Human Leukocyte Antigen Testing Research Articles

Reporting a Rare HLA Allele with Sequence Analysis Prevents Potentially Lethal Allopurinol Hypersensitivity Reaction

Abstract Introduction/Objective In addition to their essential role in histocompatibility testing, human leukocyte antigen (HLA) alleles have informative pharmacogenomic and disease associations. For example, HLA-B*58:01 carriers have 100- fold greater risk of allopurinol hypersensitivity syndrome (AHS), a lethal T-cell mediated Type IV reaction with a 20- 25% mortality rate. To prevent AHS, patients are tested for carrier status before treatment. Methods/Case Report Patient presented for workup of intermittently flaring right knee pain and uricemia. Uric acid is elevated, plain film imaging is ordered, arthrocentesis is planned, and HLA testing is performed to inform uricemia treatment. Next generation sequencing (NGS) typing reveals the patient carries HLA-B*58:11. Sequence analysis demonstrates the allele’s open reading frame differs from HLA-B*58:01 by a single I194V substitution. Amino acid sequences of peptide binding regions (PBR) encoded by these alleles are identical. Presentation of allopurinol/oxypurinol peptides to T-cells by B*58:01 is the putative mechanism underlying AHS pathogenesis. Identical protein sequence in the PBR of B*58:11 favors similar function. Findings are reported and treatment with allopurinol foregone. Results (if a Case Study enter NA) NA Conclusion High resolution HLA testing is essential to appropriately interpret and report results for disease risk and pharmacogenomics assessments. However, NGS detects rare alleles that have yet to be associated with a disease process. When pathogenesis is thought to be linked to the PBR, rare HLA alleles with identical or similar PBR to disease associated alleles may confer similar risk. In this case, NGS identified PBR similarity between the patient’s allele and an established AHS risk allele. Although B*58:11 has not been shown to be associated with AHS, likely due to low prevalence, the risk was deemed sufficient to select an alternative therapy and potentially prevent a lethal drug reaction.

Human leukocyte antigen compatibility and incidence of donor-specific antibodies in pediatric liver transplant recipients.

Antibody-mediated rejection following liver transplantation (LT) has been increasingly recognized, particularly with respect to the emergence of de novo donor-specific antibodies (DSAs) and their impact on graft longevity. While substantial evidence for adult populations exists, research focusing on pediatric LT outcomes remains limited. To investigate the prevalence of human leukocyte antigen (HLA) mismatches and DSA and evaluate their association with rejection episodes after pediatric LT. A cohort of pediatric LT recipients underwent HLA testing at Santa Casa de Porto Alegre, Brazil, between December 2013 and December 2023. Only patients who survived for > 30 days after LT with at least one DSA analysis were included. DSA classes I and II and cross-matches were analyzed. The presence of de novo DSA (dnDSA) was evaluated at least 3 months after LT using the Luminex® single antigen bead method, with a positive reaction threshold set at 1000 MFI. Rejection episodes were confirmed by liver biopsy. Overall, 67 transplanted children were analyzed; 61 received grafts from living donors, 85% of whom were related to recipients. Pre-transplant DSA (class I or II) was detected in 28.3% of patients, and dnDSA was detected in 48.4%. The median time to DSA detection after LT was 19.7 [interquartile range (IQR): 4.3-35.6] months. Biopsy-proven rejection occurred in 13 patients at follow-up, with C4d positivity observed in 5/13 Liver biopsies. The median time to rejection was 7.8 (IQR: 5.7-12.8) months. The presence of dnDSA was significantly associated with rejection (36% vs 3%, P < 0.001). The rejection-free survival rates at 12 and 24 months were 76% vs 100% and 58% vs 95% for patients with dnDSA anti-DQ vs those without, respectively. Our findings highlight the importance of incorporating DSA assessment into pre- and post-transplantation protocols for pediatric LT recipients. Future implications may include immunosuppression minimization strategies based on this analysis in pediatric LT recipients.

Advances in Human Leukocyte Antigen Testing Technologies and Management Strategies for Platelet Transfusion Refractoriness.

