Human Leukocyte Antigen Genotypes Research Articles

Hypoglycemia Caused by Exogenous Insulin Antibody Syndrome: A Large Single-Center Case Series From China.

Exogenous insulin antibody syndrome (EIAS) can lead to unexpected and potentially life-threatening recurrent hypoglycemia. We aimed to better define autoimmune hypoglycemia caused by EIAS in patients with diabetes and shed light on the improvements in the identification and intervention for this rare but possibly life-threatening condition. We summarized the clinical characteristics of autoimmune hypoglycemia caused by EIAS in 23 patients with diabetes. Furthermore, we performed human leukocyte antigen (HLA) genotyping of 10 patients. We identified a high frequency of autoimmune comorbidities (21.7%), food or drug allergy (48%), insulin allergy (30%), lipodystrophy at the insulin injection sites (22%), and antinuclear antibodies (25%) in the patients. Alternation between hyperglycemia and hypoglycemia was observed in more than 90% of the patients. Most patients showed a high insulin autoantibody titer (>90%) and inappropriately increased insulin concentration (insulin/C-peptide molar ratio >7, >85%). We detected similar frequencies of DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 compared with previously reported frequencies in type 1 diabetes, and a lower frequency of DRB1*0406 compared with insulin autoimmune syndrome. The spontaneous remission rate exceeded 70%. Predisposing factors for autoimmune hypoglycemia caused by EIAS include a strong autoimmune background. Susceptible HLA genotypes for type 1 diabetes or insulin autoimmune syndrome might not explain susceptibility to this condition. Additionally, insulin autoantibodies and the insulin/C-peptide molar ratio are reliable screening options. The prognosis for this condition is favorable. Monitoring of insulin and insulin autoantibodies may contribute to treatment effectiveness.

SARS-CoV-2 Epitope Presentation by Class II HLA Genotypes Common in North American Populations: A Proposed Computational Approach for Vaccine Efficacy Evaluation

Background: Human Leukocyte Antigen (HLA) gene polymorphisms between ethnic groups have been shown to play a role in the heterogeneity of response to SARS-CoV-2, in terms of COVID-19 disease severity and susceptibility, in addition to socioeconomic factors. It was predicted that this finding may extend to vaccine responsiveness. Purpose: To the best of our knowledge, this study was the first that aimed to predict and evaluate the effectiveness of four COVID-19 vaccines across North American ethnic groups, in terms of their ability to trigger CD4+ T cell help, based on class II HLA allele frequencies. Methods: Various databases including the Immune Epitope Database (IEDB) were used in this computational approach. The number of peptide-HLA high-affinity pairs between the most common HLA II haplotypes and SARS-CoV-2 peptides in various vaccine types were retrieved and compared between ethnicities. From this, the efficiency of antigen presentation to CD4+ T cells was evaluated, a crucial component in the context of vaccination for cellular immunity and support in antibody generation. Results: Multiple discrepancies in vaccine effectiveness for ethnic minorities relative to the Caucasian group, overrepresented in vaccine clinical trials, were highlighted. Recommendations were issued in terms of which vaccine types could be most effective for particular ethnicities. Conclusion: There exists a genetic basis for differential responses to vaccines among ethnic groups in North America. However, given the multifactorial nature of vaccine responsiveness and limitations of computational methods, this study offers future research directions to undertake before the findings can be transferred to clinical and public health settings.

HLA Associations in pediatric autoimmune liver diseases: Current state and future research initiatives.

The strongest genetic association with autoimmunity is within chromosome 6p21, where the human leukocyte antigen (HLA) complex resides. This review will focus on the HLA associations within pediatric autoimmune hepatitis, autoimmune sclerosing cholangitis and primary sclerosing cholangitis. In general, there is considerable overlap in HLA genotypes conferring susceptibility to pediatric autoimmune liver diseases, however unique HLA associations and protective HLA genotypes exist. There are numerous areas for future research initiatives in pediatric autoimmune liver diseases and HLA associations with clinical outcomes, autoantigen discovery and novel therapeutics targeting the HLA- autoantigen- T cell pathway will be highlighted.

