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Background and Objectives: Antibodies to human leucocyte antigen (HLA) Class‐I antigens can lead to refractoriness to platelet transfusion. Although this can be overcome by transfusion of HLA‐compatible platelets, they are not always available. Disruption of HLA antigens on platelets by acid treatment may be a suitable alternative when no other components are available. The aim of this study was to assess the effect of HLA disruption and subsequent storage of platelet components. Materials and Methods: Platelet components were treated with 0.9% saline or citric acid solution (pH 3.0), and then stored until expiry (Day 7). HLA and platelet glycoprotein expression, platelet viability, activation and sialylation were measured by flow cytometry. Release of soluble factors was measured by ELISA and metabolism by biochemistry analyser. Reactivity to patient anti‐sera containing anti‐HLA antibodies was measured using platelet immunofluorescence tests (PIFTs) and monoclonal antibody immobilization of platelet antigen (MAIPA) assays. Platelet function was measured using aggregometry and thromboelastography (TEG). Results: Acid treatment reduced detection of HLA Class‐I on platelets by 75%, with significant reductions in reactivity to patient anti‐sera. Acid treatment reduced platelet content and viability, increased platelet activation and accelerated metabolism. Glycan cleavage was increased by acid treatment. Treatment reduced platelet activation following agonist stimulation by ADP and TRAP‐6, but platelets remained functional, displaying increased aggregation response and reduced time to clot formation by TEG. Conclusion: Although HLA disruption had some detrimental effects, acid‐treated platelets remained functional, retaining their capacity to respond to agonists and form clots, and with further development could be used to support refractory patients. [ABSTRACT FROM AUTHOR]

Aims: To report the clinicopathological features of Kikuchi disease in patients with acute leukaemia, emphasising similarities among cases. Methods and results: In a cohort of 454 Kikuchi disease patients, we identified three cases of concurrent acute leukaemia. These patients shared similar clinical traits, with Kikuchi disease emerging approximately a month after induction chemotherapy onset, featuring neck‐region lymphadenopathy. Notably, two patients were middle‐aged, deviating from the typical age distribution of Kikuchi disease. Histologically, these cases aligned with typical Kikuchi disease. Negative immunohistochemical stains (CD34, CD117, ERG, TdT) indicated the absence of extramedullary leukaemic infiltration. Herpes simplex virus immunohistochemical staining was also negative. Significantly, a human leucocyte antigen (HLA) association was observed in these three cases. HLA‐B*15:01, C*04:01, and DRB1*04:06 were more prevalent in these patients compared to the general population (compared with three independent control cohorts: Taiwanese Han Chinese (n = 504), Tzu Chi Taiwanese bone marrow donors (n = 364) and Hong Kong Chinese (n = 5266)). Conclusions: Our study underscores the unique link between Kikuchi disease and acute leukaemia, characterised by specific features and HLA associations. This underlines Kikuchi disease as a possible differential diagnosis in pertinent clinical scenarios. Furthermore, this syndrome offers insights into postchemotherapy immunology in acute leukaemia, enhancing comprehension. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune disorder, that is triggered by gluten ingestion in genetically predisposed individuals. The HLA‐DQB1*02 allele is the main predisposing genetic factor and a candidate for first‐line genotyping screening. We designed and validated a simple, DNA purification‐free PCR protocol directly from crude saliva, enabling the detection of the DQB1*02 allele. This assay also distinguishes homozygous from heterozygous carriers. We propose this method for use in mass screening and/or epidemiological studies. [ABSTRACT FROM AUTHOR]

Aims: Idiopathic type 1 diabetes (T1D) is a neglected subtype of T1D. Our aim was to investigate the frequency, clinical characteristics, and human leucocyte antigen (HLA) genotypes of idiopathic T1D. Methods: We enrolled 1205 newly diagnosed T1D patients in our analysis. To exclude monogenic diabetes in autoantibody‐negative patients, we utilised a custom monogenic diabetes gene panel. Individuals negative for autoantibodies and subsequently excluded for monogenic diabetes were diagnosed with idiopathic T1D. We collected clinical characteristics, measured islet autoantibodies by radioligand assay and obtained HLA data. Results: After excluding 11 patients with monogenic diabetes, 284 cases were diagnosed with idiopathic T1D, accounting for 23.8% (284/1194) of all newly diagnosed T1D cases. When compared with autoimmune T1D, idiopathic T1D patients showed an older onset age, higher body mass index among adults, lower haemoglobin A1c, higher levels of fasting C‐peptide and 2‐h postprandial C‐peptide, and were likely to have type 2 diabetes (T2D) family history and carry 0 susceptible HLA haplotype (all p < 0.01). A lower proportion of individuals carrying 2 susceptible HLA haplotypes in idiopathic T1D was observed in the adult‐onset subgroup (15.7% vs. 38.0% in child‐onset subgroup, p < 0.001) and in subgroup with preserved beta‐cell function (11.0% vs. 30.1% in subgroup with poor beta‐cell function, p < 0.001). Multivariable correlation analyses indicated that being overweight, having T2D family history and lacking susceptible HLA haplotypes were associated with negative autoantibodies. Conclusions: Idiopathic T1D represents about 1/4 of newly diagnosed T1D, with adult‐onset and preserved beta‐cell function patients showing lower HLA susceptibility and more insulin resistance. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we evaluated whether SARS‐CoV‐2 mRNA vaccines induce anti‐human leukocyte antigen (HLA) antibodies and anti‐ ABO blood type antibodies (ABOAb) in kidney transplant recipients (KTRs). Methods: Sixty‐three adult KTRs with functioning grafts who received two doses of the SARS‐CoV‐2 mRNA vaccine were enrolled in this cohort. Changes in anti‐ABO blood type immunoglobulin IgM and IgG antibody titers, flow panel reactive antibody (PRA), de novo donor‐specific anti‐human leukocyte antigen antibodies (DSA), and kidney allograft function before and after vaccination were evaluated. Results: Only one patient experienced conversion from negative to positive flow PRA after vaccination. However, there was no DSA in single antigen flow‐bead assays. The mean fluorescence intensity (MFI) in the eight DSA‐positive recipients did not significantly change before and after vaccination (p =.383), and no additional DSA was produced after vaccination in those patients. No significant elevation of ABOAb titer was observed for either IgM (p =.438) or IgG (p =.526) after vaccination. There was no significant deterioration in estimated glomerular filtration rate (eGFR) after vaccination (p =.877) or elevation of the urine protein‐to‐creatinine ratio (p =.209) after vaccination. One episode of AMR was observed in addition to a preexisting acute cellular rejection. Conclusions: The SARS‐CoV‐2 mRNA vaccine did not induce anti‐HLA antibody or ABOAb production in KTRs. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells recognize and eliminate cancer cells. However, immune evasion, downregulation of immune function by the tumour microenvironment and resistance of cancer cells are major problems. Although CTL and NK cells are both important to eliminate cancer, most studies address them individually. We quantified sequential primary human CTL and NK cell cytotoxicity against the melanoma cell line SK‐Mel‐5. At high effector‐to‐target ratios, NK cells or melan‐A (MART‐1)‐specific CTL eliminated all SK‐Mel‐5 cells within 24 h, indicating that SK‐Mel‐5 cells are not resistant initially. However, at lower effector‐to‐target ratios, which resemble numbers of the immune contexture in human cancer, a substantial number of SK‐Mel‐5 cells survived. Pre‐exposure to CTL induced resistance in surviving SK‐Mel‐5 cells to subsequent CTL or NK cell cytotoxicity, and pre‐exposure to NK cells induced resistance in surviving SK‐Mel‐5 cells to NK cells. Higher human leucocyte antigen class I expression or interleukin‐6 levels were correlated with resistance to NK cells, whereas reduction in MART‐1 antigen expression was correlated with reduced CTL cytotoxicity. The CTL cytotoxicity was rescued beyond control levels by exogenous MART‐1 antigen. In contrast to the other three combinations, CTL cytotoxicity against SK‐Mel‐5 cells was enhanced following NK cell pre‐exposure. Our assay allows quantification of sequential CTL and NK cell cytotoxicity and might guide strategies for efficient CTL–NK cell anti‐melanoma therapies. Key points: Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells eliminate cancer cells. Both CTL and NK cells attack the same targets, but most studies address them individually.In a sequential cytotoxicity model, the interdependence of antigen‐specific CTL and NK cell cytotoxicity against melanoma is quantified.High numbers of antigen‐specific CTL and NK cells eliminate all melanoma cells. However, lower numbers induce resistance if secondary CTL or NK cell exposure follows initial CTL exposure or if secondary NK cell exposure follows initial NK cell exposure. On the contrary, if secondary CTL exposure follows initial NK cell exposure, cytotoxicity is enhanced.Alterations in human leucocyte antigen class I expression and interleukin‐6 levels are correlated with resistance to NK cells, whereas a reduction in antigen expression is correlated with reduced CTL cytotoxicity; CTL cytotoxicity is rescued beyond control levels by exogenous antigen.This assay and the results on interdependencies will help us to understand and optimize immune therapies against cancer. [ABSTRACT FROM AUTHOR]

