HLA-A Locus Research Articles

The Influence of HLA Alleles on the Affective Distress Profile.

(1) Background: Affective distress can be triggered by aggressive stimuli with an unfavorable role for the individual. Some of the factors that lead to the development and evolution of a mental disorder can be genetic. The aim of this study is to determine some correlations between the human leukocyte antigen (HLA) genes and the affective distress profile (PDA). (2) Methods: A psychological assessment and testing tool for anxiety was applied to 115 people. The low-resolution HLA alleles of class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1 and HLA-DQB1) were identified by the PCR technique after DNA extraction from the blood. Depending on the PDA, the subjects were divided into two groups: a group with a low PDA and another one with a medium and high PDA. The IBM SPSS software was used to compare the frequency of HLA alleles between the two groups. (3) Results: The univariate analysis revealed a significant association of the HLA-A locus (A*01, A*30), HLA-B (B*08), and HLA-DRB1 (DRB1*11) with the low PDA group and of the HLA-A locus (A*32), HLA-B (B*52), and HLA-C (C*12) with the medium and high PDA group. (4) Conclusions: The present study highlighted potential associations between HLA alleles and anxiety disorders.

Simultaneous genotyping for human platelet antigen systems and HLA-A and HLA-B loci by targeted next-generation sequencing.

In order to treat the alloimmunization platelet transfusion refractoriness (PTR), human leukocyte antigen (HLA)-type and/or human platelet antigen (HPA)-type matched platelets between donors and patients are usually used. Therefore, genotyping of HLA-A and HLA-B loci, as well as HPA systems, for donors and patients, is of great significance. However, there is a rare report of genotyping for HLA-A and HLA-B loci as well as HPA systems at the same time. In this study, a high-throughput method for simultaneous genotyping of HLA-A and HLA-B loci, as well as HPA genotyping, was developed. A RNA capture probe panel was designed covering all exon sequences of the GP1BA, GP1BB, ITGA2, CD109, ITGB3, and ITGA2B genes and HLA-A and HLA-B loci. The HLA-A, HLA-B, and 34 HPA systems were genotyped using a targeted next-generation sequencing (NGS) method. The genotypes of the HLA-A and HLA-B loci, as well as the HPA, were assigned based on the nucleotides in the polymorphism sites. Using the NGS method, 204 unrelated blood specimens were successfully genotyped for all 34 HPA systems as well as HLA-A and HLA-B loci. The accuracy of the NGS method was 100%. Only HPA-2, HPA-3, HPA-5, HPA-6w, HPA-15, and HPA-21w showed polymorphism with frequencies of 0.9412, 0.6863, 0.9853, 0.9779, 0.4314, and 0.9951 for a allele, respectively. Thirty-two single nucleotide variants (SNVs) were detected. Of them, 12 SNVs can lead to amino acid change. HLA-A*11:01 and HLA-B*46:01 are the most common alleles for HLA-A and HLA-B loci. A targeted next-generation sequencing method for simultaneously genotyping HPA systems and HLA-A and HLA-B loci was first established, which could be used to create a database of HLA-typed and/or HPA-typed unrelated donors.

Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade-resistant Melanoma for Anti-PD-L1 Rechallenge.

Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma. A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed. The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87-21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67-86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration. Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma. There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.

HLA homozygosity is associated with Non-Hodgkin lymphoma

The “heterozygote advantage” hypothesis has been postulated regarding the role of human leukocyte antigen (HLA) in non-Hodgkin lymphoma (NHL), where homozygous loci are associated with an increased risk of disease. In this retrospective study, we analyzed the HLA homozygosity of 3789 patients with aplastic anemia (AA), acute lymphocytic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) at HLA-A, B, C, DRB1 and DQB1 loci compared to 169,964 normal controls. HLA homozygosity at one or more loci was only associated with an increased risk in NHL patients (OR = 1.28, 95% CI [1.09, 1.50], p = 0.002). This association was not seen in any of the other hematologic diseases. Homozygosity at HLA-A alone, HLA-B + C only, and HLA-DRB1 + DQB1 only was also significantly associated with NHL. Finally, we observed a 17% increased risk of NHL with each additional homozygous locus (OR per locus = 1.17, 95% CI [1.08, 1.25], p trend = 2.4 × 10−5). These results suggest that reduction of HLA diversity could predispose individuals to an increased risk of developing NHL.

