuals, family relationships and third-generation Venezuelan and their corresponding linkage disequilibrium. We included 765 individuals belonging to 218 families who underwent HLA typing HLA A and B by PCR-SSOP (polymerase chain reaction-sequence specific oligonucleotide probe) in low resolution. 265 haplotypes were identified of which the most frequent were HLA A * 24 B * 35 (11.98%), A * 02 B * 51 (9.7%) and A * 02 B * 35 (8.6%). Calculations of linkage disequilibrium were considered frequencies above 1% (28.7%) and did not show statistically significant the 6.78% of these haplotypes. The results support the historically known tri-ethnic composition of our population, in which genes predominantly Caucasian, Mongoloid and Negroid, and make a difference with other American populations studied. These data can be used as reference to applications of benefit to this population.

Polymorphism research of HLA-A, B, DRB1 high resolution alleles and haplotypes in population from Heilongjiang / 中国免疫学杂志

Objective:To research the distribution features of HLA-A,B and DRB1 high resolution alleles and haplotypes in Heilongjiang population.Methods:PCR-SBT methods was applied for HLA-A,B,DRB1 high resolution genotyping of 13 670 unrelated and healthy donors in region of Heilongjiang,and haplotype frequencies were calculated by counting and maximum likelihood method. Results:A total of 286 HLA alleles were observed and the most frequent alleles(>0.1)were A*02∶01,A*24∶02,A*11∶01,DR*07∶01,DR*09∶01 and DR*15∶01.Among 1 087 kinds of HLA-A-B haplotype ,there were 22 kinds frequency higher than 0.01,and 267 kinds with statistically significant and positive linkage disequilibrium(ALD>0,HF≥1.09×10-4,χ2>3.84).Moreover,among 1 329 kinds of HLA-B-DRB1 haplotype,there were 19 haplotypes frequency higher than 0.01,and 357 kinds with statistically significant and positive linkage disequilibrium.1 348 kinds of A-B-DR Haplotype were informative with frequency≥1.66 ×10-4 in 4 428 haplotypes, and a total of 17 kinds of A-B-DR haplotype frequency higher than 0.005.Conclusion: Get the distribution features of HLA high resolution allele and haplotype in Heilongjiang population, and associated genetic parameters, Distribution of alleles and haplotypes close to northern Han population,but have their own distribution.

Safety of the bone marrow derived mesenchymal stem cells after HLA A 2 gene silencing / 西安交通大学学报(医学版)

Objective To explore the safety of the human bone marrow‐derived mesenchymal stem cells (hBMSCs) after silencing of human leukocyte antigen A2 expression .Methods We divided the cells into three groups:normal cultured cells of the 8th passage served as control group , and hBMSCs after HLA A2 silencing expression of the 5th and 15th passage as experimental groups 1 and 2 ,respectively .The hBMSCs were recultured by sterile methods .The growth curve ,telomerase activation ,and expressions of P27 ,cyclin D2 and cyclin‐dependent kinase 4 (CDK4) were utilized to explore the safety of the hBMSCs induced by LV‐siRNA‐HLA A2 .The BMSCs were transplanted to the subcutaneous layer of nude mice .Tissue types were detected 24 weeks after transplantation . Results The cell curves had no obvious left or right shift in all the groups . The telomerease activation in experimental groups 1 and 2 did not significantly differ from those in control group . The expressions of anti‐oncogene P27 ,cyclin D2 and CDK4 had no obvious difference between the two experimental groups and control group , either . There was only ectopic osteogenesis 24 weeks after the BMSCs (HLA A2 gene silenced ) were transplanted to the subcutaneous layer of the nude mice .Conclusion There was no obvious evidence to support that hBMSCs had undergone change in safety after the silencing of HLA A 2 expression .