Aim: Paediatric acute-onset neuropsychiatric syndrome (PANS) is defined by an acute onset of obsessive-compulsive disorder and/or eating restrictions and at least two other severe neuropsychiatric symptoms. The condition is suspected to have an immune-mediated pathophysiology, but reliable biomarkers have not been identified.Methods: We hypothesised that PANS, like narcolepsy, might have a human leucocyte antigen (HLA) association, as found in 95% of children developing narcolepsy after H1N1 immunisation. Low resolution genotyping of the MHC class II antigens HLA-DRB1 and HLA-DQB1 was performed using two different PCR-based methods. In addition, parents were interviewed regarding a detailed family history of autoimmune diseases in first-degree relatives. A total of 18 children, aged 5-14 (mean 8.2) years at onset of PANS met symptom criteria.Results: No evident association between PANS and the specific HLA alleles examined was observed. In first-degree relatives of 10 of the 18 children, an autoimmune disease had been diagnosed, and three of the 18 children themselves had an autoimmune disease.Conclusion: No HLA allele association such as seen in children with narcolepsy after H1N1 immunisation could be confirmed in this group of children with PANS. However, more than half the group had a first-degree relative with a diagnosed autoimmune disease. [ABSTRACT FROM AUTHOR]

Background: Human leucocyte antigen (HLA) class I genes and haplotypes correlate with hepatitis B virus (HBV) infection. Occult HBV infection (OBI), a special type of chronic HBV infection, is defined as HBV surface antigen negative patients with or those without serologic markers by the means of HBV DNA detection in human plasma or in liver tissue by a diagnostic test. So far, the associations of HLA I haplotypes with OBI have not been reported previously in China. Methods: A case–control study between 107 OBI subjects and 280 healthy controls from blood donors in the Blood Center of the Shaanxi Province was conducted in the present association analysis. The HLA‐A, ‐B and ‐C loci of case–control subjects were detected and genotyped by polymerase chain reaction‐sequence based typing. The HLA‐A, ‐B and ‐C haplotypic frequencies were calculated by the maximum likelihood method. Results: The HLA‐A*33:03‐C*07:01G (pc = 0.039, odds ratio [OR] = 8.996, 95% confidence interval [CI] = 1.825–44.338), B*44:03‐C*07:01G (pc = 0.0069, OR = 12.000, 95% CI = 2.507–57.436) and A*33:03‐B*44:03‐C*07:01G (pc = 0.04, OR = 7.094, 95% CI = 1.387–36.288) haplotypes showed a a significant positive association with OBI. Independent effects demonstrated that HLA‐B*44:03 and HLA‐C*07:01G gave the main contribution to risk, whereas HLA‐A*33:03 was associated only by linkage disequilibrium. Conclusions: This present study is the first to demonstrate that HLA I haplotypes are associated with OBI in the Shaanxi Han population. The present results suggest that HLA‐B*44:03‐C*07:01G might be a potential risk factor for OBI. Comparisons of the frequencies of HLA I haplotypes at high resolution were made between OBI from northern Chinese Han and controls. Frequencies of HLA‐A‐B, A‐C, B‐C, A‐B‐C between the OBI group (gray column) and the control group (blank column) were compared. Haplotypes with p < 0.05 in either group were shown. p values for multiple comparisons (pc) were corrected by Bonferroni correction (*pc < 0.05). [ABSTRACT FROM AUTHOR]

Summary: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV)‐infected individuals may have a faster progression of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development when influenced by host, viral and environmental factors. Hepatitis C virus disease progression is also associated with genetic variants of specific killer cell immunoglobulin‐like receptors (KIRs) and genes of the major histocompatibility complex (MHC). The aim of the present study was to correlate clinical, virologic and biochemical parameters and to evaluate the possible influence of KIR genes and their HLA class I ligands in patients infected with hepatitis C virus. The present study analysed a total of 127 chronic HCV‐infected patients for various biochemical and genetics factors that can influence disease progression and prognosis. Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyl transferase (GGT), direct bilirubin (DB), alpha‐fetoprotein (AFP), HCV RNA levels and fibrosis indices were analysed using well‐established biochemical methods. At the same time, KIR and HLA genotyping was performed using a polymerase chain reaction sequence‐specific primer technique. Analysis of HLA class I and HLA ligands revealed that HLA‐C*12:02 and HLA‐A3 and HLA‐A11 were positively associated with the F3‐F4 fibrosis group (p =.026; OR = 8.717, CI = 1.040–73.077; respectively, p =.047; OR = 2.187; 95% CI = 1.066–4.486). KIR2DL2‐positive patients had high median levels of AST after treatment and direct bilirubin levels when compared to KIR2DL2‐negative patients (p =.013, respectively, p =.028). KIR2DL2/KIR2DL2‐C1C1 genotype was associated with increased AST, ALT and GGT levels. A higher GGT level was also observed in KIR2DS2‐C1‐positive patients when compared to KIR2DS2‐C1‐negative patients. The present research demonstrates several links between specific clinical, virologic and biochemical parameters and the expression of KIR genes and their HLA ligands in HCV‐infected patients. These connections should be taken into account when considering disease development and treatment. [ABSTRACT FROM AUTHOR]