O-312 Does infertility relate to Human Leucocyte Antigen similarity? – a genetic analysis based on 609 couples

Abstract Study question Do infertile couples differ from the average population in Human Leukocyte Antigen (HLA) similarity? Summary answer Infertile couples share a significantly higher number of genes than expected by chance in four out of six HLA loci. What is known already HLA genes encode the peptides for the formation of the innate immune system and are highly polymorphic. To allow increased variability of the innate immune system for the offspring, it is necessary that the parental alleles of the HLA complex are dissimilar. In animal studies, such mechanisms have been shown to play a role in mate choice. While some large studies show that humans in Western cultures do not engage in HLA-based mate choice, it has also long been hypothesized that a couple's fertility and pregnancy outcome is influenced by the degree of HLA similarity. Study design, size, duration A multicenter study including a total number of 609 couples was performed between May 2020 and November 2021 at a private fertility center and a department of reproductive medicine of a university clinic. All couples were diagnosed with primary infertility prior to assisted reproductive techniques. Buccal swab samples were provided by both partners to determine HLA profiles. Participants/materials, setting, methods Primary infertile couples (mean age women: 34.35 years, men: 37.59 years) were recruited before undergoing IVF or ICSI therapy. Couples with former pregnancies, tubal factor, azoospermia or donor therapies were excluded. Six different HLA genes (HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) were analysed using next-generation sequencing. Subsequently the number of HLA similarities was determined per couple. Comparison against chance level was performed using a random permutation approach with 100,000 repetitions. Main results and the role of chance Our analysis revealed a higher degree of HLA similarity in infertile couples, than expected by chance, for the loci HLA-C, -DPB1, -DRB1 and HLA-DQB1, but not for the loci HLA-A and HLA-B. A priori power analysis was performed to statistically ensure a small effect size at a � = 0.05 ������������ 1 − � = 0.95 and resulted in a number of 536 couples. Limitations, reasons for caution Conclusions are limited due to the inclusion of predominantly Caucasian couples. Wider implications of the findings This study adds new evidence to former publications with small study groups. HLA similarities may be a contributing factor to primary infertility. Further on, we will examine whether HLA similarities relate to success rates of infertility treatment and outcome of pregnancies. Trial registration number not applicable

Abstract LB176: Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network identifies microenvironment features as drivers of metastasis

