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The class I and class II Human Leucocyte Antigens (HLA) are an integral part of the host adaptive immune system against viral infections. The characterization of HLA allele frequency in the population can play an important role in determining whether HLA antigens contribute to viral susceptibility. In this regard, global efforts are currently underway to study possible correlations between HLA alleles with the occurrence and severity of SARS-CoV-2 infection. Specifically, this study examined the possible association between specific HLA alleles and susceptibility to SARS-CoV-2 in a population from the United Arab Emirates (UAE). The frequencies of HLA class I (HLA-A, -B, and -C) and HLA class II alleles (HLA-DRB1 and -DQB1); defined using Next Generation Sequencing (NGS); from 115 UAE nationals with mild, moderate, and severe SARS-CoV-2 infection are presented here. HLA alleles and supertypes were compared between hospitalized and non-hospitalized subjects. Statistical significance was observed between certain HLA alleles and supertypes and the severity of the infection. Specifically, alleles HLA-B*51:01 and HLA-A*26:01 showed a negative association (suggestive of protection), whilst genotypes HLA-A*03:01, HLA-DRB1*15:01, and supertype B44 showed a positive association (suggestive of predisposition) to COVID-19 severity. The results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies.

The avoidance of antibody-mediated rejection (AMR) attributed to human leucocyte antigen (HLA) antibody incompatibility remains an essential function of clinical Histocompatibility and Immunogenetics (H&I) laboratories who are supporting solid organ transplantation. Developments in HLA antibody identification assays over the past thirty years have greatly reduced unexpected positive cellular crossmatches and improved solid organ transplant outcomes. For sensitized patients, the decision to register unacceptable HLA antigen mismatches is often heavily influenced by results from solid phase antibody assays, particularly the Luminex® Single Antigen Bead (SAB) assays, although the clinical relevance of antibodies identified solely by these assays remains unclear. As such, the identification of non-clinically relevant antibodies may proportionally increase the number of unacceptable transplant mismatches registered, with an associated increase in waiting time for a compatible organ. We reflect on the clinical relevance of antibodies identified solely by the Luminex SAB® assays and consider whether the application of additional assays and/or tools could further develop our ability to define the clinical relevance of antibodies identified in patient sera. Improvements in this area would assist equity of access to a compatible transplant for highly sensitized patients awaiting a solid organ transplant.

ObjectiveAntibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.MethodsA cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.ResultsCluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/−; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/−; 11/56, 19.6%). LE/− and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10−10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (pInterpretationSymptoms’ distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Objectives Certain human leucocyte antigen (HLA)-B alleles (protective alleles) associate with durable immune control of HIV-1, but with substantial heterogeneity in the level of control. It remains elusive whether viral factors including Nef-mediated immune evasion function diminish protective allele effect on viral control. Design The naturally occurring non-Ser variant at position 9 of HIV-1 subtype C Nef has recently exhibited an association with enhanced HLA-B downregulation function and decreased susceptibility to recognition by CD8 T cells. We therefore hypothesized this Nef genotype leads to diminished immune control mediated by protective HLA alleles. Methods Nef sequences were isolated from HIV-1 subtype C-infected patients harboring protective alleles and several Nef functions including downregulation of HLA-A, HLA-B, CD4, and SERINC5 were examined. Association between Nef non-Ser9 and plasma viral load was examined in two independent South African and Botswanan treatment-naive cohorts. Results Nef clones isolated from protective allele individuals encoding Nef non-Ser9 variant exhibited greater ability to downregulate HLA-B when compared with the Ser9 variant, while other Nef functions including HLA-A, CD4, and SERINC5 downregulation activity were unaltered. By analyzing a cohort of South African participants chronically infected with subtype C HIV-1, Nef non-Ser9 associated with higher plasma viral load in patients harboring protective alleles. Corroboratively, the Nef non-Ser9 correlated with higher plasma viral load in an independent cohort in Botswana. Conclusion Taken together, our study identifies the Nef genotype, non-Ser9 that subverts host immune control in HIV-1 subtype C infection.