Summary: Hepatitis B virus (HBV) infection causes a self‐limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin‐like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA‐A‐Bw4 and HLA‐C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004–0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA‐A‐Bw4 and HLA‐C2 was highly sensitive to predict the outcome of HBV infection. [ABSTRACT FROM AUTHOR]

Background: Adult‐onset idiopathic isolated adrenocorticotropic hormone deficiency (id‐IAD) is a rare disease with unknown aetiology. Recently, numerous cases of anti‐PD‐1 antibody‐induced IAD (PD1‐IAD) have been reported, but the clinical course, predictive factors and relationship to id‐IAD have not been clarified. Moreover, associations of id‐IAD and PD1‐IAD with human leucocyte antigen (HLA) require elucidation. Methods: Clinical characteristics of 13 Japanese patients with id‐IAD and eight Japanese patients with PD1‐IAD were analysed, and HLA‐typing test was performed for each patient. Allele and haplotype frequencies of the patients were compared to those of healthy Japanese controls. Results: In the HLA allele and haplotype analyses of id‐IAD, the frequencies of HLA‐C*14:02, HLA‐DPB1*05:01, HLA‐DRB1*04:05‐DQB1*04:01‐DPB1*05:01 and HLA‐DRB1*09:01‐DQB1*03:03‐DPB1*05:01 were significantly increased. On the other hand, HLA alleles account for PD1‐IAD susceptibility as follows: HLA‐DQB1*06:01, HLA‐DPB1*09:01 and HLA‐DRB5*01:02. Moreover, protective effect for HLA‐C*03:03 was suggested in combined id‐IAD and PD1‐IAD patients. Comparison of the effects of HLA on id‐IAD and PD1‐IAD revealed some differences. Alleles or haplotypes frequencies increased in id‐IAD group were as follows: HLA‐DPB1*05:01, HLA‐DRB1*09:01, HLA‐DRB4*01:03:02, HLA‐DQB1*03:03 and HLA‐DRB1*09:01‐DQB1*03:03. In clinical settings, hyponatremia, disturbance of consciousness and hypoglycaemia were less frequently seen in patients with PD1‐IAD than in patients with id‐IAD. Conclusions: Distinct clinical characteristics and predisposing HLA allele contributions were proposed between id‐IAD and PD1‐IAD. Further investigations with greater number of cases are warranted to clarify the detailed mechanisms of id‐IAD and PD1‐IAD. [ABSTRACT FROM AUTHOR]

Background and Objectives Timely detection of human leucocyte antigen (HLA) antibodies plays a key part in transplant outcome. Conventionally, several cellbased assays are available for detection of HLA antibodies upgrading to virtual crossmatch in which single-antigen bead (SAB) assay is widely used for characterization of pre-formed HLA donor-specific antibodies (DSAs). The main objective here is to find the prevalence and specificity of anti-HLA antibodies in Indian population using Luminex single-antigen (LSA) bead assay. Materials and Methods A total of 179 patients are included in the study for analysing anti-HLA antibodies by Luminex bead assays that comprise a panel of beads coated with purified HLA antigens (both class I and class II). Results HLA-A*24:02, HLA-A*02:02, HLA-B*15:02 and HLA-B*27:08 and HLAC* 07:01, HLA-C*07:02 and HLA-C*06:02 are frequently identified HLA antibodies against class I, whereas HLA-DRB1*09:01, HLA-DRB3*01:01, HLA-DQA1*01:02, HLA-DQB1*06:04, HLA-DQA1*05:01, HLA-DQB1*03:01, HLA-DPA1*02:01, HLADPB1* 14:01, HLA-DPA1*01:03 and HLA-DPB1*18:01 are most common anti-HLA antibodies against class II. Conclusions To conclude, this study helps to select the population-specific best possible donor and hence improve transplant outcome to decrease risk of antibody- mediated rejection. [ABSTRACT FROM AUTHOR]

The detection and semiquantitative measurement of circulating human leucocyte antigen (HLA)‐specific antibodies is essential for the management of patients before and after transplantation. In addition, the pretransplant cross‐match to assess the reactivity of recipient HLA antibody against donor lymphocytes has long been the gold standard to prevent hyperacute rejection. Whilst both of these tests assume that recipient HLA‐specific antibody is the only variable in the assessment of transplant risk, this is not the case. Transplant immunologists recognize that some HLA antigens are expressed at levels a magnitude lower than others (e.g., HLA‐C, HLA‐DQ), but within loci, and between different cell types there are many factors that influence HLA expression in both resting and activated cells. HLA is not usually expressed without the specific promoter proteins NLRC5, for HLA class I, and CIITA, for class II. The quantity of HLA protein production is then affected by factors including promoter region polymorphisms, alternative exon splice sites, methylation and microRNA‐directed degradation. Different loci are influenced by multiple combinations of these control mechanisms making prediction of HLA regulation difficult, but an ability to measure the cellular expression of each HLA antigen, in conjunction with knowledge of circulating HLA‐specific antibody, would lead to a more informed algorithm to assess transplant risk. [ABSTRACT FROM AUTHOR]

Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA‐B*56:02 has been previously reported. We report the allele frequency of HLA‐B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.4–7.8%) and the other European (0%). We compared the frequency with publicly available information on HLA‐B*56:02 status in other Indigenous Australian (n = 4) and European Australian cohorts (n = 1). In the Indigenous Australian cohorts, HLA‐B*56:02 allele frequency ranged from 1.3 to 19%. We also describe an additional case of phenytoin DRESS (RegiSCAR DRESS score 7) in an Aboriginal Australian that was associated with HLA‐B*56:02 and with CYP2C9*1/*3 genotype. In Aboriginal Australians, phenytoin DRESS appears distinctly linked to HLA‐B*56:02 with an allele carriage rate substantially higher than in Europeans, but also with considerable regional variation. Investigations of human leucocyte antigen and other contributing genes and severe adverse drug reactions in understudied non‐European populations are required to optimize safe medication use and inform risk mitigation strategies. [ABSTRACT FROM AUTHOR]