Abstract Background: Metastatic breast cancer (MBC) patients often have short survival, and successful treatment represents one of the most challenging aspects of cancer care. This poor prognosis is likely multifactorial, including increased clonal heterogeneity, drug resistance mechanisms, and alterations of the tumor microenvironment. Methods: The primary data source was multi-platform data coming from the AURORA US Project that includes RNAseq, DNAseq, and DNA methylation arrays, which assayed 55 MBC patients representing 51 primary cancers and 102 linked metastatic specimens. In addition, RNA sequencing data from two other datasets of primary tumor-metastasis pairs were also used (i.e. UNC Tumor Donation Program/RAP dataset (24 primary and 74 metastasis specimens), and the GEICAM/2009-03 ConvertHER trial dataset (102 primaries and 102 metastatic pairs)). In total, this combined RNAseq dataset contained 177 primary tumors and 278 metastases, including 28 liver, 18 lung, 12 brain, and 24 lymph node metastases. We used these data to address two pressing questions, namely: 1) do gene expression features vary in primary tumors vs metastases according to PAM50 expression subtype, and 2) do gene expression features vary according to site of metastasis. Results: Using the AURORA multi-platform data, we determined that 17% of metastatic tumors (mainly TNBC/Basal-like) showed reduced expression of HLA-A that was associated with DNA methylation and/or focal DNA deletions near the HLA-A locus; these methylated tumors also showed concomitant lower immune cell infiltrates. Reduced expression of HLA-A gene and immune cell infiltrates were also validated at the RNA level in RAP dataset. Next, RNA expression differences were examined using the combined data set and varied according to tumor subtype. ER+/Luminal metastases had lower fibroblast and endothelial cell content, while triple negative (TNBC)/Basal-like metastases showed a dramatic decrease in T cell and B cell signatures/features. Comparative analyses between primary and site-specific metastasis (i.e., primary vs liver metastasis) or between sites of metastases (i.e., liver vs lung metastasis) revealed that both liver and brain, on average, had low immune cell features regardless of the primary tumor phenotype. Even within the same patient, we detected low immune cell features in brain and liver metastases compared to lung and lymph node metastases. Lastly, liver metastases showed a gain of Luminal B/HER2E gene expression features and MYC targets, and brain TNBC metastasis showed a gain of cell differentiation/Luminal-related gene signatures. Conclusions: These findings could have direct implications for the treatment of MBC patients with immune-based therapies and suggest new therapeutic avenues depending upon the tumor metastasis phenotype, and site of metastasis. Citation Format: Susana Garcia Recio, Toshinori Hinoue, Gregory L. Wheeler, Benjamin J. Kelly, Justin M. Balko, Katherine A. Hoadley, Peter W. Laird, Elaine R. Mardis, Charles M. Perou. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network identifies microenvironment features as drivers of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB176.

Ethnic diversity and cord blood banking: satisfying the unmet need

Background aimsIn this study, the authors sought to assess whether cord blood units (CBUs) collected from donors of non-European ethnic backgrounds are utilized for umbilical cord blood transplantation (UCBT) at a different rate than those of European ethnic backgrounds. The authors also examined potential methods of enriching these under-represented ethnic backgrounds in cord blood bank (CBB) inventories without increasing financial overheads and without compromising total inventory utilization or post-transplant outcomes. MethodsData from N = 6506 searchable or shipped Anthony Nolan Cell Therapy Centre grafts were used in this study. Banked grafts were graded from A+ to D based on total nucleated cell and CD34+ cell content. Utilizations of each grade group were further stratified by graft ethnic background. The Mantel–Cox log-rank test was performed in conjunction with Kaplan–Meier survival analysis to compare utilization rates and post-transplant outcomes. For shipped grafts, levels of HLA matching at HLA-A, HLA-B and HLA-DR loci were also analyzed by graft ethnic background and grade using data from the Eurocord/EBMT registry. ResultsOverall utilization of non-European grafts did not significantly differ from that of European grafts (2.5% versus 2.2%, P = 0.23). However, significant differences were found when stratifying utilization rates by cell content. The probability of non-European D grade grafts being utilized was 3-fold higher than that of European D grade grafts (1.1% versus 0.4%, P = 0.03) and comparable to that of European C grade grafts (1.1% versus 0.9%, P = 0.90). No significant differences were found between D and C grade grafts in terms of overall survival (OS) (P = 0.12), in part due to a disproportionate utilization of D grade grafts for pediatric UCBT (74% versus 39%, age difference P < 0.001). Furthermore, non-European graft shipments were 4-fold less likely to be a 6/6 HLA match to their recipients relative to European graft shipments (7% versus 29%). ConclusionsThe authors have identified a niche for CBUs of low cell content collected from donors of non-European ethnic backgrounds that has been overlooked by previous studies. Banking of these CBUs for pediatric UCBT instead of CBUs from European donors containing modestly higher cell content is an ethical approach to increasing the ethnic diversity of CBB inventory—and, consequently, the probability of non-European recipients finding a 6/6 HLA-matched graft—without compromising post-transplant OS or overall rate of inventory utilization.