Objective: Based on the HLA profile of Indian Gorkhas, Debnath and Chaudhuri (2006) proposed that Gorkhas are genetically closer to Mongoloids, and they may have originated from Mongolians or Tibetan stocks. However, the major limitation of the earlier study was that Gorkhas comprise 2 broad groups, i.e. Tibeto-Burmans and Indo-Aryans. Besides, Gorkhas have an assemblage of many sociocultural and linguistically distinct populations such as Rai, Magar, Limbu, Tamang, Newar, Bahun, Kami, and so on. Thus, the generalization of the findings on Gorkhas by considering them as a single homogenous population may not be free from biases. Therefore, the present study aims to understand the genetic affinity of a constituent population from the Gorkha community, i.e. Kami, based on HLA polymorphism. Methods: First field HLA typing was performed among 158 Kami individuals by PCR-SSP methods. Results: The most frequent genes observed were HLA-A*11, HLA-B*15, HLA-DRB1*15. The frequency of HLA-DRB1*15 reported here is the highest recorded among the North Indian population to date, which is a noteworthy finding of the study. The hierarchical cluster analysis and principal component analysis showed that the Kami population lies within the cluster of the Indian subcontinental population. Conclusion: The study refutes the earlier proposition of exclusive belongingness of all the Gorkhas to Mongoloids.

The novel HLA-C*07:977 allele was characterized using two next generation sequencing technologies. This article is protected by copyright. All rights reserved.

HLA-DQB1*05:236N differs from HLA-DQB1*05:03:01:01 by one nucleotide substitution at codon 34.1 in exon 2.

The novel HLA-A*26:208 allele was characterized using two next generation sequencing technologies.

The novel HLA-B*15:514 allele was characterized using two next-generation sequencing technologies.

Background: There is little experience of human leucocyte antigen (HLA) desensitization in India based on the Luminex single-antigen bead (SAB) testing. We retrospectively analyzed our patients, who underwent HLA desensitization based on Luminex SAB results. Method: Between 2014 and 2018, patients with complement-dependent cytotoxicity cross-match (CDC-XM) negativity but flow cytometry crossmatch (FC-XM) positivity were further analyzed with Luminex SAB for donor-specific antibodies (DSAs). A total of 12 patients who had DSA mean fluorescent intensity (MFI) of >1000 and 2000. All underwent desensitization successfully. Two patients had an increase in posttransplant DSA titers requiring posttransplant PP. The mean follow-up was 26.6 ± 13.9 months. On follow-up, only one patient developed acute T cell-mediated rejection 1 year after transplant, which responded to pulse steroids. There was no graft or patient loss until the last follow-up. Conclusion: This study shows that HLA desensitization is feasible and successful in the Indian setting if patients are properly selected.

HLA-C*02:185 differs from HLA-C*02:02:02:01 by one nucleotide substitution at codon 180 in exon 3.

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However

The anti-HLA antibody detection has been improved in sensitivity and specificity with solid-phase antigen bead (SAB) assays based on Luminex. However, false positive results due to denatured HLA (dHLA) may arise after single antigen test. The aim of this study was to compare the performance of the two Luminex technology-based anti-HLA detection kits available in the market in showing undesired anti-HLA antibody results. A prospective cohort was assessed for anti-HLA antibodies with single antigen A manufacturer (AM) kit and a comparison cohort with single antigen B manufacturer (BM) kit. A total of 11 out of 90 patients in a prospective cohort presented monospecific HLA-I antibodies with AM, and 5 out of 11 confirmed monospecific reaction with BM. Despite the confirmation of monospecific reaction with both manufacturers, 80% were assigned as dHLA reaction by specific crossmatch. Further comparative cohorts detected four out of six monospecific reactions with BM that were confirmed as possible dHLA reactions. A positive SAB test should rule out a reaction against a dHLA molecule, thus avoidance of prolonged waitlist periods or misattribution of anti-HLA reactions after transplantation.

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.

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.

International audience; With more than 16,000 alleles identified, the human leucocyte antigen (HLA) system is one of the most polymorphic regions of the human genome. Regarding the crucial role of HLA compatibility in transplantation and especially in Hematopoietic Stem Cell Transplantation, identification of HLA polymorphisms at a high-resolution level is of major interest. Recently, NGS technology has been proposed which appears to be simpler and more informative than the classical molecular methods such as SSP, SSOr and SBT. In the present report, a new set of NGS reagents and the appropriate associated software for sequence analysis are described. Through different studies, the performances of the system are illustrated and demonstrate that the method herein described overcomes current limitations in performing high-resolution HLA typing in clinical laboratories.

HLA-DQB1*03:01:46 differs from HLA-DQB1*03:01:01:01 by one nucleotide substitution at codon 142.3 in exon 3.