Donor-derived urologic cancers after renal transplantation: A retrospective non-randomized scientific analysis.

BackgroundMalignancies in the urinary tract and the kidney graft are quite common after kidney transplantation. In some selected cases tumours develop from donor-derived tissue.ObjectivesWe hypothesised that there is a clinical value to investigate donor/recipient origin in urologic malignancies in renal transplant recipients.MethodsIn this retrospective study, including patients transplanted between the years 1969 and 2014 at Uppsala University Hospital, Sweden, 11 patients with malignancies in urinary tract and 4 patients with malignancies in kidney transplants were investigated. Donor/recipient origin of tumour tissue was analysed by polymerase chain reaction (PCR) of human leucocyte antigen (HLA) genotypes or by fluorescence in situ hybridization (FISH analysis) of sex chromosomes. HLA genotype and sex chromosomes of the tumour were compared to the known HLA genotype and sex chromosomes of recipient and donor.ResultsThree of ten cancers in the urinary tract and three of four cancers in the kidney transplants were donor-derived.ConclusionsWe suggest that urologic malignancies in renal transplant recipients can be investigated for transplant origin. In addition to conventional therapy the allograft immune response against these tumours can be valuable to treat donor-derived cancers.

Serum IL-1ra Is Associated with but Has No Genetic Link to Type 1 Diabetes

Interleukin-1 antagonism is a proposed biomarker and potential therapy for the delay and/or treatment of type 1 diabetes (T1D). We evaluated the role of circulating interleukin-1 receptor antagonist (IL-1ra) in a prospectively monitored cohort of T1D patients. In order to determine a mechanistic association between IL-1ra and T1D, we performed co-localization analyses between serum IL-1ra protein quantitative trait loci and T1D genome-wide analysis studies. Adjusting for human leukocyte antigen (HLA) genotypes, first degree relative status, gender, and age, serum levels of IL-1ra were lower in subjects who progressed to T1D compared to the controls (p = 0.023). Our results suggest that females have higher levels of IL-1ra compared to males (p = 0.005). The 2q14.1 region associated with serum IL-1ra levels is not associated with a risk of developing T1D. Our data suggest that IL-1 antagonism by IL-1ra is not an effective therapy in T1D, but IL-1ra may be a biomarker for progression to T1D.

Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond.

Structural and functional variability of human leukocyte antigen (HLA) is the foundation for competent adaptive immune responses against pathogen and tumor antigens as it assures the breadth of the presented immune-peptidome, theoretically sustaining an efficient and diverse T cell response. This variability is presumably the result of the continuous selection by pathogens, which over the course of evolution shaped the adaptive immune system favoring the assortment of a hyper-polymorphic HLA system able to elaborate efficient immune responses. Any genetic alteration affecting this diversity may lead to pathological processes, perturbing antigen presentation capabilities, T-cell reactivity and, to some extent, natural killer cell functionality. A highly variable germline HLA genotype can convey immunogenetic protection against infections, be associated with tumor surveillance or influence response to anti-neoplastic treatments. In contrast, somatic aberrations of HLA loci, rearranging the original germline configuration, theoretically decreasing its variability, can facilitate mechanisms of immune escape that promote tumor growth and immune resistance.The purpose of the present review is to provide a unified and up-to-date overview of the pathophysiological consequences related to the perturbations of the genomic heterogeneity of HLA complexes and their impact on human diseases, with a special focus on cancer.