Aims: Antithyroid drug (ATD)‐induced agranulocytosis is a life‐threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD‐induced agranulocytosis. To examine the associations between HLA genotypes and ATD‐induced agranulocytosis, we conducted a systematic review and meta‐analysis of pharmacogenomics studies. Methods: We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case–control studies on the associations between HLA genotypes with ATD‐induced agranulocytosis. The Newcastle–Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random‐effects model meta‐analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD‐induced agranulocytosis. Results: We included 5 studies with 142 ATD‐induced agranulocytosis cases, 1529 matched ATD‐tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD‐induced agranulocytosis was associated with HLA‐B*27:05 (OR 10.97; 95% CI 0.75–159.99), HLA‐B*38:02 (OR 19.85; 95% CI 7.94–49.57) and HLA‐DRB1*08:03 (OR 5.29; 95% CI 3.44–8.14). After excluding propylthiouracil, the associations of ATD‐induced agranulocytosis with HLA‐B*27:05 and HLA‐B*38:02 were strengthened (OR being 20.61 (95% CI 5.21–81.58) and 40.59 (95% CI 13.24–124.47), respectively). The associations of ATD‐induced agranulocytosis with HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86–14.07), 36.43 (95% CI 12.80–103.70) and 5.42 (95% CI 2.36–12.47), respectively). HLA‐B*27:05, HLA‐B*38:02, and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis. Conclusions: HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated associations between human leucocyte antigen (HLA) and some types of ischaemic stroke. In the present study, we genotyped HLA‐A,‐B and ‐DRB1 alleles in 140 Iranian patients with history of ischaemic stroke and 140 age‐/sex‐matched healthy subjects. No significant difference has been found in the distribution of HLA‐A and B alleles between cases and controls. The DRB1*16 allele was significantly over‐represented in patient group compared with control group (Adjusted p value = 0.048). Other HLA‐DRB1 alleles were not associated with stroke risk. The HLA‐B*35,B*52 genotype was significantly more prevalent among patients compared with controls (Adjusted p value = 0.03, OR [95% CI] = 9.3 [1.3, 407.2]). Several HLA haplotypes were associated with risk of stroke in the assessed population. The current study provides further evidences for participation of HLA in conferring risk of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Background & Aims: Acute hepatitis B virus (HBV) infections may clear spontaneously or become chronic and run through different phases. The single nucleotide polymorphisms (SNPs) rs3077, rs9277535 and rs9277534 within the human leucocyte antigen (HLA)‐DP gene have been found to be associated with HBV susceptibility and persistence in Asians. However, evidence for the influence of these variants in Caucasians has been limited so far. The aim of our study was to investigate the impact of these polymorphisms on the outcome of HBV infections in a large Caucasian population. Methods: In this case‐control study, we retrospectively analysed 1111 Caucasian individuals, including 618 with chronic HBV infections (CHB), 239 with spontaneous HBsAg seroclearance (SC) and 254 healthy controls (HC). The rs3077, rs9277535 and rs9277534 SNPs were genotyped by a polymerase chain reaction from blood samples and melting curve analysis. Results: A significant difference in the allele distributions was observed only for the rs3077 SNP between the HC and the CHB group as well as between the SC and CHB groups. The rs3077‐C allele was associated with a lower probability for spontaneous HBsAg seroclearance in comparison with the rs3077‐T allele (OR 0.704, 95% CI 0.509‐0.974; P = 0.033). No association of the three SNPs with the stages of chronic HBV infection was found. Conclusion: This is the first study demonstrating an association of the rs3077‐T allele with spontaneous HBsAg seroclearance in Caucasians. Further studies are needed to elucidate the role of HLA‐DP variants in disease pathogenesis and their potential role for individualized disease management. [ABSTRACT FROM AUTHOR]

The distributions of HLA allele and haplotype are variable in different ethnic populations and the data for some populations have been published. However, the data on HLA‐C and HLA‐DQB1 loci and the haplotype of HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1 and HLA‐DQB1 loci at a high‐resolution level are limited in Zhejiang Han population, China. In this study, the frequencies of the HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1 and HLA‐DQB1 loci and haplotypes were analysed among 3,548 volunteers from the Zhejiang Han population using polymerase chain reaction sequencing‐based typing method. Totals of 51 HLA‐A, 97 HLA‐B, 45 HLA‐C, 53 HLA‐DRB1 and 27 HLA‐DQB1 alleles were observed. The top three frequent alleles of HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1 and HLA‐DQB1 loci were A*11:01 (23.83%), A*24:02 (17.16%), A*02:01 (11.36%); B*40:01 (14.08%), B*46:01 (12.20%), B*58:01 (8.50%); C*07:02 (18.25%), C*01:02:01G (18.15%), C*03:04 (9.88%); DRB1*09:01 (17.52%), DRB1*12:02 (10.57%), DRB1*15:01 (9.70%); DQB1*03:01 (22.63%), DQB1*03:03 (18.26%) and DQB1*06:01 (10.88%), respectively. A total of 141 HLA‐A‐C‐B‐DRB1‐DQB1 haplotypes with a frequency of ≥0.1% were found and the haplotypes with frequency greater than 3% were A*02:07‐C*01:02:01G‐B*46:01‐DRB1*09:01‐DQB1*03:03 (4.20%), A*33:03‐C*03:02‐B*58:01‐DRB1*03:01‐DQB1*02:01 (4.15%), A*30:01‐C*06:02‐B*13:02‐DRB1*07:01‐DQB1*02:02 (3.20%). The likelihood ratios test for the linkage disequilibrium of two loci haplotypes was revealed that the majority of the pairwise associations were statistically significant. The data presented in this study will be useful for searching unrelated HLA‐matched donor, planning donor registry and for anthropology studies in China. [ABSTRACT FROM AUTHOR]

The novel HLA‐B*15:514 allele was characterized using two next‐generation sequencing technologies. [ABSTRACT FROM AUTHOR]

Two novel HLA alleles were detected using two next generation sequencing technologies. [ABSTRACT FROM AUTHOR]

Summary: The human leucocyte antigen (HLA) is the most polymorphic region of the human genome. Compared with Sanger‐sequencing‐based typing (SBT) methods, next‐generation sequencing (NGS) has significantly higher throughput and depth sequencing characteristics, having dramatic impacts on HLA typing in clinical settings. Here, we performed NGS technology with Ion Torrent S5 platform to evaluate the potential four novel HLA alleles detected in five donors from Chinese Marrow Donor Program (CMDP, Shaanxi Province) during routine Sanger SBT testing. We also predicted the highest estimated relative frequency novel allele‐bearing haplotypes according to their phenotypes and HaploStats database. NGS assays, as it provided the phase‐defined and complete sequencing information, undoubtedly increase novel allele identification which will greatly enrich HLA database and provide more information for donor selection. [ABSTRACT FROM AUTHOR]

Abstract: The development of techniques to define the human leucocyte antigen (HLA) region has proven to be challenging due to its high level of polymorphism. Within a clinical laboratory, a technique for high‐resolution HLA typing, which is rapid and cost effective is essential. NGS has provided a rapid, high‐resolution HLA typing solution, which has reduced the number of HLA ambiguities seen with other typing methods. In this study, the One Lambda NXType NGS kit was tested on the Ion Torrent PGM platform. A total of 362 registry donors from four ethnic populations (Europeans, South Asians, Africans and Chinese) were NGS HLA typed across 9‐loci (HLA‐A, ‐B, ‐C, ‐DRB1,‐DRB345 ‐DQB1 and ‐DPB1). Concordance rates of 91%–98% were obtained (for HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1 and ‐DPB1) when compared to historical PCR‐SSO HLA types, and the identification of uncommon alleles such as A*24:07:01 and C*04:82 were observed. A turnaround time of four days was achieved for typing 44 samples. However, some limitations were observed; primer locations did not allow all ambiguities to be resolved for HLA Class II where Exon I and IV amplification are needed (HLA‐DRB1*04:07:01/04:92, HLA‐DRB1*09:01:02/*09:21 and HLA‐DRB1*12:01:01/*12:10). This study has demonstrated high‐resolution typing by NGS can be achieved in an acceptable turnaround time for a clinical laboratory; however, the Ion Torrent workflow has some technical limitations that should be addressed. [ABSTRACT FROM AUTHOR]