As an immune escape mechanism tumor cells may downregulate expression of Human Leukocyte Antigens (HLA). Loss of HLA class I and class II has been described in various subtypes of diffuse large B cell lymphoma (DLBCL), including the not otherwise specified (NOS) subgroup. 1,2 We analyzed HLA class I and class II expression in DLBCL not otherwise specified (NOS) to investigate whether there is an association between HLA expression, cell of origin (COO) and the recently reported FOXP1 expression in non-GCB DLBCL. 3 This article is protected by copyright. All rights reserved.

Human CD4+ T lymphocytes play an important role in inducing potent immune responses. T cells are activated and stimulated by peptides presented in human leucocyte antigen (HLA)-class II molecules. These HLA-class II molecules typically present peptides of between 12 and 20 amino acids in length. The region that interacts with the HLA molecule, designated as the peptide-binding core, is highly conserved in the residues which anchor the peptide to the molecule. In addition, as these peptides are the product of proteolytic cleavages, certain conserved residues may be expected at the N- and C-termini outside the binding core. To study whether similar conserved residues are present in different cell types, potentially harbouring different proteolytic enzymes, the ligandomes of HLA-DRB1*03:01/HLA-DRB > 1 derived from two different cell types (dendritic cells and EBV-transformed B cells) were identified with mass spectrometry and the binding core and N- and C-terminal residues of a total of 16,568 peptides were analysed using the frequencies of the amino acids in the human proteome. Similar binding motifs were found as well as comparable conservations in the N- and C-terminal residues. Furthermore, the terminal conservations of these ligandomes were compared to the N- and C-terminal conservations of the ligandome acquired from dendritic cells homozygous for HLA-DRB1*04:01. Again, comparable conservations were evident with only minor differences. Taken together, these data show that there are conservations in the terminal residues of peptides, presumably the result of the activity of proteases involved in antigen processing. Electronic supplementary material The online version of this article (10.1007/s00251-019-01129-6) contains supplementary material, which is available to authorized users.

Background Human Leucocyte Antigens (HLA) play a vital role in disease pathogenesis and transplant rejection. HLA-typing is a useful tool in predicting disease progression and to identify potential organ donors. Due to human migration and known ethnic variation, frequent targeted HLA sequencing of specific populations is crucial to increase their representation in global reference panels. Materials and methods We performed a retrospective file audit of all HLA-typings done in our setting from 2005-2019. We discuss data for the major HLA-A, HLA-B, HLA-C, and HLA-DRB1 allele groups. Results Overall, the most common allele groups were HLA-A∗02, HLA-B∗15, HLA-C∗07 and HLA-DRB1∗03. For the African descent group, the most common alleles were HLA-A∗30, HLA-B∗15, HLA-C∗07 and HLA-DRB1∗03. For the European descent group, the most common alleles were HLA-A∗02, HLA-B∗07, HLA-C∗07 and HLA-DRB1∗15. For the mixed ancestry group, the most common allele groups were HLA-A∗02, HLA-B∗15, HLA-C∗02 and HLA-DRB1∗13. HLA-B∗44 was identified as the most common allele group in patients with renal failure. Discussion and conclusion The significant variation within the HLA frequencies between the different ethnic groups highlights the value of population-specific HLA-typing. Furthermore, the identification of HLA-B∗44 as a prominent HLA in our renal failure population warrants in-depth investigation of this group., Human leucocyte antigen, Allele frequency, Transplantation, South Africa.

Summary Human leucocyte antigen (HLA) genes play a central role in response to pathogens and in autoimmunity. Research to understand the effects of HLA genes on health has been limited because HLA genotyping protocols are labour intensive and expensive. Recently, algorithms to impute HLA genotype data using genome-wide association study (GWAS) data have been published. However, imputation accuracy for most of these algorithms was based primarily on training data sets of European ancestry individuals. We considered performance of two HLA-dedicated imputation algorithms – SNP2HLA and HIBAG – in a multiracial population of n = 1587 women with HLA genotyping data by gold standard methods. We first compared accuracy – defined as the percentage of correctly predicted alleles – of HLA-B and HLA-C imputation using SNP2HLA and HIBAG using a breakdown of the data set into an 80% training group and a 20% testing group. Estimates of accuracy for HIBAG were either the same or better than those for SNP2HLA. We then conducted a more thorough test of HIBAG imputation accuracy using five independent 10-fold cross-validation procedures with delineation of ancestry groups using ancestry informative markers. Overall accuracy for HIBAG was 89%. Accuracy by HLA gene was 93% for HLA-A, 84% for HLA-B, 94% for HLA-C, 83% for HLA-DQA1, 91% for HLA-DQB1 and 88% for HLA-DRB1. Accuracy was highest in the African ancestry group (the largest group) and lowest in the Hispanic group (the smallest group). Despite suboptimal imputation accuracy for some HLA gene/ancestry group combinations, the HIBAG algorithm has the advantage of providing posterior estimates of accuracy which enable the investigator to analyse subsets of the population with high predicted (e.g. >95%) imputation accuracy.