Destructive inflammatory reaction after an autologous retinal pigment epithelium and choroid transplantation: no detection of an auto-immune response

PurposeFive patients who underwent uncomplicated retinal pigment epithelium (RPE)-choroid transplantation for neovascular age-related macular degeneration developed a destructive inflammatory reaction causing subretinal fluid accumulation and extensive RPE atrophy in the graft. We hypothesized that this inflammation could be caused by an auto-immune response against the graft, resulting in circulating auto-antibodies. The aim of our study was to examine a potential autoimmune origin, which would allow a more targeted therapy approach.MethodsFive above-mentioned patients and four control groups of five patients each were included: 1) after uncomplicated RPE-choroid transplantation, 2) after full macular translocation, 3) treated with anti-vascular endothelial growth factor, and 4) healthy controls. Histopathology of rejected graft tissue was performed using standard procedures. Presence of RPE-choroid autoantibodies in serum was examined by indirect immunofluorescence and Western blot, and human leukocyte antigen (HLA) typing was performed.ResultsHistopathological examination of an explanted graft showed infiltration of T-lymphocytes and macrophages in the choroid and RPE, and an increased number of B-cell lymphocytes were found in the choroid. Indirect immunofluorescence showed weak RPE-choroid autoantibody immunoreactivity in three patients of different groups. Western blot did not show specific RPE-choroid autoantibody immunoreactivity and no difference of HLA genotypes between the groups was found.ConclusionsAlthough local mononuclear inflammatory cell infiltration and a high number of B-lymphocytes were observed in an explanted graft, we did not detect serological evidence of an autoimmune origin of the postoperative inflammation using direct immunofluorescence and Western Blot. Alternatively, the graft failure may have been caused by local innate inflammation, triggered by breakdown of tolerance. Based on our current findings of this small study group, we have no rationale to pursue therapies targeted towards autoreactive graft failure. More research is needed to confirm our findings.

HLA-DRB1 ALLELE DISTRIBUTION IN HEALTHY INDIVIDUALS CLASSIFIED BASED ON MIZAJ (TEMPERAMENT) OF UNANI SYSTEM OF MEDICINE

Objective: Assessment of Mizaj of 500 healthy individuals between the age group of 25and 40 years of the age group of either gender was carried out by validated Unani questionnaire and Sheldon’s somatotype. The present study was designed to investigate if the frequency of HLA-DRB1 alleles in the healthy adult population has any association with four Mizaj. Methods: Mizaj of the healthy individuals (n=500) was assessed by a validated Unani questionnaire based on 10 parameters related to phenotypic and psychological entities known as Ajnas-e-Ashra. Mizaj of the same subjects was further assessed by Sheldon’s somatoplot. Polymerase chain reaction-sequence-specific typing method was used for human leukocyte antigen (HLA) genotyping of 180 healthy volunteers. Conclusion: An expected correlation between HLA-DRB1 alleles and Mizaj types is observed. Five single-nucleotide polymorphisms (p<0.05) were significantly associated with different Mizaj. The study suggests that the Mizaj classification of the Unani system of medicine has a genetic basis. This study would be one step toward a personalized approach as per the Mizaj of an individual to disease proneness, lifestyle modification, and medicine.

028 Patient genetics shape the autoimmune response in pemphigus vulgaris

Pemphigus Vulgaris (PV) is a rare autoimmune blistering disease with a multifactorial origin. Key Human Leukocyte Antigen (HLA) alleles, including DRB1*0402 and DQB1*0503, have been linked to the development of PV. However, it is not known how HLA types vary with ethnicity and how they shape autoimmunity in PV. We assessed correlations between factors including HLA genotype, ethnicity, auto-antibody levels, and lesion distribution in a cohort of 293 patients. Eighty-one percent of patients typed as either DRB1*0402 or DQB1*0503 with a high prevalence of DRB1*0402 in patients of Ashkenazi Jewish or Caucasian (non-Jewish) descent and DQB1*0503 in patients of Southeast Asian descent.

Frequency of celiac disease and distribution of HLA-DQ2/DQ8 haplotypes among siblings of children with celiac disease.