Summary: Natural killer (NK) cells provide a major defence against human cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin‐like receptors (KIRs), and human leucocyte antigen (HLA) class I molecules. Also γ marker (GM) allotypes, able to influence the NK antibody‐dependent cell‐mediated cytotoxicity, appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim of gaining insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK responses, and HCMV infections. In a previous study we assessed whether the KIR and HLA repertoire might influence the risk of developing symptomatic (n = 60) or asymptomatic (n = 60) disease after primary HCMV infection in the immunocompetent host. In the present study, the immunocompetent patients with primary symptomatic HCMV infection were genotyped for GM3/17 and GM23 allotypes, along with the 60 participants with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that individuals carrying the GM23 allotypes, both homozygous and heterozygous, GM17/17, HLA‐C2 and Bw4T KIR‐ligand groups are associated with the risk of developing symptomatic infection. Our findings on the role of both cellular and humoral immunity in the control of HCMV infection should be of value in guiding efforts to reduce HCMV‐associated health complications in the elderly, including immunosenescence, and in transplantation. [ABSTRACT FROM AUTHOR]

Summary: The predicted indirectly recognizable human leucocyte antigen (HLA) epitopes (PIRCHE) algorithm is a novel in silico algorithm to determine donor–recipient compatibility. The PIRCHE algorithm determines donor–recipient compatibility by counting the number of mismatched HLA‐derived epitopes that are involved in indirect T‐cell alloimmune responses; these epitopes are designated as PIRCHE. Over the last few years, the PIRCHE algorithm has been investigated in both hematopoietic stem cell transplantation and solid organ transplantation. This review describes the theory of the algorithm, its application in transplantation, and highlights the future perspectives on the clinical application of the PIRCHE algorithm. [ABSTRACT FROM AUTHOR]

We determined the high-resolution allele and haplotype frequencies at the human leucocyte antigen ( HLA)A, B and DRB1 loci in the Han population of Hubei province, the TB endemic area of Central China, with pulmonary tuberculosis ( PTB), and established the relationship between HLA-A, B and DRB1 alleles as well as haplotypes and susceptibility to multidrug-resistant and rifampicin-resistant tuberculosis ( MDR/ RR- TB). Blood samples were drawn from 174 patients with MDR/ RR- TB and 838 patients with drug-susceptible PTB in ethnic Han population from Hubei province (central China). Four-digit allele genotyping of HLA- A, B and DRB1 loci was performed using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR- SSOP). The allele and haplotype frequencies of HLA-A, B and DRB1 were determined and compared between patients with MDR/ RR- TB and patients with drug-susceptible PTB. Statistical analysis of the generated data indicated no departure from expectation of Hardy-Weinberg equilibrium ( HWE) at all loci of the control group. Multivariate analysis identified allele DRB1*08:01 ( p < .0001; OR = 174.5, 95% CI 15.3-1987.2) as independent predictor of MDR/ RR- TB, except for old age ( p < .0001; OR = 10. 9, 95% CI 7.6-15.8), previous treatment history ( p < .0001; OR = 11.0, 95% CI 7.2-16.7) and poor compliance to treatment ( p < .0001; OR = 12.9, 95% CI 8.4-20.0). While in the subgroup of new TB cases, DRB1*08:01 ( p < .0001; OR = 80.3, 95% CI 7.0-917.1) and older age ( p < .0001; OR = 3.9, 95% CI 2.4-6.4) were independent susceptibility factors for primary MDR/ RR- TB. Our results suggest that a combination of clinical and host genetic information about tuberculosis patients may contribute to prediction and early detection of MDR/ RR- TB. [ABSTRACT FROM AUTHOR]

SUMMARY Background Red blood cell (RBC) alloimmunisation is an event that may occur due to factors such as numerous blood transfusions, age, gender and genetic factors such as human leukocyte antigen (HLA). Aims/Objectives The aim of the present study was to investigate the possibility of alloimmunisation to red blood cell group antigens associated with the HLA of individuals and to relate alloimmunisation to risk factors. Methods A total of 172 polytransfused patients with sickle cell anaemia (SCA) (44 alloimmunised, 128 non-alloimmunised) participated in this study. Blood group genotyping was performed by the DNA microarray method and HLA genotyping by polymerase chain reaction - specific sequence of oligonucleotides. Results The number of transfusions received directly influenced the incidence of alloimmunisation, and the most common alloantibodies were against Rh (48·8%) and Kell (17%) systems. The HLA-C*06 and HLA-DQB1*03 variants were significantly higher in alloimmunised patients. The HLA-DRB1*04 and HLA-DRB1*11 were more often found in individuals who developed the alloantibodies anti-Fya and anti-K, respectively. Conclusion This study suggests that polytransfused patients with SCA possessing the HLA-DQB1*03 and HLA-C*06 allele variants are more susceptible to alloimmunisation. In addition, HLA-DRB1*04 and HLA-DRB1*11 alleles were seen to be associated with the production of anti-Fya and anti-K antibodies, respectively. [ABSTRACT FROM AUTHOR]

Over the past several decades, there has been an increasing use of haematopoietic cell transplantation for patients with malignant and non-malignant blood disorders. Blood transfusion support is essential for successful patient outcomes, as recipients have unique transfusion needs both pre- and post-transplantation. These needs must be carefully managed by transplant teams in partnership with the transfusion service. Patients may present to haematology clinic anaemic, thrombocytopenic and/or neutropenic related to their underlying blood disorder. They will need transfusions of blood products for support prior to transplantation. Following transplantation, multiple red blood cell and platelet transfusions may be required especially until engraftment occurs. Often there is an ABO mismatch between the donor and the recipient, and blood will need to be selected for major and minor ABO compatibility of red blood cell and plasma-containing blood components during the peri-transplant period. Both myeloablative and non-myeloablative preparative regimens are immunosuppressive, so irradiated blood products should be provided to minimize the risk of transfusion-associated graft-versus-host disease and cytomegalovirus-negative patients should receive cytomegalovirus-reduced risk blood products to prevent transfusion-associated infection. Leucocyte-reduced blood components are used to minimize adverse effects of transfused donor leucocytes including febrile reactions, alloimmunization and immunomodulation. Alloimmunization to red blood cell or platelet antigens may pose a challenge in the selection of compatible blood components and platelet refractoriness may develop. In short, patients undergoing haematopoietic cell transplantation require considerable blood component support and collaboration between the transfusion and clinical transplant services is essential to effectively manage their transfusion needs. [ABSTRACT FROM AUTHOR]

Aim: The human leucocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland.Methods: The study cohort comprised 19 paediatric patients (13 female) aged three years to 15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011, and followed up for four years and three months to 14.6 years. We genotyped HLA-B and HLA-DRB1 in the children, and the HLA antigen frequencies were compared with 19 807 records from the Finnish Bone Marrow Donor Registry.Results: All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort.Conclusion: Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients. [ABSTRACT FROM AUTHOR]