Análise das frequências dos grupos alélicos e haplótipos HLA -A*, -B* e -DRB1* por cor/raça e regionalidade do Brasil em uma amostra do Registro Brasileiro de Doadores Voluntários de Medula Óssea (REDOME) / [Analysis of the frequencies of allele groups and HLA -A *, -B * and -DRB1 * haplotypes by color / race and regionality of Brazil in a sample from the Brazilian Registry of Bone Marrow Donors (REDOME)]

Para melhorar a assistência aos pacientes que estão em lista de espera para um transplante de medula óssea de um doador não aparentado, é importante caracterizar geneticamente os doadores voluntários de medula óssea que são recrutados pelo REDOME e suas diferenças regionais. O objetivo é descrever as frequências alélicas e haplótipos de HLAA, HLA-B e HLA-DRB1 em todas as regiões do Brasil, assim como por cor/raça usando o banco de dados do REDOME. Esse estudo é composto pela análise de 3.038.286 indivíduos. As frequências dos grupos alélicos HLA e haplótipos foram estimados pelo algoritmo EM. As distâncias genéticas de Nei para cada combinação de amostras também foram calculadas usando as frequências de haplótipos. Todos os grupos alélicos para HLA-A, -B e -DRB1 foram identificados neste estudo. HLA-A*02 (25,9%), HLA-B*35 (11,83%) e HLA-DRB1*13 (13,4%) compreendem os grupos de alelos mais frequentes no REDOME e A*01-B*08-DRB1*03 é o haplótipo mais frequente (2,19%) em nossas amostras. Foi observado através de distâncias genéticas que existem diferenças entre regiões do Brasil e entre os grupos de cor/raça e formações de aglomerados que compartilham semelhanças quando são considerados as frequências de haplótipos. Os resultados relatados aqui são as primeiras análises detalhadas do polimorfismo dos três loci HLA-A*, HLA-B* e HLA-DRB1* na população brasileira. Os dados dos grupos alélicos e das frequências de haplótipos obtidos neste estudo são relevantes para facilitar a pesquisa de doador não-aparentado compatível e pode ser útil para o planejamento nacional de recrutamento de doadores

To improve assistance for patients who are on a waiting list for a bone marrow transplant from an unrelated donor, it is important to genetically characterize the volunteer bone marrow donors that are recruited by REDOME and their regional differences. The objective is todescribe the allele and haplotype frequencies of HLA-A, HLA-B and HLA-DRB1 in all Regions of Brazil as well as by its color/race groups using REDOME data set. This study consists of the analysis of 3.038.286 individuals. HLA allelic groups and haplotypesfrequencies were estimated by EM algorithm. Pairwise Nei’s genetic distance for each population combination were also calculated using haplotype frequencies. All allelic groups for HLA-A* HLA-B* HLA-DRB1 were identified in this study. HLA-A*02 (25,9%), HLA-B*35 (11,83%) and HLA-DRB1*13 (13,4%) comprise the most frequent allelic groups in REDOMEand A*01-B*08-DRB1*03 is the most frequent haplotype (2,19%). It was observed through genetic distances that there are differences between regions and race/ethnic groups andformations of clusters that share similarities when considering haplotype frequencies. The results reported here are the first detailed analyses of three loci HLA-A*, HLA-B* e HLADRB1*polymorphisms in Brazilian population. The allelic groups and haplotype frequency data obtained in this study are relevant to facilitate searching for unrelated matched donor and could be helpful for national donor recruitment planning

Histocompatibility testing for kidney graft survival / Эрүүл мэндийн лаборатори

Background:Kidney transplantation has being performed in Mongolia since 2006. However there is currently no published data available on long-term graft and patient survival.Objective:Our aim was to assess the long-term graft and patient survival rate correlation with HLA-A-B-DR matching. Material and Methods:We retrospectively analyzed data from 70 adult kidney transplants performed at our hospital from August 2006 through January 2014. The data was retrospectively collected from patient fles, including characteristics of the recipient and donor, post transplant features and HLA-A-B-DR DNA based typing results. The KaplanMeier method was used to analyze graft and patient survival.Results:The mean patient follow-up period after kidney transplantation was 39,6±25.9 months, and the mean kidney graft follow-up period was 36.6±23.7 months for 70 cases. Overall graft and patient survivals were 52 (74.3%) and 60 (85.7%) respectively in 70 cases. Five-year graft and patient survivals were 23 (67.6%) and 29 (85.3%) respectively in 34 cases. The group with four to six mismatched were found to have a signifcantly lower 3 and 5-year graft and patient survival (71%; 35%); (80%; 40%) compared to 0 to 1 mismatched group (100%) (p=.030; p=.015). Furthermore we analyzed the association of HLA matching, immunosuppressive therapy and long-term graft survival. We selected CNI mono-therapy group for long-term survival analysis and observed a similar pattern. In mono-therapy group, the group with four to six mismatched were found to have a significantly lower 3 and 5-year graft and patient survival (75%; 30%); (65%; 30%) compared to 0 to 1 mismatched group (100%) (p=.037; p=.001).Conclusion:The results showed that graft and patient survival rates were lower compared with results from established centers. Statistically highly signifcant effect of HLA matching on kidney graft and patient survival rates was found in our analysis. Five years after transplantation the graft survival rate of frst adult kidney transplant with 4-6MM was 65-70% lower than that of grafts with 0-1MM. Longitudinal cohort study needed in the future to exhibit an improved transplantation outcome.