BACKGROUNDCeliac disease (CD) is a multifactorial disease, but genetic factors play a major role in its etiology. It has been known that human leucocyte antigen (HLA)-DQ2/DQ8 haplotypes are one of the most important predisposing genetic factors. The risk of developing CD in first-degree relatives and especially siblings of celiac patients is quite high because of having the same HLA haplotypes.AIMTo evaluate the frequency of CD and the distribution of the HLA-DQ2/DQ8 haplotypes in siblings of celiac patients.METHODSPatients with biopsy-proven CD and their siblings were included in the study; those who did not have HLA genotyping were excluded from the study. All siblings were on a gluten-containing diet. The HLA genotyping, tissue transglutaminase antibody IgA antibody test, and total IgA test were performed in all participants.RESULTSA total of 57 celiac patients and their 112 siblings were included in the study. The mean age of celiac patients and siblings were 10.30 ± 3.87 years and 9.90 ± 6.11 years, respectively. HLA-DQ2/DQ8 alleles were detected in 98.2% of patients with CD and 90.2% of siblings of celiac patients. HLA-DQ genotypes were present in all siblings diagnosed with CD. Tissue transglutaminase antibody IgA test was found to be positive in 16 siblings. CD was diagnosed in 12 siblings (10.7%) by intestinal biopsy.CONCLUSIONThe prevalence of CD was found to be 10.7% in siblings of celiac patients in our study. One-third of the siblings diagnosed with CD were asymptomatic. We detected HLA-DQ alleles in 98.2% of celiac patients and 100% in siblings diagnosed with CD. In addition, 1 of the 2 siblings was diagnosed with CD 1 year later and the other 4 years later. Therefore, we suggest that siblings of celiac patients should be followed up with clinical findings as well as HLA analysis and serological examination. Since the risk of developing CD is much higher in asymptomatic siblings, we recommend that siblings should be screened for CD even if they are asymptomatic.

Binding Affinity Calculations of Gluten Peptides to HLA Risk Modifiers: DQ2.5 versus DQ7.5.

Free energy perturbation (FEP) calculations can predict relative binding affinities of an antigen and its point mutants to the same human leukocyte antigen (HLA) with high accuracy (e.g., within 1.0 kcal/mol to experiment); however, a more challenging task is to compare binding affinities of wholly different antigens binding to completely different HLAs using FEP. Researchers have used a variety of different FEP schemes to compute and compare absolute binding affinities, with varied success. Here, we propose and assess a unifying scheme to compute the relative binding affinities of different antigens binding to completely different HLAs using absolute binding affinity FEP calculations. We apply our affinity calculation technique to HLA-antigen-T-cell receptor (TCR) systems relevant to celiac disease (CeD) by investigating binding affinity differences between HLA-DQ2.5 (enhanced CeD risk) and HLA-DQ7.5 (CeD protective) in the binary (HLA-gliadin) and ternary (HLA-gliadin-TCR) binding complexes for three gliadin derived epitopes: glia-α1, glia-α2, and glia-ω1. Based on FEP calculations with our carefully designed thermodynamic cycles, we demonstrate that HLA-DQ2.5 has higher binding affinity than HLA-DQ7.5 for gliadin and enhanced binding affinity with a common TCR, agreeing with known results that the HLA-DQ2.5 serotype exhibits increased risk for CeD. Our findings reveal that our proposed absolute binding affinity FEP method is appropriate for predicting HLA binding for disparate antigens with different genotypes. We also discuss atomic-level details of HLA genotypes interacting with gluten peptides and TCRs in regard to the pathogenesis of CeD.

Immunologic risk stratification of pediatric heart transplant patients by combining HLAMatchmaker and PIRCHE-II.

Molecular-level human leukocyte antigen (HLA) mismatch is a powerful biomarker of rejection; however, few studies have explored its use in heart transplant recipients, and none have attempted to use the results of separate algorithms synergistically. Here we tested the hypothesis that a combination of HLAMatchmaker and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) can be used to identify more patients at low risk of rejection. We studied 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC) performing class I and II HLA genotyping by next-generation sequencing to determine eplet mismatch (epMM) load and PIRCHE-II score. Correlation with clinical outcomes was performed on 131 cases. Of the 131 patients, 100 without pre-formed donor specific antibody (DSA) were used to identify cutoffs for the Class I, HLA-DR, and HLA-DQ epMM load and PIRCHE-II score for risk of developing post-transplant DSA (epMM: Class I/DR/DQ=9/9/6; PIRCHE-II: 141/116/111) and antibody-mediated rejection (ABMR) (epMM: 9/8/8; PIRCHE-II: 157/80/201). Patients with above cut-off epMM load appear to be less likely to develop DSA and ABMR if their PIRCHE-II score is below cut-off (high epMM/high PIRCHE-II: 12.3%-20.3% DSA and 9%-13.5% ABMR vs high epMM/low PIRCHE-II: 4%-10% DSA and 0%-2% ABMR). For the first time in a pediatric heart transplant cohort, immunologic risk cut-offs for DSA and ABMR have been established. When used together, epMM load and PIRCHE-II score allow us to reclassify a portion of cases with high epMM load as having a lower risk for developing DSA and ABMR.