Umbilical cord blood ( UCB) emerged in the last 20 years as a valid alternative source of hematopoietic stem cell ( HSC) in allogeneic transplantation setting, mainly in the absence of a fully human leucocyte antigen ( HLA)-matched sibling. The probability of finding a matched unrelated donor through the registries varies from 20 to 70%, depending on the ethnicity of the patients. Therefore, patients in need may benefit of an HLA-mismatched hematopoietic stem cell transplantation from haploidentical donors or from UCB. One of the advantages of using UCB is the lower incidence of acute graft-versus-host-disease and allowance of greater HLA mismatch. Conversely, the low number of HSCs and lymphocytes and specific immunological features of T cells are associated with delayed engraftment and immune reconstitution and consequently, increased opportunistic infections. Nevertheless, retrospective studies showed similar results comparing UCB with other stem cell sources, both in pediatric and adult setting. The ability to use partially HLA-matched UCB units allows expanding the donor pool. Many UCB banks have strategies to increase their inventory including UCB grafts that have rare haplotypes. HLA and cell dose are very important factors associated with outcomes after umbilical cord blood transplantation (UCBT) that interact with each other. Increasing cell dose counterbalances the number of HLA disparities. Understanding those interactions, the role of HLA mismatches and other immunogenic factors, are important to allow clinicians to choose the best cord blood graft for patients. This review will describe the role of HLA in UCBT setting. [ABSTRACT FROM AUTHOR]

The article discusses a study related to combined loss of human leucocyte antigens (HLA) I and HLA II expression, which is more common in the non-germinal center B-cell–like (GCB) type of diffuse large B cell lymphoma. it mentions high expression of FoxP1 with a low expression of HLA class II expression in normal pre-plasma cells and non-GCB-type DLBCL maturing to plasmablasts. it also mentions FoxP1-positive cases showed homogeneous staining of the tumour cells.

A case study of a pair of 4-year-old female monozygotic twins with thalassaemia major, who had undergone successful haematopoietic stem cell transplantation with paternal haploidentical- peripheral blood, is presented. It mentions KIR B haplotype would promote engraftment in unrelated cord blood (UCB) transplantation to reduce graft-versus-host disease and graft failure in haplo-HSCT.

In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury ( DILI). In addition, a relatively small number of human leukocyte antigen ( HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI. [ABSTRACT FROM AUTHOR]

Human leucocyte antigen ( HLA) compatibility is the main factor determining the occurrence of graft- vs-host disease (GVHD) in patients. It has also been shown that minor histocompatibility antigen differences as well as genetic polymorphisms that are not sequenced by standard methodology for HLA typing can play a role. We used mixed lymphocyte cultures (MLCs) as a functional cellular test and investigated gene expression changes driven by HLA incompatibility in an effort to better understand the mechanisms involved in the disease. Gene expression profile of HLA matched and HLA mismatched MLC identified differentially regulated genes and pathways. We found that a great number of genes related to immune function were differentially regulated; these genes were also found to be associated with GVHD and graft rejection. The majority of differentially regulated genes were interferon-gamma ( IFNγ)-inducible genes and IFNγ neutralisation in MLCs abrogated their induction. The microRNA-155, a recently identified target for acute GVHD (aGVHD), was also found to be significantly induced in HLA mismatched MLC but not in the matched setting and its induction was not diminished by blocking IFNγ. In this proof-of-principle study we show gene expression changes in mismatched MLC that represent alloreactive responses, correlate with markers involved in GVHD and can potentially be useful in the study of the biological processes involved in this disease. [ABSTRACT FROM AUTHOR]

How human leucocyte antigen ( HLA) expression levels on human lymphocytes relate to clinically relevant in vitro cytotoxicity testing has not been defined. Here, cross-sectional ( n = 14) and longitudinal ( n = 6) semi-quantitative assessment of HLA expression on lymphocytes was performed. Complement-dependent cytotoxicity (CDC) and cellular allo-reactivity were assessed vis-à-vis target cells with defined levels of HLA expression. On CD4+ and CD8+ T-cells, and on B-cells, intra-individual HLA levels varied ≤1.5-fold, whereas inter-individual HLA expression varied 2.34-fold and 2.07-fold on CD4+ and CD8+ T-cells, respectively, and 2.90-fold on B-cells. Importantly, CDC crossmatch reactions induced by anti- HLA-A2 monoclonal antibody as well as patient sera solely containing HLA-A2 antibodies were significantly impacted by HLA-A2 expression levels on donor cells. Likewise, cytotoxicity of HLA-A2 reactive effector cells was induced proportionate to availability of HLA-A2. These data demonstrate that human HLA expression on lymphocytes from healthy blood donors is fairly stable intra-individually, yet varies significantly from person to person. Variability in HLA expression levels can impact functional cytotoxic reactions in vitro, including the widely used CDC crossmatch assay. Prospective studies are required to test the clinical relevance of this finding. [ABSTRACT FROM AUTHOR]

The present study investigates the human leucocyte antigen ( HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation ( HSCT). We determined HLA class I (A, B, and C) and HLA class II ( DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B- DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation ( MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies. [ABSTRACT FROM AUTHOR]

The diagnosis of platelet refractoriness is made when at least on two sequential occasions, a 10-min to 1-h post-transfusion, the CCI is less than 5 × 109/l, using ABO-identical fresh platelets of less than 72 h old. In practice, an increase in the patient's platelet counts of <10 × 109/l after the transfusion can be used. Refractoriness to platelet transfusion can be due to non-immune and immune causes. Non-immune causes include sepsis and disseminated intravascular coagulation. Twenty percent of cases have a combination of both immune and non-immune causes. Immune causes include alloimmunization to human leukocyte antigen ( HLA) and/or human platelet antigens( HPA). The pattern of refractoriness and clinical condition may assist in determining the cause. Patients who are likely to receive multiple platelet transfusion should have their post transfusion platelet count estimated. If refractoriness is suspected, HLA typing and antibody investigation should be done. While waiting for the test result and the supply of HLA matched platelets, ABO compatible platelets may be given. Doubling the dose or giving more frequent transfusion maybe necessary in non-immune cases. Where patient's HLA type is known, an identical or closely identical platelet can be given. Another approach is by giving platelet from donors lacking HLA antigens that correspond to the recipient's alloantibodies. Crossmatched platelets can be given in the absence of typed HLA platelets. Approximately 20-25% cases may be due to platelet-specific antibodies, and undetected HLA incompatibility, in which case, the patient can be given antigen negative platelet. [ABSTRACT FROM AUTHOR]

