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Background: The HLA polymorphism is a powerful genetic tool to study population origins. By analysing allele frequencies and haplotypes in different populations, it is possible to identify ethnic groups and establish the genetic r...
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Background: The HLA polymorphism is a powerful genetic tool to study population origins. By analysing allele frequencies and haplotypes in different populations, it is possible to identify ethnic groups and establish the genetic relationships among them. Aim: The Berber (endogenous Tunisians) HLA class I and class II genotypes were analysed and compared with those of Mediterranean and Sub-Saharan African communities using genetic distances, Neighbour-Joining dendrograms, correspondence and haplotype analysis. Subjects and methods: One hundred and five unrelated Berbers were typed for HLA class I (A, B) and class II (DRB1, DQB1) gene alleles using reverse dot-blot hybridization. Results: High frequencies of A*0201 (24.76%), A*3402 (22.38%) and B*44 (32.85%) alleles were recorded for Berbers, the highest recorded for Mediterranean and North African populations. This study shows a close relatedness of Tunisian Berbers to other Tunisians, North Africans and Iberians. Conclusion: The apparent relatedness of Tunisian Berbers to present-day (North African) Tunisians, Algerians and Moroccans suggests that the Arab invasion of North Africa (7th-11th centuries AD) did not significantly impact the genetic makeup of North Africans. Furthermore, Tunisian Berbers appear to be closely related to Iberians (Spaniards and Basques), indicating that the 7th century AD gene flow of invaders was low in Iberians and that the main part of their genetic pool came after the Northward Saharan migration, when hyper-arid conditions were established in Sahara (before 6000 BC). Other studied populations belong to the old Mediterranean substratum, which has been present in the area since pre-Neolithic times. This study indicates a higher proportion of Iberian than Arab ancestry in Tunisian Berbers, which is of value in evaluating the evolutionary history of present-day Tunisians. Greeks seem to share genetic HLA features (Chr 6) with Sub-Saharans. The relatedness of Greeks to Sub-Saharans has been confirmed by other studies based on chromosome 7 genetic markers.
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Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31) is one of the human minor histocompatibility antigens that are the main targets of alloreactive T-cells after hematopoietic stem cells or solid organs transplantation. I...
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Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31) is one of the human minor histocompatibility antigens that are the main targets of alloreactive T-cells after hematopoietic stem cells or solid organs transplantation. In order to investigate its polymorphism in Tunisians, three single nucleotide polymorphisms (SNPs) (rs668, rs12953 and rs1131012) were selected to perform an allele and haplotype analysis. Hundred-and-forty-two healthy and unrelated subjects were enrolled in this survey. Genomic DNAs were extracted using salting out method. SNP genotyping assays were performed with home-designed sequence-specific primers polymerase chain reaction (SSP-PCR). As a result, molecular analysis showed that PECAM-1 is one of the most polymorphic markers in the Tunisian population because minor allele frequency was 0.3, and minimum haplotype frequency was 0.03. A low linkage disequilibrium (D' = 0.45) between rs12953 and rs1131012 was noticed, although all other loci were in the Hardy-Weinberg equilibrium (minimum P value = 0.07). The frequencies were close to those reported in African-American and Caucasian groups.
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Several studies confirmed the association of HLA-DRB1 and -DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Ar...