Non-Classical HLA Determinants of the Clinical Response after Autologous Stem Cell Transplantation for Systemic Sclerosis.

Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.

HLA-DRB1∗1502 Is Associated With Anti-N-Methyl-D-aspartate Receptor Encephalitis in Thai Children

BackgroundAnti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is one of the most common types of autoimmune encephalitis. Most patients have no apparent immunologic triggers, which suggests a genetic predisposition. This study was conducted to identify human leukocyte antigen (HLA) class II alleles associated with anti-NMDARE in Thai children. MethodsThis case-control study enrolled patients younger than 18 years who were diagnosed with anti-NMDARE between January 2010 and December 2020. A “good outcome” was determined as a patient with a modified Rankin scale score of less than 2 at any follow-up visit. HLA genotypes were determined at four-digit alleles using reverse sequence-specific oligonucleotide probe hybridization. The HLA class II allele frequency in patients was compared with that in a database of 101 healthy control Thai children. ResultsThirty-four patients were enrolled with a mean age of 12.8 ± 5.6 years (females 85.3%). The HLA-DRB1∗1502 allele frequency was significantly higher in patients than in controls (odds ratio, 2.32; 95% confidence interval, 1.11-4.8, P = 0.023). A good outcome was noted in 14 of 14 (100%) HLA-DRB1∗1502-positive patients (median time to a good outcome, 6 months) and 14 of 17 (82.3%) HLA-DRB1∗1502-negative patients (median time to a good outcome, 3 months). Two (11.8%) HLA-DRB1∗1502-positive patients had one relapse each, and six (35.3%) HLA-DRB1∗1502-negative patients had one to three relapses. ConclusionsHLA-DRB1∗1502 was significantly associated with anti-NMDARE in our patients. Most patients had good outcomes. HLA-DRB1∗1502-positive patients tended to require a longer time to achieve a good outcome but had less frequent relapses than HLA-DRB1∗1502-negative patients.

Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy

IntroductionBiomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments. MethodsWe carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). ResultsHomozygosity at one or more HLA-I loci, but not HLA-II, was associated with a reduced risk of irAE (relative risk (RR) = 0.61, 95% CI 0.33–0.95, P = 0.035) especially pneumonitis or any grade 3 toxicity. Patients with HLA-A03 supertype had a higher risk of developing irAE (RR = 1.42, 95% CI 1.02–2.01, P = 0.039). The occurrence of any irAE was significantly associated with improved CBR (RR = 1.48, P < 0.0001), PFS (HR = 0.45, P = 0.0003) and OS (HR = 0.34, P < 0.0001). ConclusionsHomozygosity at one or more HLA-I loci may serve as biomarker to predict patients who are unlikely to experience severe irAEs among patients with NSCLC and treated with anti-PD1/PDL1, but less likely to derive clinical benefit. Patients with HLA-I homozygous might benefit from additional therapy.