Transplantation of organ and haematopoietic stem cells is an established medical therapy, and success is dependent on finding the right donor bearing the appropriate human leucocyte antigen typing consisting mainly of class I ( HLA-A, HLA-B and HLA-C) and class II (class DP, DR and DQ) genes. These molecules engage with peptide fragments resulting in a complex interaction with dendritic cells and T cells. This plays an integral part in immune surveillance and modulates the recognition between self and nonself antigens. The principle of transplant biology is that any HLA disparity between donor and recipient triggers an 'alloreactive response' primarily mediated by T cells. This can result in graft-versus-host disease or graft-versus-leukaemia effect and has a significant role in graft rejection. Historically, HLA typing was performed via serological methods, but the advent of molecular techniques including DNA sequencing has allowed for higher resolution typing resulting in improvements in survival. This has historically been across 6 alleles ( HLA-A, HLA-B and HLA- DR) but has recently been expanded to include HLA-C and HLA- DQ. Consistent data have demonstrated the superiority in transplantation success with a 10/10 HLA-matched donor. The stringent HLA matching in allogeneic stem cell transplantation ( SCT) requires a careful selection of unrelated donors and may be more difficult for ethnic minority patients. To circumvent this, novel methods have been developed including alternative conditioning regimens, T-cell depletion and haplo-identical/mismatched transplants. The pioneering use of cord blood as a donor source has enabled transplants to be performed despite some degree of HLA mismatching. [ABSTRACT FROM AUTHOR]

The novel HLA‐A*26:208 allele was characterized using two next generation sequencing technologies. [ABSTRACT FROM AUTHOR]

Acquired immunoglobulin G (IgG)-mediated thrombotic thrombocytopenic purpura ( TTP) has not yet been described in non-twin siblings. We report two cases of acquired TTP in Caucasian sisters with inactive ADAMTS13 metalloprotease due to ADAMTS13 autoantibodies suggesting a role of genetic determinants in this life-threatening disease. However, human leucocyte antigen ( HLA) class II types presumably associated with acquired TTP were not identified in the patients, indicating that HLA class II typing may not be useful in acquired TTP risk assessment of family members. [ABSTRACT FROM AUTHOR]

We have determined the frequencies of human leucocyte antigen ( HLA)- B*57:01, HLA-B*35:05, HLA-C*04 and HLA-C*08 in healthy individuals of South African Indian ( SAI) ethnicity ( n = 50) and South African mixed ( SAM) ancestry ( n = 50) using real-time allele-specific polymerase chain reaction ( AS-PCR) assay. HLA-B*57:01 associates with immune hypersensitivity reaction ( IHR) in individuals exposed to abacavir ( ABC), while nevirapine ( NVP) IHR associates with HLA-B*35:05, HLA-C*04 and HLA-C*08. Real-time AS-PCR assays typically use less DNA, are more cost-effective and rapid compared with conventional genotyping methods, such as sequence-based typing ( SBT). The assay was developed using samples of known HLA class I genotype and subsequently applied to the SAI and SAM samples. HLA-B*57:01 was detected in SAM and SAI populations at frequencies of 8.0% and 12.0%, respectively, while HLA-B*35:05 was not found in SAI individuals, but was present in 6.0% of SAM individuals. HLA-C*04 was detected in 22.0% and 24.0% of SAM and SAI individuals, respectively, while 10.0% and 8.0% of SAM and SAI individuals, respectively, were HLA-C*08 positive. This study reports the development of a novel real-time AS-PCR assay to identify HLA class I alleles associated with ABC and NVP IHR and has established the frequencies of these alleles present in healthy SAI and SAM populations. Using South African demographic data, our hypothetical analysis suggests that a substantial number of individuals would benefit from the assay. [ABSTRACT FROM AUTHOR]

Background & Aims Primary biliary cirrhosis ( PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen ( HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. Methods We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. Results Significant associations existed between HLA- DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03- DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01- DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02- DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody ( ANA) ( OR = 0.25) and anti-gp210 antibody ( OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody ( OR = 5.70) production. Conclusion These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population. [ABSTRACT FROM AUTHOR]

. Purpose: To evaluate the efficacy of keratectomy in treating irregular astigmatism caused by peripheral hypertrophic subepithelial corneal degeneration (PHSD) and to study the possible underlying immunological risk factors. Materials and methods: Patients (14 eyes) with diagnosed PHSD were treated with superficial keratectomy with or without the assistance of phototherapeutic keratectomy (VisX S4; VisX Inc., Santa Ana, CA, USA). Thirteen patients were subjected to analysis of human leucocyte antigen (HLA) genes, complement C4 gene numbers and total plasma immunoglobulin levels. Immunological risk factors between patients and a control group comprising 150 individuals were compared. Results: The mean preoperative best spectacle corrected visual acuity (BCVA) improved from 0.16 ± 0.22 (LogMAR scale range 0-0.7) to 0.06 ± 0.13 (−0.1-0.4) (p < 0.01). The mean preoperative astigmatism decreased significantly from 3.8 ± 2.1 D (range 1.2-8.2) to 2.1 ± 1.4 (range 0.6-5.0, p = 0.02) based on corneal topography. The HLA-B*44 allele and the ancestral haplotype (AH) 8.1 were found significantly more often in PHSD patients than in controls (both p = 0.03). No differences in the C4 genes were found. Conclusions: Astigmatism secondary to PHSD can be effectively treated with keratectomy. Peeling of the fibrotic tissue reduced astigmatism and improved visual performance. We suggest that HLA-B*44 allele and AH 8.1 haplotype are immunological factors predisposing to the development of PHSD. The consequent disruption/alteration of the limbal barrier may lead to corneal peripheral fibrous formation inducing astigmatism. [ABSTRACT FROM AUTHOR]

In order to study the impact of human leucocyte antigen ( HLA) polymorphism distribution in identifying a matched haematopoietic stem cells unrelated donor (UD), we performed a multi-centric retrospective analysis with the aim of comparing the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 phenotypes of 2126 patients (772 patients for whom a donor search failed to identify a matched UD, and 1354 patients who received a 10/10 allele level matched UD). Our results showed that rare HLA-C is often responsible for difficulty in identifying a donor. This locus may add a degree of complexity to a supposed 'frequent' HLA-A HLA-B and HLA-DRB1 phenotype, turning this phenotype into a less frequent one. For example, 32.5% of the phenotypes in the non-transplanted patients could not be explained by any of the pairs of known HLA-A, HLA-B, HLA-C and HLA-DRB1 haplotypes while this percentage dropped to less than 2% if combinations of only HLA-A, HLA-B and HLA-DRB1 haplotypes were considered. Such situations can be anticipated by computing an index, based on HLA haplotype frequency, the average registry sample size ( ARS). ARS is defined as the inverse of the phenotype frequency computed using all corresponding pairs of haplotype frequencies. ARS confirmed that the most significant difference between transplanted and non-transplanted patients was correlated with the introduction of the locus HLA-C in the analysis (median: 8.3e + 4 vs 3.1e + 6, P < 0.0001). The higher the ARS the lower the likelihood of finding a 10/10 match UD reflecting the rareness of the patient's HLA. The area under receiver operator characteristics ( AUROC) values of the ARS computation for HLA-A, HLA-B and HLA-DRB1 was 0.82 (0.80; 0.84) at a low-resolution level (two digits). Overall, our study promotes the use of haplotype frequency-based computations to develop computer-assisted donor search. [ABSTRACT FROM AUTHOR]