The blood bank is often consulted for transfusion support of patients with suspected platelet transfusion refractoriness (PTR). The workup is complex because testing includes specialized assays that are uncommonly ordered with limited availability. Add to this the variety of possible products-crossmatched platelets, human leukocyte antigen (HLA)-matched platelets, HLA antigen-negative platelets-and the approach to PTR can be overwhelming. Moreover, most literature on the subject is published in transfusion medicine journals aimed at transfusion medicine physicians and blood bank specialists in academic settings. Resources tailored to community hospital blood banks are lacking. To provide pathologists who may not have subspecialized training in transfusion medicine and who direct blood banks algorithmic workflows based on clinical scenario and test availability to provide appropriate transfusion support for patients with PTR. This review is a comprehensive overview of terminology, HLA testing procedures, interpretations, and practical recommendations for managing PTR in various scenarios based on expert opinion as well as relevant medical literature published from 2007 to 2022. Consultation on PTR is complicated and encompasses many clinical and laboratory aspects. The lack of guidelines derived from high-quality prospective studies poses challenges in the workup and management of PTR. Hindering the process further are limited test availability, unfamiliarity with the technical assays, and the various specialized platelet products. The clinical evaluation algorithm presented herein along with the workflow pathways offer pathologists user-friendly and best-practice guidelines with different options based on the clinical scenario and the tests available.

Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Abstract 6570: HLA genotyping and HLA-based clinical trial matching using MSK-IMPACT, a targeted next-generation sequencing assay

Abstract Purpose: Performing tumor next-generation sequencing (NGS) and human leukocyte antigen (HLA) typing in a single test can maximize the likelihood of matching patients with cancer to clinical trials. We investigated the utility of a clinical-grade NGS assay for this purpose. Methods: HLA class I genotypes were determined on an investigational basis by MSK-IMPACT (FDA-authorized hybrid-capture, tumor and matched normal DNA-based NGS) using POLYSOLVER for patients with cancers of any histology between March 2014 and September 2023. Patient HLA genotype matches for phase I clinical trials were identified; for a subset of patients, concordance between HLA genotyping was compared to a CLIA-certified laboratory test. Results: 60,565 patients successfully underwent complete class I HLA genotyping (two alleles each of HLA-A, HLA-B, and HLA-C). The median age at diagnosis was 64 years old and most patients were female (55%) and white (76%). The most common genotypes were HLA-A*02:01 (42%, n=25,457), HLA-C*04:01 (28%, n=17,274), HLA-A*01:01 (25%, n=14,867), HLA-C*07:01 (24%, n=14,538), HLA-A*03:01 (21%, n=12,668), HLA-C*07:02 (21%, n=12,493), and HLA-B*07:02 (16%, n=9,787). Most patients (96%, n=58,287) were HLA genotype eligible [HLA-A*02:01 (n=28), HLA-A*11:01 (n=3), HLA-A*01:01 (n=1), and HLA-C*07:02 (n=1)] for ≥1 of 33 active early phase adoptive T cell therapy or T cell receptor bispecific trials on Clinicialtrials.gov. 280 patients with HLA class I matches were screened for phase I trial candidacy by the MSK phase I group. 117 were candidates for confirmatory HLA and neoantigen testing, of whom 43 patients were enrolled on a trial after additional screening. 72 patients had HLA genotyping both by MSK-IMPACT and an outside CLIA-certified laboratory; 100% (72/72) of these subjects had concordant genotypes. Conclusions: MSK-IMPACT successfully determined class I HLA genotypes in a large, multi-ethnic population of patients. A substantial proportion of patients were identified as potential candidates for HLA-matched trials, supporting local trial enrollment. Citation Format: Monica F. Chen, Michael V. Gormally, Anne Marie Noronha, Kristalla Panageas, Maggie Reynolds, Kaelyn Kohlasch, Bryan Novak, Tatiana Kee-Velez, Nikeysha Clarke, Chrisann Kyi, Claire Friedman, Sandra D'Angelo, Mark G. Kris, Christopher A. Klebanoff, Ronak Shah, Michael Berger, Chaitanya Bandlamudi, Alexander Drilon, Mark T. Donoghue. HLA genotyping and HLA-based clinical trial matching using MSK-IMPACT, a targeted next-generation sequencing assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6570.