Generation of hypoimmunogenic induced pluripotent stem cells by CRISPR-Cas9 system and detailed evaluation for clinical application

In order to expand the promise of regenerative medicine using allogeneic induced pluripotent stem cells (iPSCs), precise and efficient genome editing of human leukocyte antigen (HLA) genes would be advantageous to minimize the immune rejection caused by mismatches of HLA type. However, clinical-grade genome editing of multiple HLA genes in human iPSC lines remains unexplored. Here, we optimized the protocol for good manufacturing practice (GMP)-compatible CRISPR-Cas9 genome editing to deplete the three gene locus (HLA-A, HLA-B, and CIITA genes) simultaneously in HLA homozygous iPSCs. The use of HLA homozygous iPSCs has one main advantage over heterozygous iPSCs for inducing biallelic knockout by a single gRNA. RNA-seq and flow cytometry analyses confirmed the successful depletion of HLAs, and lineage-specific differentiation into cardiomyocytes was verified. We also confirmed that the pluripotency of genome-edited iPSCs was successfully maintained by the three germ layers of differentiation. Moreover, whole-genome sequencing, karyotyping, and optical genome mapping analyses revealed no evident genomic abnormalities detected in some clones, whereas unexpected copy number losses, chromosomal translocations, and complex genomic rearrangements were observed in other clones. Our results indicate the importance of multidimensional analyses to ensure the safety and quality of the genome-edited cells. The manufacturing and assessment pipelines presented here will be the basis for clinical-grade genome editing of iPSCs.

Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n=4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6×107/kg and .8×105/kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection.

Human Leukocyte Antigen-A, B, and DRB1 Diversity in Renal Transplant Patients and Donors

Background: The understanding of transplant acceptance or rejection derives directly from knowing human leukocyte antigen (HLA) involved in the immune response. The HLA of the major histocompatibility complex contains a numerous family of genes located on the short arm of the chromosome number 6 and divided majorly into two classes, Class I (HLA-A, B, and C) and Class II (HLA-DR, DQ, and DP). The detection and detailed information of these histocompatibility genes are essential for the better outcome of organ transplants. Aims and Objectives: The aim of the present study is to analyze the frequencies of HLA-A, B, and DRB1 in chronic kidney disease (CKD) patients and their prospective donors as well as to see the prevalence of heterogenicity. Materials and Methods: A total of 264 patients diagnosed with CKD and 333 potential donors were studied retrospectively in the present study. All these cases were analyzed for HLA-A, B, and DRB1 loci typing by PCR-SSOP method based on the Luminex platform. Results: We identified 15 different alleles of HLA-A, 29 of HLA-B, and 13 of HLA-DRB1 amongst studied samples. Out of these identified HLA alleles, HLA-A*02, HLA-B*35, and HLA-DRB1*15 were more frequent as compared to others. The results showed significant heterogenicity in the identified HLA-A, B, and DRB1alleles. Conclusion: The result highlights the diversity of HLA-A, B, and DRB1 alleles and is valuable as a reference for organ transplantations. Further, these findings can also guide in better donor selection and hence improved transplant outcome. In addition, this information could be a starting point for the development of an indigenous transplant assay kit.

Alloimmunity to Class 2 Human Leucocyte Antigens May Reduce HIV-1 Acquisition - A Nested Case-Control Study in HIV-1 Serodiscordant Couples.