Objectives: The aim of this study was to investigate the associations between major histocompatibility complex (MHC) class I and II alleles and disease characteristics in Turkish patients with myasthenia gravis (MG). Subjects and Methods: The MHC class I and II alleles of 108 unrelated MG patients were genotyped. The human leucocyte antigen (HLA) distribution of all MG patients and subgroups of MG patients (grouped according to disease characteristics) was compared to that of 250 healthy controls. Results: Overall distributions of HLA-B*61 and C*05 were more frequent in MG patients (7.4 vs. 2.0% and 14.8 vs. 6.8%, respectively) than in non-MG patients. Subgroup analyses revealed that HLA-DRB1*14 and DQB1*02 alleles were more frequent in early-onset MG [n = 10 (20.8%) vs. n = 25 (10.0%) and n = 21 (43.8%) vs. n = 59 (23.6%)]. In patients seropositive for anti-AchR antibodies, the frequencies of HLA-B*50 and C*05 were higher. HLA-C*05, DRB1*01, and DRB1*11 were higher in patients with ocular MG. In addition, HLA-A*01, A*31, B*08, and DRB1*14 were higher among patients with thymic hyperplasia, whereas DQB1*03 was lower. However, all of these differences lost significance after correction of the p value for multiple comparisons. No allele association was found among patients with thymoma. Strikingly, patients with generalized MG who had pure ocular symptoms at disease onset had significantly increased HLA-B*50 compared to the controls (corrected p < 0.001, OR = 9.92; 95% CI 3.05-32.22). Conclusion: The HLA-B*50 allele was associated with conversion to generalized disease in patients with pure ocular symptoms at disease onset. This finding could extend our understanding of the complex interactions between the pathogenesis of MG and genetic heritage.

Luminex single antigen bead (SAB) assays have become an essential tool in monitoring the status of antibody to the Human Leucocyte Antigen (HLA) of patients both before and after transplantation. In addition SAB data is used to aid risk stratification to assess immunological risk of humoral rejection in solid organ transplantation (CTAG/BTAG guidelines) [1]. Increasingly laboratories are reporting false negative results at high antibody titre due to a prozone effect. Here we report a case study where the prozone effect led to a false negative antibody result that could have resulted in adverse outcome. We describe a method to reliably remove the prozone effect through heat inactivation and the addition of Ethylenediaminetetraacetic acid (EDTA) to the Luminex wash buffer.

Mothers are able to identify the body odour (BO) of their own child and prefer this smell above other BOs. It has hence been assumed that the infantile BO functions as a chemosignal promoting targeted parental care. We tested this hypothesis and examined whether children's BOs signal genetic similarity and developmental status to mothers. In addition, we assessed whether BOs facilitate inbreeding avoidance (Westermarck effect). In a cross-sectional design, N = 164 mothers participated with their biological children ( N = 226 children, aged 0–18 years) and evaluated BO probes of their own and four other, sex-matched children. Those varied in age and in genetic similarity, which was assessed by human leucocyte antigen profiling. The study showed not only that mothers identified and preferred their own child's BO, but also that genetic similarity and developmental status are transcribed in BOs. Accordingly, maternal preference of their own child's odour changes throughout development. Our data partly supported the Westermarck effect: mothers' preference of pubertal boys' BOs was negatively related to testosterone for the own son, but not for unfamiliar children. This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.