A Case of Asymmetrical Vogt-Koyanagi-Harada Disease in a Patient with Ota Nevus Following Laser Treatment

Purpose: To report a case of Vogt-Koyanagi-Harada (VKH) disease exhibiting asymmetric symptoms, predominantly in the affected eye, aside from the bilateral findings noted in indocyanine green angiography (ICG) in a patient who had undergone treatment for nevus of Ota.Case summary: A 33-year-old male presented with decreased visual acuity, ocular pain in the right eye, and a 3-week history of headache. The patient had undergone two laser treatments at 1-month intervals to address a nevus of Ota on the upper and lower eyelids and the maxillary area of the right side. He had no notable medical history. Fundus examination and optical coherence tomography indicated multiple serous retinal detachments. ICG displayed multiple hyperfluorescent spots in both eyes. Given these findings, the patient was diagnosed with VKH disease, predominantly affecting the right eye. Human leukocyte antigen (HLA) testing revealed the presence of the HLA-DRB1*09 and HLA-DQB1*03 (DQ8) alleles. The patient initially received high-dose intravenous steroid therapy, later transitioning to oral steroids. After a month of treatment, the serous retinal detachments had resolved and his vision improved. No signs of recurrence were evident during a 6-month follow-up.Conclusions: VKH disease can manifest asymmetrically, especially in the eye affected after laser treatment for nevus of Ota. Despite potential monocular presentation, it is crucial to assess for binocular involvement through comprehensive examinations.

Eligibility for hematopoietic stem cell transplantation in a cohort of children with sickle cell disease: a single-center report

BackgroundHematopoietic stem cell transplantation (HSCT), is the only currently available curative option for SCD. Yet, the eligibility of SCD patients for HSCT is always limited by the significant associated toxicity and lack of suitable donors. At Cairo University’s pediatric hematology outpatient clinic, we aimed to determine hematopoietic stem cell transplantation (HSCT) candidates among a sickle cell disease (SCD) cohort, estimate the number of possible donors, and analyze the differences between patients with and without an HSCT indication.MethodsThis study was a cross-sectional analytic study including 128 SCD children. Their demographic, clinical, and laboratory profiles, total number, and number of siblings with SCD were obtained from their medical records.ResultsSixty-nine (53.9%) had at least one HSCT indication. Recurrent severe pain episodes despite hydroxyurea were the most common indication. Hemoglobin was lower, while reticulocyte count, serum ferritin, and aspartate aminotransferase were higher in HSCT candidates (p value < 0.001). Additionally, the prevalence of splenomegaly, the dose of hydroxyurea, and the number of transfusions were noticeably higher in HSCT candidates (p value = 0.013, 0.005, and < 0.0001 respectively). Among those indicated for HSCT; 75.3% had at least one healthy sibling who might be a potential donor.ConclusionMore than half were eligible for HSCT which should always be considered to provide a possible cure for the disease. Of the transplantation-eligible cases, about two-thirds had at least one healthy sibling who might potentially serve as a donor. Those meeting the requirements for HSCT eligibility should routinely undergo human leukocyte antigen (HLA) testing of their unaffected siblings.

HLA Typing and Donor-Specific Antibody Screening in Kidney Transplantation: Bridging the Past to the Future

Human leukocyte antigens (HLA) are unique proteins expressed on the surface of human cells, playing a pivotal role in the immune system, particularly in the contexts of infection, cancer, and transplantation. The widespread adoption of HLA typing methods has become an essential component in assessing donor-recipient compatibility, a crucial limiting factor in solid organ transplantation. In general, the greater the disparity between a donor's and recipient's HLA types, the higher the likelihood of provoking an alloimmune response, which frequently results in alloimmune graft rejection. With significant advancements in organ transplantation techniques, immunosuppressive medications, and surgical procedures, attention has increasingly turned toward understanding and managing humoral rejection processes. Pre-transplant antibody screening plays a critical role in identifying individuals with elevated levels of antibodies against potential donor antigens. This screening aids in risk assessment and planning to mitigate the risk of antibody-mediated rejection (AbMR). Several methods are available for assessing circulating antigen-specific antibodies and HLA tissue typing, including cell-based assays like serological assays, complement-dependent cytotoxicity, and flow cytometry. However, non-cell-based approaches, such as molecular methods, HLA imputation techniques and high-throughput HLA-matchmaker assays have gained significant popularity due to their ability to provide higher resolution and robust donor-recipient matching. Despite the advancements in precision and sensitivity observed in HLA cutting-edge technologies, numerous challenges still persist. These challenges involve complexities linked to allelic ambiguities, the differentiation of closely related alleles, and the ongoing effort to establish a standardized HLA testing methodology across diverse laboratories. Additionally, correlating the HLA crossmatch results with the clinical outcomes for transplant donors poses another important aspect that warrants attention and requires expert analysis. In this review, we will enumerate the different methods of HLA typing and DSA screening and discuss the unmet needs and future directions for HLA typing methods.