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Several studies confirmed the association of HLA-DRB1 and -DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta-analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using RevMan, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and publication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results. Background: Several studies confirmed the association of HLA-DRB1 and –DQB1 alleles with altered risk of type 1 diabetes (T1D). However, data from individual studies based on small sample sizes yielded often conflicting findings in African Arabs. This is a systematic review and meta-analysis aimed at comprehensively evaluating this association with T1D, using molecular HLA data. Methods: Relevant studies were identified through systemic search of Medline/PubMed, Cochrane, Science Direct, ResearchGate, and EMBASE databases. Statistical analysis was carried out using Revman, and Comprehensive Meta-analysis programs. Given the heterogeneity of African Arabs, we also performed subgroup analysis according to ethnicity. Analysis of sensitivity, heterogeneity, and pub?lication bias were performed to validate the outcome of the findings. This meta-analysis included 862 T1DM cases, along with 1,390 normoglycemic control, and comprised ten comparisons. Results: Our study indicates that DRB1*03 (OR = 2.86), DRB1*04 (OR = 2.78), and DQB1*02 (OR = 2.29), are positively associated with increased risk of T1DM, while DRB1*07 (OR = 0.48), DRB1*11 (OR = 0.20), DRB1*13 (OR = 0.47), DRB1*15 (OR = 0.30), DQB1*05 (OR = 0.39), and DQB1*06 (OR = 0.27) were negatively associated with T1D, suggesting a protective role against T1D. Conclusion: This meta-analysis was characterized by low heterogeneity, sensitivity, and publication bias, indicating the robustness and reliability of the results.
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Minor histocompatibility antigens (MiHAgs), such as HA-1 and HA-2, are the main targets of immune responses after allogeneic stem cell transplantation (SCT). HA-1 and HA-2 are two hematopoietic system-restricted antigens encoded, ...
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Minor histocompatibility antigens (MiHAgs), such as HA-1 and HA-2, are the main targets of immune responses after allogeneic stem cell transplantation (SCT). HA-1 and HA-2 are two hematopoietic system-restricted antigens encoded, respectively, by HMHA1 and MYO1G genes. In order to estimate their frequencies in Tunisians, we performed a molecular-based allele analysis for 160 healthy and unrelated subjects. Genomic DNAs were extracted mainly by the salting out method. Single nucleotide polymorphism (SNP) genotyping assays for selected sites at HMHA1 gene (rs3764653 and rs1801284) and at MYO1G gene (rs61739531) were performed with a sequence specific primers-polymerase chain reaction (SSP-PCR) method. Statistical analysis of our results showed that the HA-2 antigen is more frequent than the HA-1 antigen in the Tunisian population because their frequencies were 97% and 57%, respectively. Allele analysis for HMHA1 gene showed that the R variant (500T-504G) was predominant in our population (64%). For the MYO1G gene, the C allele was predominant (84%). All loci were in Hardy-Weinberg equilibrium (minimum P value = 0.06). Our frequencies were close to those reported in African and Caucasian groups.
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BACKGROUND: The Duffy blood group system, besides its relevance in transfusion medicine, is of major interest for population genetics. In fact, the Duffy molecule is the only red cell receptor for Plasmodium vivax, thus the fixati...
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BACKGROUND: The Duffy blood group system, besides its relevance in transfusion medicine, is of major interest for population genetics. In fact, the Duffy molecule is the only red cell receptor for Plasmodium vivax, thus the fixation of FY*silent allele in western south-Saharan Africa resulted in the absence of this type of malaria in that area (for a review see Kwiatowski, Am J Hum Genet 77:171-192, 2005). For the Duffy functional role see, for example, Daniels (Vox Sanguinis 93:331-340, 2007). METHODS: Duffy blood group distribution in 115 unrelated Tunisians was determined using the polymerase chain reaction with sequence specific primer (PCR-SSP) method detecting the five allelic versions of the FY gene. The red cell antigenic FY phenotype, for each donor, was deduced through DNA analysis. The blood samples of the positive FY*X alleles were investigated by serological methods, mainly the fixation-elution technique. RESULTS: The following allele frequencies were found (after having excluded FY*X, which had frequency of 0.0174): FY*1 = 0.291 (expressed 0.260; silent 0.031); FY*2 = 0.709 (expressed 0.427; silent 0.282). The most surprising result in this work is the detection of the FY*1 silent allele, usually quite rare, in four samples (1.74%). For FY*2 silent, the predominant allele in Africans, genotyping results showed a prevalence of 29.57%. The FY locus was in Hardy-Weinberg equilibrium in the present sample. CONCLUSION: When compared with European and African data, Tunisian samples demonstrated the presence of the common signs of these two ancestries (FY*2 and FY*X for the first population; and FY*2 silent for the last one). These data confirm the mixed roots of this urban Tunisian population already suggested by numerous studies on other haematological markers.