Enveloped viruses, including the Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as human leucocyte antigens (HLA) into their envelope. Pre-existing antibodies against HLA, termed HLA antibodies, may bind to these surface proteins and reduce viral infectivity. Related evidence includes macaque studies which suggest that xenoimmunization with HLA antigens may protect against simian immunodeficiency virus infection. Since HIV gp120 shows homology with class 2 HLA, including shared affinity for binding to CD4, class 2 HLA antibodies may influence HIV acquisition via binding to gp120 on the viral envelope. We conducted a nested case-control study on HIV serodiscordant couples, comparing the frequency of HLA antibodies among highly exposed persistently seronegative controls with those who went on to acquire HIV (HIV-seroconverters). We first performed low resolution HLA typing on 143 individuals who were HIV-infected at enrollment (index partners) and their corresponding sexual partners (115 highly exposed persistently seronegative individuals and 28 HIV-seroconverters). We then measured HLA class 1 and 2 antibodies in the highly exposed persistently seronegative individuals and HIV-seroconverters at early and late timepoints. We analyzed whether such antibodies were directed at HLA specificities of their HIV-infected index partners, and whether autoantibodies or complement-fixing class 2 HLA antibodies were present. Seventy-nine percent of highly exposed persistently seronegative individuals had HLA antibodies; 56% against class 1 and 50% against class 2 alleles. Half of the group of highly exposed persistently seronegative individuals, prior to seroconversion, expressed class 2 HLA antibodies, compared with only 29% of controls (p=0.05). HIV infection was a sensitizing event leading to de novo development of antibodies against HLA-A and HLA-B loci, but not against class 2 loci. HLA autoantibodies were present in 27% of highly exposed persistently seronegative individuals. Complement-fixing class 2 HLA antibodies did not differ significantly between highly exposed persistently seronegative individuals and seroconverters. In multivariable regression, presence of class 2 HLA antibodies at early timepoints was associated with reduced odds of HIV acquisition (odds ratio 0.330, confidence interval 0.112-0.976, p=0.045). These epidemiological data suggest that pre-existing class 2 HLA antibodies were associated with reduced odds of HIV acquisition.

How is transfusion-associated graft-versus-host disease similar to, yet different from, organ transplantation-associated graft-versus-host disease?

Graft-versus-host disease (GVHD) is a rare, usually fatal complication following blood transfusion or organ transplantation, namely transfusion-associated GVHD (TA-GVHD) and organ transplantation-associated GVHD (OA-GVHD). The dominant mechanism of GVHD is exposure to viable donor lymphocytes that are not recognized as foreign by, but able to respond to, the recipient. The clinical features and relative risk factors of either TA-GVHD or OA-GVHD are yet to be fully understood. The current review article aims to discuss and summarize the similarities and differences between TA-GVHD and OA-GVHD to gain a deeper understanding of the pathogenesis.It is evident that the shared human leukocyte antigens (HLA) between donor and recipient and immunocompromised status of the recipient are the two main risk factors for the development of both TA-GVHD and OA-GVHD. In particular, the homozygous donor with donor-dominant one-way matching at the three loci HLA-A, -B, and -DR has a high risk of developing GVHD following liver transplantation, and such donors should be excluded to prevent it. However, the development of GVHD is thought to be related to a combination of several risk factors, and the contribution of each risk factor remains unknown. Further studies are warranted to determine the important contributing factors that lead to an accurate prediction of GVHD development.

High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients.

BackgroundThe diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury.MethodsWe identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes.ResultsTotal PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003).ConclusionsHigh PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.

HLA class I and II alleles profile in Indian patients with aplastic anemia

Several HLA allele associations with aplastic anemia have been reported around the world. However, due to a lack of such association studies in the Indian population, the current study looked at the frequency of HLA class I (A, B, and C loci) and II (DRB1 and DQB1 loci) with aplastic anemia to see if there was an association between the HLA allele and the disease. A total of 49 aplastic anemia patients (cases) and 100 healthy participants (controls) were included in the study. All of these samples were HLA typed for HLA-A, -B, -C, -DRB1, and DQB1 loci using a polymerase chain reaction sequence-specific oligonucleotide probe approach. A positive association of HLA-DRB1*15:02 (p = 0.00001269, OR = 4.275), was found with AA. Whereas HLA-C*07:01 (p = 0.0017318, OR = 0.179) and HLA-DQB1*02:01 (p = 0.00017033, OR = 0.371) were found to be negatively associated. Our findings are the first to show an association between class I and II HLA alleles and aplastic anemia in the Indian population, and they can be used to further investigate aplastic anemia studies.