Pathogenesis, clinical features and treatment of anti‐IgLON5 disease

AbstractAnti‐immunoglobulin‐like cell adhesion molecule 5 (IgLON5) disease is an autoimmune encephalitis that targets the cell adhesion molecule, IgLON5. The disease presents with various clinical features, including sleep disorders, bulbar palsy, movement disorders, cognitive dysfunction and neuromuscular manifestations. Sleep disorders are characterized by parasomnias and sleep‐disordered breathing (stridor and sleep apnea). Bulbar palsy includes dysarthria, dysphagia, vocal cord paralysis and stridor. Movement disorders include a variety of symptoms and signs, such as chorea, dystonia, rigidity, tremor, myoclonus and myorhythmia. Cognitive dysfunction includes executive dysfunction, impairment of attention, and verbal and visual memory dysfunction. Neuromuscular manifestations include fasciculations in the tongue and peripheral muscles, limb weakness, and muscle atrophy. Some patients resemble those with neurodegenerative diseases, such as progressive supranuclear palsy or amyotrophic lateral sclerosis. On video polysomnography, undifferentiated non‐rapid eye movement sleep and poorly structured N2 sleep are characteristic. Brain magnetic resonance imaging and cerebrospinal fluid studies are often normal or non‐specific. Human leukocyte antigen testing shows that HLA‐DRB1*10:01‐DQB1*05:01 is highly associated with the disease. Pathologically, neuronal deposition of both hyperphosphorylated 3‐repeat and 4‐repeat tau isoforms, neuronal loss, and gliosis in the hypothalamus, brainstem tegmentum, and upper cervical cord are observed. Some patients are responsive to immunotherapies, such as steroids, intravenous immunoglobulin, plasma exchange therapy and rituximab. Factors associated with a favorable response to immunotherapies include early initiation of treatment, cerebrospinal fluid inflammation and immunoglobulin G1 (IgG1) predominance of IgLON5 antibody compared with immunoglobulin G4 (IgG4). Anti‐IgLON5 disease should be suspected in patients with atypical movement disorders complicated by sleep disturbances.

Assessment of Need for Improved Identification of a Culprit Drug in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe hypersensitivity reaction. Identifying a culprit drug is critical for patient care, yet identification is based on clinical judgment. Data are limited on the accuracy in or approach to identifying a culprit drug. To evaluate patient allergy list outcomes, current approaches in identifying culprit drugs, and potential methods of improving culprit drug identification. This retrospective cohort study spanned 18 years (January 2000 to July 2018), was conducted at Brigham and Women's Hospital and Massachusetts General Hospital (Boston), and included patients with clinically and histologically confirmed cases of SJS/TEN overlap and TEN. This study descriptively analyzed potential culprits to SJS/TEN, patients' allergy lists, and currently used approaches that led to those lists. It then tested the theoretical contribution of incorporating various parameters to allergy list outcomes. Of 48 patients (29 women [60.4%]; 4 Asian [8.3%], 6 Black [12.5%], 5 Hispanic [10.4%], and 25 White [52.1%] individuals; median age, 40 years [range, 1-82 years]), the mean (SD) number of drugs taken per patient at disease onset was 6.5 (4.7). Physicians labeled 17 patients as allergic to a single culprit drug. Comparatively, 104 drugs were added to allergy lists across all patients. Physicians' approaches relied largely on heuristic identification of high-notoriety drugs and the timing of drug exposure. Use of a vetted database for drug risk improved sensitivity. Algorithm for Drug Causality for Epidermal Necrolysis scoring was discordant in 28 cases, labeling an additional 9 drugs missed by physicians and clearing 43 drugs labeled as allergens by physicians. Human leukocyte antigen testing could have potentially affected 20 cases. Consideration of infection as a culprit was limited. The results of this cohort study suggest that currently used approaches to identify culprit drugs in SJS/TEN are associated with overlabeling patients allergic to likely nonculprit drugs and less commonly missed possible culprit drugs. Incorporation of a systematized unbiased approach could potentially improve culprit drug identification, although ultimately a diagnostic test is necessary.

Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics

The genetic variants of HLAs (human leukocyte antigens) play a crucial role in the virus-host interaction and pathology of COVID-19. The genetic variants of HLAs not only influence T cell immune responses but also B cell immune responses by presenting a variety of peptide fragments of invading pathogens. Peptide cocktail vaccines produced by using various conserved HLA-A2 epitopes provoke substantial specific CD8+ T cell responses in experimental animals. The HLA profiles vary among individuals and trigger different T cell-mediated immune responses in COVID-19 infections. Those with HLA-C*01 and HLA-B*44 are highly susceptible to the disease. However, HLA-A*02:01, HLA-DR*03:01, and HLA-Cw*15:02 alleles show resistance to SARS infection. Understanding the genetic association of HLA with COVID-19 susceptibility and severity is important because it can help in studying the transmission of COVID-19 and its physiopathogenesis. The HLA-C*01 and B*44 allele pathways can be studied to gain insight into disease transmission and physiopathogenesis. Therefore, integrating HLA testing is suggested in the ongoing pandemic, which will help in the rapid identification of highly susceptible populations worldwide and possibly acclimate vaccine development. Therefore, understanding the correlation between HLA and SARS-CoV-2 is critical in opening new insights into COVID-19 therapeutics, based on previous studies conducted.

New cost-effective human leukocyte antigen testing algorithm for screening of human leukocyte antigen-matched related donor in thalassemia major patient pretransplant workup

Introduction: India has a huge disease burden of thalassemia major with an estimated 40 million carriers and over a million thalassemia major patients. Very few patients are optimally treated, and the standard of care “hematopoietic stem cell transplant” (HSCT) is out of reach for most patients and their families. The cost of HSCT is significant, and a substantial proportion of it goes to human leukocyte antigen (HLA) testing of family members (HLA screening) in hope of getting a matched related donor (MRD) for HSCT. The aim of this study was to establish that a new proposed testing algorithm of HLA typing would be more cost-effective as compared to the conventional HLA screening within MRD families for possible HSCT. Material and Methods: Buccal swab samples of 177 thalassemia patients and their prospective family donors (232) were collected. Using a new HLA testing algorithm, samples were tested for HLA typing in a sequential manner (first HLA-B, then HLA-A, and finally HLA-DR) using the sequence-specific oligonucleotide probe method on the Luminex platform. Results: The new sequential HLA-A, HLA-B, and HLA-DRB1 testing algorithm showed a 49.1% reduction in cost compared to the conventional HLA testing algorithm. Furthermore, 40 patients (22.59%) were found to have HLA-MRD within the family among other samples that were tested. Conclusion: The new HLA testing algorithm proposed in the present study for identifying MRD for HSCT resulted in a substantial reduction in the cost of HSCT workup.

Virtual crossmatch for deceased donor kidney transplantation in the United States: A survey of histocompatibility lab directors and transplant surgeons

Virtual crossmatch (VXM) is used as an alternative to or in conjunction with a cell-based physical crossmatch (PXM) for assessing HLA (human leukocyte antigen) compatibility prior to deceased donor kidney transplantation (DDKT). Data on practice patterns and perceptions regarding VXM use in the US are limited. We performed a survey of US HLA directors and transplant surgeons regarding HLA testing and crossmatch strategies. 53 (56 %) HLA directors and 68 surgeons (representing ∼ 23 % of US transplant centers) completed the survey. Both groups agreed that VXM could reduce cold ischemia time (CIT), costs and improve allocation efficiency. VXM use increased following the 2021 kidney allocation change. Reducing CIT was the primary reason for favoring VXM over PXM. Preference for VXM reduced as candidates’ panel reactive antibodies increased. Regulations, program policies and limitations of HLA technology were cited as important reasons for preferring PXM over VXM. Surgeons reported similar perceptions, but findings are limited by the low response rate. Finally, half the labs reported lacking specific protocols for VXM use. In conclusion, improved HLA technology and protocols along with changes to institutional procedures and policy regulations are needed for safer expansion of VXM in DDKT.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury.