Discovery of Human Leukocyte Antigen HLA-A/C Gene Recombination / 现代检验医学杂志

Objective To investigate the recombination events occurring between HLA-A and-C loci discovered in two Chi-nese families.Methods HLA class I (HLA-A and-B)and II (HLA-DRB1)alleles low resolution typing were typed by pol-ymerase chain reaction-sequence specific oligonucleotide,(PCR-SSO)and PCR-sequence specific primer (PCR-SSP).HLA class I and II high resolution typing was done by sequencing-based typing (SBT).Then the recombination sites were ana-lyzed by family study.Results The results indicates that the recombination events occurred in one family between A*30∶01/32∶01-C*06∶02 and another family between A*11∶01/26∶01-C*07∶06 during meiosis.The recombination both came from fathers and resulted in new HLA haplotypes that were inherited by the children.Conclusion Two HLA-A/C re-combination events occurring between HLA-A and-C loci have been found in two Chinese families,which help further study the mechanisms of HLA recombination.

Relationship between Poor Immunogenicity of HLA-A2-Restricted Peptide Epitopes and Paucity of Naive CD8+ T-Cell Precursors in HLA-A2-Transgenic Mice

We examined the immunogenicity of H-2 class I-restricted and HLA-A2-restricted epitopes through peptide immunization of HLA-A2-transgenic mice that also express mouse H-2 class I molecules. All four of the tested epitopes restricted by H-2 class I robustly elicited T-cell responses, but four of seven epitopes restricted by HLA-A2 did not induce T-cell responses, showing that HLA-A2-restricted peptide epitopes tend to be poorly immunogenic in HLA-A2-transgenic mice. This finding was confirmed in HLA-A2-transgenic mice infected with a recombinant vaccinia virus expressing hepatitis C virus proteins. We examined the precursor frequency of epitope-specific naive CD8+ T cells in HLA-A2-transgenic and conventional C57BL/6 mice and found that the poor immunogenicity of HLA-A2-restricted peptide epitopes is related to the paucity of naive CD8+ T-cell precursors in HLA-A2-transgenic mice. These results provide direction for the improvement of mouse models to study epitope repertoires and the immunodominance of human T-cell responses.

HLA-A*31 como marcador de suscetibilidade genetica em sepse / HLA-A*31 as a marker of genetic susceptibility to sepsis

Objetivo: Haplótipos do HLA têm sido associados a muitas doenças autoimunes, mas não foi descrita qualquer associação na sepse. O objetivo desse estudo é investigar o sistema HLA como um possível marcador de suscetibilidade genética à sepse. Métodos: Estudo prospectivo de coorte, incluindo pacientes admitidos em unidade de terapia intensiva e controles-saudáveis obtidos em lista de doadores de transplante renal. Foram excluídos pacientes abaixo dos 18 anos de idade, gestantes ou HIV positivos, pacientes com doença maligna metastática ou sob quimioterapia, pacientes com hepatopatia avançada, com condições de fim de vida. O DNA foi extraído de sangue total, e a haplotipagem de HLA foi realizada com a tecnologia MiliPlex®. Resultados: Foram incluídos 1.121 pacientes (1.078 doadores de rim, 20 pacientes com sepse grave e 23 pacientes admitidos por choque séptico) entre outubro de 2010 e outubro de 2012. Os participantes positivos para HLA-A*31 tiveram risco aumentado de desenvolver sepse (OR: 2,36 IC95%: 1,26-5,35). Não foi identificada outra associação significativa, quando considerado como nível de significância o valor de p<0,01. Conclusão: A expressão de HLA-A*31 está associada ao risco de desenvolvimento de sepse. .