Background: Multiple sclerosis (MS) is an autoimmune and demyelinating disease. Genome-wide association studies have shown that MS is associated with many genetic variants in some human leucocyte antigen genes and other immune-related genes, however, those studies were mostly specific to Caucasian populations. We attempt to address whether the same associations are also true for Asian populations by conducting whole-exome sequencing on MS patients from southern China.Methods: Genomic DNA was extracted from the peripheral blood mononucleocytes of 8 MS patients and 26 healthy controls and followed by exome sequencing.Results: In total, 41,227 variants were found to have moderate to high impact on their protein products. After filtering per allele frequencies according to known database, 17 variants with the allele frequency T, Ala322Ser, rs201693690) was found to be a novel missense variant.Conclusion: MS in southern China may have association with unique genetic variants, our data suggest TRIOBP as a potential novel risk gene.

In our recent study published in Proceedings of the Royal Society B [1], we investigated the effects of major histocompatibility complex (MHC; or human leucocyte antigen system, HLA in humans) on men's preferences for women's body odours. Using rigorous methods, we found no evidence that men find body odours of HLA-dissimilar women more attractive than odours of HLA-similar women. In his comment, Wedekind [2] claims that our conclusions were premature, because he found (using our data) a stronger negative relationship between pleasantness and intensity for HLA-dissimilar odours than for similar ones. Although this is an interesting finding, it cannot be considered as a support for HLA-related mate preferences. Wedekind's comment is rather misleading, for various reasons. First, empirical evidence for HLA-mediated body odour preferences in humans is not nearly as clear as the author would like to assume. In the 20 years since Wedekind et al .'s seminal work [3], various studies examining HLA-influences on body odour preferences in humans have been published and the reported findings are mixed. In fact, a recent meta-analysis by Winternitz, Abbate [4] revealed that over all studies with human and non-human primates, results on MHC-mediated body odour preferences are inconsistent and non-significant. It is important to note that Wedekind [2] misinterprets the meta-analysis by Winternitz et al . [4]: These authors found preferences for MHC heterozygosity but not for …

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.

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.

Objectives: To determine the frequency of alloimmunization against human platelet antigens (HPAs) and human leucocyte antigen class 1 (HLA1) in multiparous women and multi-transfused patients. Methods: This prospective study was conducted between January and August 2013, on 50 multiparous women with no history of previous blood transfusion recruited from the Obstetrics and Gynecology Clinic, and 50 patients, who received multiple platelet transfusions, recruited from the Hematology/Oncology Ward, King Khalid University Hospital, Riyadh, Saudi Arabia. Results: The frequency of alloimmunization among multiparous pregnant women was 76%, as follows: 16% against HLA1 only, 8% against HPAs only, 52% against both HPAs and HLA1 antigens. In multi-transfused patients, the rate of alloimmunization was 42% as follows: 2% against HLA1 only, 22% against HPAs only, 18% against both HPAs and HLA1 antigens. The frequency of alloimmunization increases with the number of pregnancies, but not with the number of platelet transfusions. Conclusion: Alloimmunization against HPAs and HLA1 is very common among Saudi multiparous women and multi-transfused patients, which encourages the search for the extent of the possible complications in the fetus and newborn and in multitransfused patients and how to prevent their occurrence. Saudi Med J 2015; Vol. 36 (6): 665-670 doi: 10.15537/smj.2015.6.11153

Natural killer (NK) cells provide a major defence against cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. Also GM allotypes, able to influence the NK antibody-dependent cell-mediated cytotoxicity (ADCC), 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 to gain insight into the immune mechanisms controlling HCMV, we have studied the possible associations among humoral and NK response, 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 GM 3/17 and GM 23 allotypes, along with the 60 subjects with a previous asymptomatic infection as controls. Notwithstanding the presence of missing data record, advanced missing data recovery techniques were able to show that subjects carrying the GM23 allotypes, both in homo- and heterozygosity, 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. This article is protected by copyright. All rights reserved.

Body odours reportedly portray information about an individual's genotype at the major histocompatibility complex (MHC, called human leucocyte antigen, HLA, in humans). While there is strong experimental support for MHC-associated mating behaviour in animals, the situation in humans is more complex. A lot of effort has been spent on testing HLA-associated odour preferences of women. To date, only very few studies have looked at HLA-linked olfactory preferences in men and these studies have revealed inconsistent results. Here, we investigate men's HLA-associated preferences for women's body odours. Importantly, and in contrast to previous studies, these odours were gathered at peak fertility (i.e. just before ovulation) when any HLA-associated odour preferences should be strongest. We scrutinized whether men's preference for women's body odours is influenced by (i) the number of shared HLA alleles between men and women, (ii) HLA heterozygosity, and (iii) the frequency of rare HLA alleles. We found that men could readily differentiate between odours they found attractive and odours they found less attractive, but that these preferences were not associated with HLA. Specifically, men did not prefer odours from women who are HLA dissimilar, HLA heterozygous, or who have rare HLA alleles. Together, these findings suggest that HLA has no effect on men's odour preferences.