Activating and inhibitory killer immunoglobulin-like receptors ( KIR) and their ligands HLA-Bw4 (loci A and B) were studied by way of establishing whether they can contribute to protection against HIV-1 infection in highly exposed and persistently seronegative ( HESN) patients. Twenty-three HIV-1 serodiscordant heterosexual couples, 100 HIV-1+ patients and 200 healthy individuals were included in this retrospective case-control study. HLA typing was performed by means of PCR followed by sequence-specific oligonucleotide probe reverse hybridization. KIR3 DL1 and KIR3 DS1 were studied by PCR sequence-specific primers. The frequency of KIR3 DS1(3 DS1/3 DL1)-Bw4 combination was significantly higher in HESN patients versus the discordant couples ( P = 0·0003) and HIV-1+ patients ( P = 0·0001). Conversely, the KIR3 DL1/ KIR3 DL1 homozygosity was significantly decreased in HESN patients versus the discordant couples ( P = 0·00003), and HIV-1+ patients ( P = 0·00066). The frequency of HLA-A*32 and HLA-B*44 was higher in HESN versus their discordant couples ( P = 0·009; P = 0·049), and HIV-1+ patients ( P = 0·00002; P = 0·0001). This had greater significance in combination with KIR3 DS1 (3 DS1/3 DL1). KIR3 DS1(3 DS1/3 DL1) could have a greater effect on protection against HIV-1 infection in HESN patients when bound to a specific HLA allele, in this case HLA-A*32 and HLA-B*44, both Bw4 alleles. The differences probably arise both in the HLA alleles and in the subtypes of KIR receptors depending on the ethnic group studied. [ABSTRACT FROM AUTHOR]

A previous Japanese study revealed that a human leucocyte antigen ( HLA)- A or - B allele mismatch was associated with higher overall mortality, whereas an HLA-C or - DRB1 allele mismatch did not affect mortality after serologically matched unrelated bone marrow transplantation ( BMT). This study reanalysed 3003 adult patients who underwent unrelated BMT from a serologically HLA- A, - B, or - DR matched unrelated donor between 1993 and 2009 using the latest database, that included 1966 HLA-matched unrelated BMT and 187, 31, 524, and 295 unrelated BMT with a single HLA- A, - B, - C, or - DRB1 allele mismatch, respectively. As opposed to our previous findings, HLA- C and - DRB1 mismatches had a significant negative impact [hazard ratio ( HR) 1·35, P < 0·001, and HR 1·45, P < 0·001] on survival in the period 2000-2009. The negative impact of each single HLA allele mismatch was not significantly different among the HLA- A, - B, - C, and - DRB1 mismatches ( P = 0·79). An interaction test revealed that the effects of single HLA- C and - DRB1 allele mismatches significantly differed over the two time periods ( P = 0·032 and P = 0·0072, respectively). In conclusion, the impact of a single HLA allele mismatch changed over time. In the recent cohort, the negative impact of HLA- DRB1 and - C mismatches became apparent. [ABSTRACT FROM AUTHOR]

Non-classical human leucocyte antigen- E ( HLA- E) mediates natural killer and CD8+ T-cell activity, suggesting a role in the regulation of autoimmunity. HLA- E*0103 X/*0103 X has been associated with Behcet's disease and HLA- E *0101/*0103 X with childhood onset diabetes. We investigated HLA- E allele status in 52 Caucasian and Ashkenazi Jewish Pemphigus vulgaris ( PV) patients and 51 healthy controls by restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system. Associations were determined via chi-square test, Fisher's exact test and logistical regression analysis. HLA- E outcomes included presumed homozygous *0101/*0101 or *0103 X/*0103 X genotype status or *0101/*0103 X heterozygous status. PV did not significantly associate with either *0101/*0101 or *0101/*0103 X genotypes. HLA- E*0103 X/*0103 X (presumed homozygote) is significantly increased in patients with PV versus controls ( P = 0.0146, OR = 3.730, 95% CI = 1.241-11.213). Our data provide the first evidence that HLA- E*0103 X is a marker for genetic risk in PV. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underpinning central nervous system damage in multiple sclerosis ( MS) are complex and it is widely accepted that there is an autoimmune component. Both adaptive and innate immune effector mechanisms are believed to contribute to tissue disease aetiology. HLA-E is a non-classical MHC class Ib molecule that acts as the ligand for the NKG2 A inhibitory receptor present on natural killer ( NK) and CD8+ cells. Peptide binding and stabilization of HLA- E is often considered to signal infection or cell stress. Here we examine the up-regulation of HLA- E in MS brain tissue. Expression is significantly increased in white matter lesions in the brain of MS patients compared with white matter of neurologically healthy controls. Furthermore, using quantitative immunohistochemistry and confocal microscopy, we show increased HLA- E protein expression in endothelial cells of active MS lesions. Non-inflammatory chronic lesions express significantly less HLA- E protein, comparable to levels found in white matter from controls. Increased HLA- E protein levels were associated with higher scores of inflammation. These results suggest the potential for an effect in central nervous system pathogenesis from HLA- E modulation in stressed tissue. Co-localization with infiltrating CD8+ cells implicates a possible role for HLA- E-restricted regulatory CD8+ cells, as has been proposed in other autoimmune diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Narcolepsy-cataplexy syndrome is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. It is strongly associated with the genetic marker, human leucocyte antigen (HLA) DQB1*06:02. A deficit in the endogenous hypocretin/orexin system due to neuronal degeneration in the lateral hypothalamus, induced by an autoimmune-mediated process, is the primary pathophysiology associated with the human disease. The important finding of an association with hypocretin genes in animal models of narcolepsy has led to the establishment of cerebrospinal fluid hypocretin measurements as a new diagnostic test for human narcolepsy. This is a fascinating story of translation of basic science research into clinical practice in sleep medicine during the past decade. Recent advances have shed light on the associations between respiratory medicine and narcolepsy-cataplexy research. The first is that upper airway infections, including H1N1 and/or streptococcal infections, may initiate or reactivate an immune response that leads to loss of hypocretin-secreting cells and narcolepsy in genetically susceptible individuals. The second is that an increased incidence of sleep disordered breathing among narcoleptic subjects may relate to the impairment of central control of breathing, linked to hypocretin deficiency or carriage of HLADQB1*06:02, in animals and human subjects with narcolepsy, respectively, indicating neural dysfunction in an area where respiratory and sleep-wake systems are closely interrelated. [ABSTRACT FROM AUTHOR]

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1* 15:01- DQA1* 01:02- DQB1* 06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1* 06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1* 15:01/3 and DQB1* 06:02 in most populations. In this study, we studied human leucocyte antigen ( HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1* 06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1* 06:02 and DRB1* 15:01, we found that the presence of DQB1* 06:02 and not DRB1* 15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1* 15:01- DQA1* 01:02- DQB1* 06:01 and DRB1* 15:01- DQA1* 01:02- DQB1* 05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1* 01 (non- DQA1* 01:02) and susceptibility effects of DQB1* 03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1* 15:01 has no effect on narcolepsy susceptibility in the absence of DQB1* 06:02. The results are also in line with a previously proposed ' HLA-DQ allelic competition model' that involves competition between non- DQA1* 01:02, non- DQB1* 06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQ α*01:02/ DQ β*06:02 narcolepsy heterodimer to reduce susceptibility. [ABSTRACT FROM AUTHOR]