Objective: The HLA haplotype has been associated with many autoimmune diseases, but no associations have been described in sepsis. This study aims to investigate the HLA system as a possible marker of genetic sepsis susceptibility. Methods: This is a prospective cohort study including patients admitted to an intensive care unit and healthy controls from a list of renal transplant donors. Patients with less 18 years of age; pregnant or HIV positive patients; those with metastatic malignancies or receiving chemotherapy; or with advanced liver disease; or with end-of-life conditions were excluded. The DNA was extracted from the whole blood and HLA haplotypes determined using MiliPlex® technology. Results: From October 2010 to October 2012, 1,121 patients were included (1,078 kidney donors, 20 patients admitted with severe sepsis and 23 with septic shock). HLA-A*31 positive subjects had increased risk of developing sepsis (OR 2.36, 95%CI 1.26-5.35). Considering a p value <0.01, no other significant association was identified. Conclusion: HLA-A*31 expression is associated to risk of developing sepsis. .

Neonatal Alloimmune Thrombocytopenia Caused by Anti-HLA-A2 Alloantibodies Determined by Luminex Single Antigen Bead Assay

Neonatal alloimmune thrombocytopenia (NAIT) occurs when maternal alloantibodies react to antigens expressed on fetal platelets, which is mainly platelet-specific alloantigen or HLA, resulting in their immune destruction. Here, we described a patient who suffered from NAIT caused by anti-HLA-A2 antibody. Sera from the mother and the newborn were screened for human platelet antigen-specific antibodies and HLA antibodies by ELISA, and HLA antibodies were detected in both of them. The antibody specificity was identified as anti-HLA-A2 by Luminex single antigen bead assay. HLA typing results showed that patient's father descended HLA-A2 antigen on the patient and the mother was HLA-A2 negative. It is most conceivable that anti-HLA-A2 alloantibody in the mother's sera crossed the placenta and subsequently caused NAIT in the case presented. The patient received platelet concentrates, oral steroid and intravenous globulin and platelet count increased to 120x10(9)/L on the 90th day of life. The Luminex single antigen bead assay used in this case is highly sensitive and specific assay to determine antibody specificity and it is faster and more convenient for routine use in clinical laboratory so that this assay could be useful to diagnose NAIT caused by HLA antibodies and treat such NAIT patients with HLA matched platelet transfusion.

HLA-A*01 allele: a risk factor for dengue haemorrhagic fever in Brazil's population

Severe forms of dengue, such as dengue haemorrhagic fever (DHF) and dengue shock syndrome, are examples of a complex pathogenic mechanism in which the virus, environment and host immune response interact. The influence of the host's genetic predisposition to susceptibility or resistance to infectious diseases has been evidenced in several studies. The association of the human leukocyte antigen gene (HLA) class I alleles with DHF susceptibility or resistance has been reported in ethnically and geographically distinct populations. Due to these ethnic and viral strain differences, associations occur in each population, independently with a specific allele, which most likely explains the associations of several alleles with DHF. As the potential role of HLA alleles in the progression of DHF in Brazilian patients remains unknown, we then identified HLA-A alleles in 67 patients with dengue fever and 42 with DHF from Rio de Janeiro, Brazil, selected from 2002-2008 by the sequence-based typing technique. Statistical analysis revealed an association between the HLA-A*01 allele and DHF [odds ratio (OR) = 2.7, p = 0.01], while analysis of the HLA-A*31 allele (OR = 0.5, p = 0.11) suggested a potential protective role in DHF that should be further investigated. This study provides evidence that HLA class I alleles might be important risk factors for DHF in Brazilian patients.

Identification of a novel human leukocyte antigen allele, HLA-A * 31 ∶ 22 / 中华微生物学和免疫学杂志

Objective To identify and confirm a novel HLA allele.Methods A new human leukocyte antigen A allele was found during routine HLA genotyping by polymerase chain reaction-sequence specific oligonucleotide probes(PCR-SSOP) and sequencing-based typing (SBT).HLA-A locus was amplified from exon 1 through exon 8,and the nucleotide sequence of exon 2 to exon 4 for HLA-A were sequenced in both directions.Results The novel HLA-A * 31 allele is identical to A * 31 ∶ 01 ∶ 02 with an exception of one base substitution at position 245 of exon 2 where an ' A' change to ' C' resulting in codon 82 changed from GAG to GCG.Conclusion A novel HLA allele,A * 31 ∶ 22,was identified,and was named officially by the WHO Nomenclature Committee for factors of the HLA system.