Background Brazil has seen a great decline in malaria and the country is moving towards elimination. However, for eventual elimination, the control program needs efficient tools in order to monitor malaria exposure and transmission. In this study, we aimed to evaluate whether seroprevalence to the circumsporozoite protein (CSP) is a good tool for monitoring the exposure to and/or evaluating the burden and distribution of Plasmodium species in the Brazilian Amazon. Methods Cross-sectional surveys were conducted in a rural area of Porto Velho, Rondônia state. Parasite infection was detected by microscopy and polymerase chain reaction. Antibodies to the sporozoite CSP repeats of Plasmodium vivax, P. falciparum, and P. malariae (PvCS, PfCS, and PmCS) were detected using the enzyme-linked immunosorbent assay technique. Human leukocyte antigen (HLA)-DRB1 and DQB1 genes were typed using Luminex® xMAP® technology. Results The prevalence of immunoglobulin G against P. vivax CSP peptide (62%) was higher than P. falciparum (49%) and P. malariae (46%) CSP peptide. Most of the studied individuals had antibodies to at least one of the three peptides (72%), 34% had antibodies to all three peptides and 28% were non-responders. Although the majority of the population was not infected at the time of the survey, 74.3% of parasite-negative individuals had antibodies to at least one of the CSPs. Importantly, among individuals carrying the haplotypes DRB1*04~DQB1*03, there was a significantly higher frequency of PfCS responders, and DRB1*16~DQB1*03 haplotype for PvCS and PfCS responders. In contrast, HLA-DRB1*01 and HLA-DQB1*05 allelic groups were associated with a lack of antibodies to P. vivax and P. falciparum CSP repeats, and the haplotype DRB1*01~DQB1*05 was also associated with non-responders, including non-responders to P. malariae. Conclusions Our results show that in low transmission settings, naturally acquired antibody responses against the CSP repeats of P. vivax, P. falciparum, and P. malariae in a single cross-sectional study may not represent a valuable marker for monitoring recent malaria exposure, especially in an area with a high prevalence of P. vivax. Furthermore, HLA class II molecules play an important role in antibody response and require further study with a larger sample size. It will be of interest to consider HLA analysis when using serosurveillance to monitor malaria exposure among genetically diverse populations. Electronic supplementary material The online version of this article (10.1186/s40249-018-0428-1) contains supplementary material, which is available to authorized users.

Objectives: Overexpression of human leukocyte antigen G (HLA-G) in several malignant tumors has been reported. The aim of our study was to investigate HLA-G expression in colorectal cancer tumors and determine HLA-G expression relation between clinico-pathological characteristics and survival time. Methods: HLA-G expression was evaluated by immunohistochemistry (IHC) using anti-HLA-G antibody in 100 primary tumors of colorectal cancer with different stages. Results: Our results showed that 25% of the colorectal cancer tissues had positive HLA-G expression and 75% no stained with anti-HLA-G antibody. The HLA-G expression in advanced stages (III and IV) was more prevalent than those in earlier clinical stages (I and II) (P = 0.0001). Results showed that HLA-G expression can serve as an independent factor for overall survival (OS). In this study, patients with HLA-G expression had significantly shorter survival time than those with negative expressions (P = 0.023). Conclusions: HLA-G expression can serve as an independent factor for OS and its expression may be directly related to aggressive tumor behavior via escape from the host antitumor immune defense. Protein expression of HLA-G correlates with poor prognosis in colorectal cancer.

Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices.

Summary Whole-organ pancreas transplantation is typically carried out using a Y-graft derived from the donor iliac vessels. We describe a case in which a 31-year-old male underwent a simultaneous pancreas-kidney transplant, but in which vessels from a different donor were used for the arterial anastomosis of the pancreas graft. Although initially there was good function, 18 months post-transplant the patient was admitted with diabetic ketoacidosis secondary to pancreas graft failure. Radiological investigations revealed complete occlusion of the vascular Y-graft, and laboratory investigations demonstrated donor-specific human leucocyte antigen (HLA) antibodies directed against HLA mismatches of the vessel donor. This case highlights the risks of using allogeneic vascular material for surgical anastomoses.