Clinical, Biochemical, Genetic, and Therapeutic Profile of Patients with Epidermal Necrolysis: A Descriptive Study.

Epidermal necrolysis (SJS/TEN) is a rare but acute severe drug reaction associated with high morbidity and mortality rates. To describe the clinical, molecular, biochemical, and therapeutic profile of these patients. A total of 24 acute SJS/TEN patients were recruited during their hospital stay and detailed clinical history and treatment course recorded. Blood samples collected were subjected to DNA and serum separation for molecular and biochemical analysis. Of 24 patients, 18 (75%) were females and six (25%) were males with six SJS, six SJS-TEN overlap, and 12 TEN cases. The inciting drugs were non-steroidal anti-inflammatory (87.50%; n = 21) followed by antibiotics (66.67%; n = 16), antiepileptics (37.50%; n = 9), and others (37.50%; n = 9). Seventeen patients (77.2%) showed skin eruptions within 7 days after drug intake. Different co-morbidities were observed in 22 (91.6%) and 20 (83.3%) patients showed ocular manifestations. Length of hospital stay ranged from 8 to 55 days, 20 (83.3%) patients were treated with corticosteroids, and four (16.6%) received antimicrobial therapy. Interleukin polymorphisms revealed significantly low frequency of IL-4 in the patients, HLA-A locus typing revealed higher frequency of HLA-A*3301 (20.8%), HLA-A*02 (25%), HLA-A*2402 (14.6%), and sera showed raised levels of granulysin and sFas L in the patients compared to controls. The preliminary study illustrates the clinical, molecular, and biochemical features of acute SJS/TEN and provides a better understanding that helps to improve patient care at an earlier stage. It also highlights the use of corticosteroids and antimicrobial therapy for effective treatment of patients.

The Impact of Letermovir (LTV) Prophylaxis on Early Cytomegalovirus Infection (CMVi) and Outcomes in the Adult Allogeneic Hematopoietic Cell Transplantation (alloHCT) Recipients with High-Risk Donor Type

The Impact of Letermovir (LTV) Prophylaxis on Early Cytomegalovirus Infection (CMVi) and Outcomes in the Adult Allogeneic Hematopoietic Cell Transplantation (alloHCT) Recipients with High-Risk Donor Type

LATIN AMERICAN GENOMICS CONSORTIUM: AN INTRODUCTION

A total of 125 Costa Ricans of Amerindian descent were genotyped at high-resolution for the human leukocyte antigen loci HLA-A, -B, -C, and -DRB1 using sequence-based typing methods. The respective allele and extended haplotype frequencies, as well as Hardy-Weinberg proportions were calculated. The most frequent extended haplotype identified was A*24:02:01-B*40:02:01-C*03:05-DRB1*04:07:01G, with an estimated frequency of 8.26%. A deviation from Hardy-Weinberg Equilibrium was detected at the DRB1 locus (p = 0.099). The HLA genotypic data of the population sample reported here are available publicly in the Allele Frequencies Net Database under the population name “Costa Rica Amerindians” and the identifier AFN3608.

Predominant HLA Alleles and Haplotypes in Mild Adverse Drug Reactions Caused by Allopurinol in Vietnamese Patients with Gout.