Allele and Haplotype Frequencies of HLA-A, -B, -C, and -DRB1 Genes in 3,750 Cord Blood Units From a Kinh Vietnamese Population.

The frequencies and diversities of human leukocyte antigen (HLA) alleles and haplotypes are representative of ethnicities. Matching HLA alleles is essential for many clinical applications, including blood transfusion, stem cell transplantation, and tissue/organ transplantation. To date, the information about the frequencies and distributions of HLA alleles and haplotypes among the Kinh Vietnamese population is limited because of the small sample size. In this study, more than 3,750 cord blood units from individuals belonging to the Kinh Vietnamese population were genotyped using PCR sequence-specific oligonucleotide (PCR-SSO) for HLA testing. The results of the study demonstrated that the most frequently occurring HLA-A, -B, -C, and -DRB1 alleles were A*11:01 (25%), A*24:02 (12.3%), A*02:01 (11.2); A*03:03 (8.95%), A*02:03 (7.81%), A*29:01 (7.03%); B*15:02 (15.1%), B*46:01 (10.7%), B*58:01 (7.65%), B*38:02 (7.29%); C*08:01 (17.2), C*07:02 (16.2%), C*01:02 (15.2), C*03:02 (8.3%), C*15:05 (6.13); DRB1*12:02 (31.0%), DRB1*09:01 (10.47%), DRB1*15:02 (7.54%); DRB1*07:01 (6.68%), DRB1*10:01 (6.63%), respectively, with the highest allele diversity level observed in locus B (93 alleles). The most frequent haplotypes of two-locus combinations of HLA-A–B, HLA-A–C, HLA-A–DRB1, HLA-B–C, HLA-B–DRB1, and HLA-C–DRB1 haplotypes were A*11:01–B*15:02 (7.63%), A*11:01–C*08:01 (7.98%), A*11:01–DRB1*12:02 (10.56%), B*15:02–C*08:01 (14.0%), B*15:02–DRB1*12:02 (10.47%), and C*08:01–DRB1*12:02 (11.38%), respectively. In addition, the most frequent haplotypes of three- and four-locus sets of HLA-A–B–C, HLA-A–B–DRB1, HLA-A–C–DRB1, HLA-B–C–DRB1, and HLA-A–B–C–DRB1 were A*11:01–B*15:02–C*08:01 (7.57%), A*11:01–B*15:02–DRB1*12:02 (5.39%), A*11:01–C*08:01–DRB1*12:02 (5.54%), B*15:02–C*08:01–DRB1*12:02 (10.21%), and A*11:01–B*15:02–C*08:01–DRB1*12:02 (5.45%), respectively. This study provides critical information on the frequencies and distributions of HLA alleles and haplotypes in the Kinh Vietnamese population, accounting for more than 85% of Vietnamese citizens. It paves the way to establish an umbilical cord blood bank for cord blood transplantation programs in Vietnam.

Combination of HLA-DQ2/-DQ8 Haplotypes and a Single MSH5 Gene Variant in a Polish Population of Patients with Type 1 Diabetes as a First Line Screening for Celiac Disease?