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Mesenchymal stromal cells (MSCs) support hematopoietic stem cells (HSCs) in vivo and enhance HSC engraftment and hematopoietic recovery upon cotransplantation with HSCs. These data have led to the hypothesis that MSCs may affect t...
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Mesenchymal stromal cells (MSCs) support hematopoietic stem cells (HSCs) in vivo and enhance HSC engraftment and hematopoietic recovery upon cotransplantation with HSCs. These data have led to the hypothesis that MSCs may affect the HSC niche, leading to changes in HSC retention and trafficking. We studied the effect of MSC administration on the HSC compartment in the bone marrow (BM) in mice. After injection of MSCs, HSC numbers in the BM were decreased coinciding with an increased cell cycle activity compared with phosphate-buffered saline (PBS)-injected controls. Furthermore, the frequency of macrophages was significantly reduced and niche factors includingCxcl12, Scf, andVcamwere downregulated in endosteal cells. These BM changes are reminiscent of events associated with granulocyte colony-stimulating factor (G-CSF)-induced hematopoietic stem and progenitor cell (HSPC) mobilization. Interestingly, coadministration of MSCs and G-CSF resulted in a twofold increase in peripheral blood HSPC release compared with injection of G-CSF alone, whereas injection of MSCs alone did not induce HSPC mobilization. After intravenous administration, MSCs were only observed in the lungs, suggesting that they exert their effect on the HSC niche through a soluble mediator. Therefore, we tested the hypothesis that MSC-derived extracellular vesicles (EVs) are responsible for the observed changes in the HSC niche. Indeed, administration of EVs resulted in downregulation ofCxcl12, Scf, andVcamand enhanced G-CSF-induced HSPC mobilization at similar levels as MSCs and G-CSF. Together, these data indicate that MSCs induce a permissive state in the BM, enhancing HSPC mobilization through the release of EVs.
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Multipotent stromal cells (MSC) have been shown to possess immunomodulatory capacities and are therefore explored as a novel cellular therapy. One of the mechanisms through which MSC modulate immune responses is by the promotion o...
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Multipotent stromal cells (MSC) have been shown to possess immunomodulatory capacities and are therefore explored as a novel cellular therapy. One of the mechanisms through which MSC modulate immune responses is by the promotion of regulatory T cell (Treg) formation. In this study, we focused on the cellular interactions and secreted factors that are essential in this process. Using an in vitro culture system, we showed that culture-expanded bone marrow-derived MSC promote the generation of CD4+CD25hiFoxP3+ T cells in human PBMC populations and that these populations are functionally suppressive. Similar results were obtained with MSC-conditioned medium, indicating that this process is dependent on soluble factors secreted by the MSC. Antibody neutralization studies showed that TGF-β1 mediates induction of Tregs. TGF-β1 is constitutively secreted by MSC, suggesting that the MSC-induced generation of Tregs by TGF-β1 was independent of the interaction between MSC and PBMC. Monocyte-depletion studies showed that monocytes are indispensable for MSC-induced Treg formation. MSC promote the survival of monocytes and induce differentiation toward macrophage type 2 cells that express CD206 and CD163 and secrete high levels of IL-10 and CCL-18, which is mediated by as yet unidentified MSC-derived soluble factors. CCL18 proved to be responsible for the observed Treg induction. These data indicate that MSC promote the generation of Tregs. Both the direct pathway through the constitutive production of TGF-β1 and the indirect novel pathway involving the differentiation of monocytes toward CCL18 producing type 2 macrophages are essential for the generation of Tregs induced by MSC. Stem Cells 2013;31:1980-1991
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Beta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antig...