Allopurinol (ALP) is commonly used as a drug for gout treatment. However, ALP is known to cause cutaneous adverse reactions (CARs) in patients. The HLA-B*58:01 allele is considered a biomarker of severe CAR (SCAR) in patients with gout, with symptoms of Stevens Johnson syndrome, and with toxic epidermal necrolysis. However, in patients with gout and mild cutaneous adverse drug reactions (MCARs), the role of HLA-allele polymorphisms has not been thoroughly investigated. In this study, 50 samples from ALP-tolerant patients and ALP-induced MCARs patients were genotyped in order to examine the polymorphisms of their HLA-A and HLA-B alleles. Our results showed that the frequencies of HLA-A*02:01/HLA-A*24:02 and HLA-A*02:01/HLA-A*29:01, the dual haplotypes in HLA-A, in patients with ALP-induced MCARs were relatively high, at 33.3% (7/21), which was HLA-B*58:01-independent, while the frequency of these dual haplotypes in the HLA-A locus in ALP-tolerant patients was only 3.45% (1/29). The HLA-B*58:01 allele was detected in 38% (8/21) of patients with ALP-induced MCARs, and in 3.45% (1/29) of ALP-tolerant patients. Notably, although HLA-B*58:01 may be a cause for the occurrence of MCARs in patients with gout, this correlation was not as strong as that previously reported in patients with SCAR. In conclusion, in addition to the HLA-B*58:01 allele, the presence of the dual haplotypes of HLA-A*02:01/HLA-A*24:02 and/or HLA-A*02:01/HLA-A*29:01 in the HLA-A locus may also play an important role in the appearance of ALP-induced MCARs in the Vietnamese population. The obtained primary data may contribute to the development of suitable treatments for patients with gout not only in Vietnam but also in other Asian countries.

Different Aspects Concerning Viral Infection and the Role of MHC Molecules in Viral Prevention

Major Histocompatibility Complex (MHC) molecules play a crucial role in inducing an adaptive immune response. T-cell epitopes require compatible MHC molecules to form MHC-peptide Complexes (pMHC) that activate the T-cell Receptors (TCR) of T-lymphocyte clones. MHCs are polymorphic molecules with wide varieties of gene alleles. There are two classes of MHC molecules, class I and II. Both classes have three classical loci HLA-A, -B, and –C are present in class I and HLA-DP, -DQ, and -DR in class II. To induce a compatible T-lymphocyte clone, the T-cell epitope requires the association of the compatible MHC molecule to form pMHC. Each MHC variant possesses a different groove that is capable of binding a different range of antigenic epitopes. Without the compatible MHC molecule, a T cell clone cannot be activated by a particular viral epitope. With the aim of preventing viral transmission, the efficiency of a viral vaccine is related to the existence of specific MHC alleles in the individual. This article proposes the roles of the MHC molecule to prevent viral infection. In addition, the association of the viral receptor molecule with the viral infection will also be discussed.

Impact of human leukocyte antigen compatibility on outcomes of living donor liver transplantation: Experience from a tertiary care center.

The role of HLA compatibility in kidney, heart, and stem cell transplantation is well known, but with regard to living donor liver transplantation (LDLT), there is a different scenario. In the present study, we aim to examine the effects of donor-recipient HLA mismatches at A, B, and DR loci on various outcomes of LDLT-like graft survival, early allograft dysfunction (EAD), acute rejection, length of hospital (LOH) stay, sepsis, and cytomegalovirus (CMV) reactivation. This is a retrospective single center study of a cohort of adult patients who underwent first time ABO-compatible (ABOc) LDLT between January 2010 and December 2018. Transplants with incomplete records or without HLA typing data were excluded. Donor-recipient HLA-A, B, and DR mismatches were assessed in the host versus graft (HVG) direction and were correlated with various post-transplant outcomes. Among 140 transplants being evaluated, approximately two third had total HLA mismatches between 2 and 3. HLA mismatches at each locus as well as cumulative HLA mismatches did not show any association with overall graft survival, EAD, acute rejection episodes, and LOH stay. However, the presence of minimum one mismatch at HLA-A and DR loci was associated with the development of CMV reactivation (P=.03) and sepsis (P=.02) post-LDLT respectively. HLA mismatch is not associated with acute rejection, early graft dysfunction, and overall survival in LDLT. Its impact on CMV reactivation and sepsis needs further evaluation.