We thank Marotte et al 1 for their interest in our study.2 They suggested to check interactions between Porphyromonas gingivalis serology, smoking and human leucocyte antigen (HLA) status as in the Etude et Suivi des Polyarthrites Indifferenciees Recentes (ESPOIR) cohort and the association between P. gingivalis serology status and radiological progression. In the ESPOIR cohort, P. gingivalis serology was increased in patients who are non-smokers and with structural damage.3 As suggested, we checked interactions …

Summary Five patients with active disseminated vitiligo were given 1 g of a chimeric (murine/human) monoclonal antibody to CD20 in a single intravenous infusion and followed-up for 6 months. Three of the patients showed an overt clinical and histological improvement of the disease, one presented slight improvement and the remaining patient showed no changes. Improvement was neither associated with changes in laboratory parameters nor to a specific human leucocyte antigen D-related (HLA-DR) phenotype. We believe that these preliminary results are encouraging, and further clinical trials should be undertaken. An important aim should be the finding of a marker with a good response to this therapeutic approach.

Summary Antibodies recognizing denatured human leucocyte antigen (HLA) can co-react with epitopes on intact HLA or recognize cryptic epitopes which are normally unaccessible to HLA antibodies. Their specificity cannot be distinguished by single antigen beads (SAB) alone, as they carry a mixture of intact and denatured HLA. In this study, we selected pretransplant sera containing donor-specific HLA class I antibodies (DSA) according to regular SAB analysis from 156 kidney transplant recipients. These sera were analysed using a SAB preparation (iBeads) which is largely devoid of denatured HLA class I, and SAB coated with denatured HLA class I antigens. A total of 241 class I DSA were found by regular SAB analysis, of which 152 (63%) were also found by iBeads, whereas 28 (11%) were caused by reactivity with denatured DNA. Patients with DSA defined either by regular SAB or iBeads showed a significantly lower graft survival rate (P = 0·007) compared to those without HLA class I DSA, whereas reactivity to exclusively denatured HLA was not associated with decreased graft survival. In addition, DSA defined by reactivity to class I SAB or class I iBeads occurred more frequently in female patients and in patients with historic HLA sensitization, whereas reactivity to denatured HLA class I was not associated with any of these parameters. Our data suggest that pretransplant donor-specific antibodies against denatured HLA are clinically irrelevant in patients already sensitized against intact HLA.

OBJECTIVE HIV-1 escape from cytotoxic T-lymphocytes results in the accumulation of human leucocyte antigen (HLA)-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of cytotoxic T-lymphocyte escape in a cohort followed from infection for 5 years. METHODS Viral loads and CD4 cell counts were monitored in 78 subtype C-infected individuals from onset of infection until CD4 cell count decline to less than 350 cells/μl or 5 years postinfection. The gag gene was sequenced and HLA-associated changes between enrolment and 12 months postinfection were mapped. RESULTS HLA-associated escape mutations were identified in 48 (62%) of the participants and were associated with CD4 decline to less than 350 cells/μl (P = 0.05). Escape mutations in variable Gag proteins (p17 and p7p6) had a greater impact on disease progression than escape in more conserved regions (p24) (P = 0.03). The association between HLA-associated escape mutations and CD4 decline was independent of protective HLA allele (B57, B58 : 01 and B81) expression. CONCLUSION The high frequency of escape contributed to rapid disease progression in this cohort. Although HLA-adaption in both conserved and variable Gag domains in the first year of infection was detrimental to long-term clinical outcome, escape in variable domains had greater impact.

Illumina first introduced their TruSight human leucocyte antigen (HLA) next-generation sequencing (NGS) typing kit in 2015 and subsequently followed up with a new version in 2016. Here we report on our experience comparing the two versions of the Illumina HLA NGS kits.

Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.

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 NKG2A 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.