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Beta cells presenting islet epitopes are recognized and destroyed by autoreactive CD8 T cells in type 1 diabetes. These islet-specific T cells are believed to react with epitopes binding with high affinity to human leucocyte antigen (HLA) expressed on beta cells. However, this assumption might be flawed in case of islet autoimmunity. We evaluated T cell recognition of the complete array of preproinsulin (PPI) peptides with regard to HLA binding affinity and T cell recognition. In a comprehensive approach, 203 overlapping 9-10mer PPI peptides were tested for HLA-A2 binding and subjected to binding algorithms. Subsequently, a high-throughput assay was employed to detect PPI-specific T cells in patient blood, in which conditional HLA ligands were destabilized by ultraviolet irradiation and HLA molecules refolded with arrays of PPI peptides, followed by quantum-dot labelling and T cell staining. Analysis of patient blood revealed high frequencies of CD8 T cells recognizing very low HLA binding peptides. Of 28 peptides binding to HLA-A2, a majority was predicted not to bind. Unpredicted peptides bound mainly with low affinities. HLA binding affinity and immunogenicity may not correlate in autoimmunity. Algorithms used to predict high-affinity HLA peptide binders discount the majority of low-affinity HLA binding epitopes. Appreciation that peptides binding HLA with very low affinity can act as targets of autoreactive T cells may help to understand loss of tolerance and disease pathogenesis and possibly point to tissue-specific immune intervention targets.
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Abstract Objective Investigation of a Jr(a‐) family samples, identification of the mutant and assessment of the differences of Jr antigen density of the Jr(a‐) family members, random adult and newborn individuals' RBCs. Backgrou...
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Abstract Objective Investigation of a Jr(a‐) family samples, identification of the mutant and assessment of the differences of Jr antigen density of the Jr(a‐) family members, random adult and newborn individuals' RBCs. Background The anti‐Jra antibody is generated when a Jr(a‐) individual pregnant or transfused with Jr(a+) blood unit, which can lead to mild‐to‐moderate hemolytic disease of the foetus and newborn (HDFN) or hemolytic transfusion reaction (HTR). Several mutations had been identified. The anti‐Jra caused HDFN is not rare in East Asia, but due to the lack of antibody and molecular background, it is likely to lead missed detection. Methods and Materials One G4P1 woman had been detected as IAT positive during prenatal examination. Suspected as anti‐Jra after the laboratory serological testing, the maternal sample was further assessed by molecular analysis. The antigen density was detected by flow cytometry after reacting with anti‐Jra serum in family members and the normal individuals. Results One novel frameshift mutation c.717delC and one previously identified mutation c.706C?>?T in ABCG2 was identified on proband. The infant haemoglobin(Hb) and bilirubin increased significantly after exchange transfusion and the severe HDFN was relieved. Flow cytometry results showed that the Jra antigens on adult RBCs were significantly less than those on the infant. Conclusion The c.717delC mutation can lead to the shortening of protein ABCG2 in the site of p.Leu307Stop, result in the loss of Jra antigen. The difference in antigen density between adult and infant RBCs may be a possible reason that leads to severe HDFN but not transfusion reaction. Breastfeeding may lead to slower recovery from HDFN.
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Umbilical cord blood (UCB) is used for HSCT. It is known that UCB can comprise Ag-specific T cells. Here we question whether solely transmaternal cell flow may immunize UCB. Twenty-three female UCB samples were collected from heal...
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Umbilical cord blood (UCB) is used for HSCT. It is known that UCB can comprise Ag-specific T cells. Here we question whether solely transmaternal cell flow may immunize UCB. Twenty-three female UCB samples were collected from healthy mothers and analyzed for minor histocompatibility Ag HY-specific responses. Forty-two of 104 tetramerpos T-cell clones, isolated from 16 of 17 UCB samples, showed male-specific lysis in vitro. Male microchimerism was present in 6 of 12 UCB samples analyzed. In conclusion, female UCB comprises HY-specific cytotoxic T cells. The immunization is presumably caused by transmaternal cell flow of male microchimerism present in the mother. The presence of immune cells in UCB that are not directed against maternal foreign Ags is remarkable and may explain the reported clinical observation of improved HSCT outcome with younger sibling donors.
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