Patients with type 1 diabetes (T1D) are at increased risk for developing celiac disease (CD). The aim of the study was to assess the usefulness of celiac-specific human leukocyte antigen (HLA) haplotype and the rs3130484 variant of MSH5 gene, a previously described non-HLA variant associated with CD in the Polish population as a first-line screening for CD in T1D pediatric patients. Serological CD screening performed in the T1D group (n = 248) and healthy controls (n = 551) allowed for CD recognition in 20 patients (8.1%) with T1D (T1D + CD group). HLA-DQ2, HLA-DQ8 and the rs3130484 variant were genotyped with TaqMan SNP Genotyping Assays. The T1D + CD group presented a higher, but not statistically significant, frequency of HLA-DQ2 in comparison with T1D subjects. Combining the rs3130484 with HLA-DQ2/HLA-DQ8 typing significantly increased the sensitivity of HLA testing from 32.7% to 68.7%, and the accuracy of estimating CD prediction from 51.7% to 86.4% but decreased the specificity from 100% to 78.2%. The receiver operating characteristic curve analysis confirmed the best discrimination for the combination of both genetic tests with an area under curve reaching 0.735 (95% CI: 0.700–0.7690) in comparison with 0.664 (95% CI: 0.632–0.696) for HLA typing alone. Results show the low utility of HLA-DQ2/HLA-DQ8 typing for CD screening in T1D pediatric patients. Combination of the rs3130484 variant of the MSH5 gene and HLA testing increases both the sensitivity and the predictive value of the test accuracy, but still, the obtained values are not satisfactory for recommending such testing as the first-line screening for CD in T1D patients.

Fulminant Antibody-Mediated Rejection in a Stable Lung Transplant Recipient Post COVID-19 Vaccination

IntroductionVaccination against COVID-19 in immunocompetent individuals has demonstrated high efficacy in disease prevention while significantly reducing severe infections and hospitalizations. COVID-19 vaccination is endorsed in immunosuppressed recipients of solid organ transplant. Trials have examined safety data in this population, with no published reports of increased risk of antibody-mediated rejection (AMR). We present a case of probable mRNA vaccine induced AMR in a previously stable lung transplant recipient.Case ReportA 27-year-old bilateral lung transplant recipient for cystic fibrosis related lung had grade 2 rejection with class II antibodies 2 months post-transplant that was treated with methylprednisolone with good response. He was then event free for over two years. He developed acute onset of dyspnea, dry cough, non-pleuritic chest pain, and general malaise 24 hours after receiving his second dose of the Pfizer mRNA vaccine. Over the subsequent 3 weeks, he deteriorated with worsening exertional dyspnea and desaturation. He was admitted to hospital with rapidly progressive type 1 respiratory failure. A CT angiogram of the chest demonstrated findings consistent with organizing pneumonia versus opportunistic infection. Bronchoscopy was negative for infectious etiology. He was treated with a methylprednisolone pulse to treat the organizing pneumonia seen on imaging and potential AMR. He required intubation and mechanical ventilation on post admission day (PAD) 4. Human leukocyte antigen testing demonstrated de novo class II donor specific antibody (DR12) and possible weak class I reactivity. With declining status and refractory hypoxemia, 5 cycles plasma exchange (PLEX) alternating with thymoglobulin were administered. He became dependent on extracorporeal membrane oxygenation with poor lung compliance. Antibody levels decreased but remained elevated. Subsequent therapy included thymoglobulin (total dose 7mg/kg), 5 additional cycles of PLEX, and intravenous immunoglobulin and Daratumumab on PAD 38. He died PAD 47 when life sustaining measures were removed due complications from Clostridium difficile infection.SummaryThis case of probable AMR post mRNA vaccination in a lung transplant recipient raises clinical suspicion for a serious adverse event and contributes to safety data for this select population.

Role of HLA-DQ typing and antitissue transglutaminase antibody titres in diagnosing coeliac disease among Sudanese children with type 1 diabetes mellitus

ObjectiveThe aim of the study was to determine the prevalence of coeliac disease (CD) and to recognise Human leukocyte antigen (HLA)-associated hereditary susceptibility to Sudanese CD patients with type 1...

HLA Allele-Restricted Immune-Mediated Adverse Drug Reactions: Framework for Genetic Prediction.

Human leukocyte antigen (HLA) is a hallmark genetic marker for the prediction of certain immune-mediated adverse drug reactions (ADRs). Numerous basic and clinical research studies have provided the evidence base to push forward the clinical implementation of HLA testing for the prevention of such ADRs in susceptible patients. This review explores current translational progress in using HLA as a key susceptibility factor for immune ADRs and highlights gaps in our knowledge. Furthermore, relevant findings of HLA-mediated drug-specific T cell activation are covered, focusing on cellular approaches to link genetic associations to drug-HLA binding as a complementary approach to understand disease pathogenesis.

HLA-B*58:01 screening to prevent allopurinol-induced severe cutaneous adverse reactions in Chinese patients with chronic kidney disease.

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.