Human leucocyte antigen (HLA) loci have a complex evolution where both stochastic (e.g. genetic drift) and deterministic (natural selection) forces are involved. Owing to their extraordinary level of polymorphism, HLA genes are useful markers for reconstructing human settlement history. However, HLA variation often deviates significantly from neutral expectations towards an excess of genetic diversity. Because HLA molecules play a crucial role in immunity, this observation is generally explained by pathogen-driven-balancing selection (PDBS). In this study, we investigate the PDBS model by analysing HLA allelic diversity on a large database of 535 populations in relation to pathogen richness. Our results confirm that geographical distances are excellent predictors of HLA genetic differentiation worldwide. We also find a significant positive correlation between genetic diversity and pathogen richness at two HLA class I loci (HLA-A and -B), as predicted by PDBS, and a significant negative correlation at one HLA class II locus (HLA-DQB1). Although these effects are weak, as shown by a loss of significance when populations submitted to rapid genetic drift are removed from the analysis, the inverse relationship between genetic diversity and pathogen richness at different loci indicates that HLA genes have adopted distinct evolutionary strategies to provide immune protection in pathogen-rich environments.

The frequencies of human leucocyte antigen (HLA)-A, -B and -DRB1 alleles and haplotypes were statistically analysed among 3238 donors from Chinese Marrow Donor Program (CMDP) Jiangsu Branch. All donors were typed using polymerase chain reaction-sequence-based typing (PCR-SBT) method or polymerase chain reaction-reverse sequence-specific oligonucleotide probe (PCR-rSSOP) method. As a result, a total of 46 A, 85 B and 51 DRB1 alleles were found in Jiangsu population. The first three frequent alleles in HLA-A, -B and -DRB1 loci respectively were A*11:01(16.52%), A*24:02(15.10%) and A*02:01(13.02%); B*13:02(11.60%), B*46:01(8.89%) and B*58:01(7.12%); and DRB1*07:01(15.78%), DRB1*09:01(15.26%) and DRB1*15:01(9.76%). The top two frequent A-B-DRB1 haplotypes were A*30:01-B*13:02-DRB1*07:01(8.87%) and A*02:07-B*46:01-DRB1*09:01(2.79%); the top three A-B haplotypes were A*33:03-B*58:01-DRB1*03:01(2.59%), A*30:01-B*13:02(9.92%) and A*33:03-B*58:01(5.48%); the top two B-DRB1 haplotypes were B*13:02-DRB1*07:01(10.23%) and B*46:01-DRB1*09:01(4.61%); the top two A-DRB1 haplotypes were A*30:01-DRB1*07:01(8.96%) and A*33:03-DRB1*13:02(3.95%). These findings provided useful information in the study of genetics and anthropology in Chinese Han population. It also served as a basic guide for selection of future donors in CMDP Jiangsu Branch.

Coeliac disease is a widespread, lifelong disorder for which dietary control represents the only accepted form of therapy. There is an unmet need for nondietary therapies to treat this condition. Most ongoing and emerging drug-discovery programmes are based on the understanding that coeliac disease is caused by an inappropriate T-cell-mediated immune response to dietary gluten proteins. Recent genome-wide association studies lend further support to this pathogenic model. The central role of human leucocyte antigen genes has been validated, and a number of new risk loci have been identified, most of which are related to the biology of T cells and antigen-presenting cells. Here, we review the status of potential nondietary therapies under consideration for coeliac disease. We conclude that future development of novel therapies will be aided considerably by the identification of new, preferably noninvasive, surrogate markers for coeliac disease activity.

Summary New human leucocyte antigen (HLA) alleles are assigned largely based on their sequence homologies due to lack of information on the serological reactivities. Artificial neural networks (ANNs) have been tested as a possible tool for helping to predict the serology of new alleles in the absence of serological information. However, an ANN analysis per se imparts no information regarding which residues are important in determining serological specificity. To address this issue, we extracted ANN weights of HLA residues. The ANN was trained using 139 HLA-A, 302 HLA-B and 136 HLA-DRB1 alleles, for which serological specificities were assigned in the 2004 Nomenclature Report. When the trained ANN was evaluated using alleles that were contained in the HLA Dictionary 2008 but had not been employed in the training set, the accuracy was 91% (29/32) for HLA-A, 91% (40/44) for HLA-B and 90% (9/10) for HLA-DR. Finally, ANN residue weights were extracted by summing the weights of directly connected ANN nodes. When we assessed the significance of the ANN residue weights by comparing our data with the results of epitope studies conducted by El-Awar and colleagues, we found that the ANN weights tended to be high at the epitopes described by El-Awar et al. Furthermore, the ANN weights extracted in this work could be used to explain ambiguous characteristics of serological specificities to some extent. Our data are thus considered to support the results of the epitope studies conducted by El-Awar and advance our understanding of the ambiguous serological specificities of some alleles.