PB1752: ANALYSIS OF HLA-PEPTIDE BINDING POCKETS IN PATIENTS WITH ACUTE LEUKEMIA UNDERGOING UMBILICAL CORD BLOOD TRANSPLANTATION

Background: Despite a better understanding of the genetic heterogeneity of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), relapse rates remain high and long-term survival is suboptimal. In this context, the association between these malignancies and the human leukocyte antigens (HLA) has been widely studied. The highly polymorphic HLA loci have significance and relevance for disease susceptibility thanks to their peptide-binding grooves-dependent antigen presentation to effector cells. Such processes trigger an algorithm of immune responses based on multiple fine-tuned combinations of amino acid sequence interactions. Thus, the HLA genetic diversity has been a focus of interest in acute leukemia settings as exemplified by studies showing the implication of both HLA class I and II polymorphisms. However, there is scarce data regarding the diversity of peptide-binding pockets per se especially in the context of umbilical cord blood transplantation (UCBT). Aims: To analyze whether variants of HLA-DQB1 and -DRB1 peptide-binding groove pockets 4 and 9 and/or their amino acid positions are associated with the diagnosis of ALL or AML among patients undergoing UCBT. Methods: A retrospective analysis was performed including 849 patients with ALL and AML undergoing an UCBT. Demographics and genotyping data were obtained from the Eurocord database. Pockets and amino acids were imputed from the four-digit HLA genotypes of patients. Easy-HLA was used for haplotype inference when needed. Descriptive statistics were applied. Risk ratios (RRs) and 95% confidence intervals (CI) were estimated by applying log-binomial regression to compare the allelic frequencies between both types of leukemia. Results: ALL and AML were diagnosed in 50.2% and 49.8%, respectively. The median age at UCBT was 8.7 and 17.9 years. Overall, they were mostly pediatric patients (61.8%), males (52%), and in first complete remission (58.7%). From the ten variants analyzed in pocket 9 of the HLA-DQB1 allele, only the variant YYVSY, corresponding to the allele HLA-DQB1*05:02/04, was more frequent in ALL when compared to AML (RR=2.12, 95% CI: 1.30-3.44; p=0.001). Also, within the 21 analyzed pocket 4 variants of the HLA-DRB1 allele, RFDRAY, corresponding to DRB1*16:01/02, was the only variant with a significant higher frequency among ALL patients versus AML patients (RR=3.26, 95% CI: 1.81-5.99; p=0.001). No differences were observed when comparing ALL and AML at either pocket 4 of HLA-DQB1 allele or pocket 9 of HLA-DRB1 allele. Further amino acid analysis revealed that the frequency of serine 57 of the HLA-DQB1 pocket 9 was higher in ALL (RR=2.03, 95% CI: 1.26-3.27; p=0.037). None of the analyzed amino acid positions in HLA-DRB1 pockets was statistically enriched neither in ALL or AML. Summary/Conclusion: Our analyses suggest that specific variants in terms of HLA pockets and amino acids might be unique to ALL. As a result of expressing HLA molecules on their surface, leukemic cells may participate to the disease development and/or to immune evasion. Thus, the immune and genetic expression profile of the leukemic microenvironment has been described as a potential useful biomarker in guiding therapeutic approaches. Interestingly, peptide binding to HLA class II molecules is frequently viewed as a merger of detached anchor residue preferences for pockets 4 and 9. In our study, these associations, at a genotypic level, might be a stepping stone towards analyzing results in acute leukemia after UCBT as there is robust evidence supporting the impact of HLA on important post-transplant outcomes.

EBV protection- and susceptibility-related HLA alleles and EBV status in the Chinese population: A single-center study.

BackgroundAlthough most adults are infected by Epstein‐Barr virus (EBV), some patients develop highly lethal diseases associated with EBV infection, including EBV‐hemophagocytic lymphohistiocytosis (EBV‐HLH), chronic active EBV infections (CAEBV), and lymphoma, the pathogeneses of which remain to be investigated. The human leukocyte antigen (HLA) complex may be associated with the viral infection pathway, and, therefore, HLA alleles may be associated with EBV‐related diseases and subpopulations of infected cells, studies related to EBV‐associated diseases, and subpopulations of infected cells that were conducted in China are scarce.MethodsIn this study, we analyzed the high‐resolution HLA genotypes of 269 patients with EBV‐associated diseases and 213 EBV‐seronegative hematopoietic stem cell donors using PCR‐SBT assay and elucidated the associations of HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1 alleles with EBV‐associated diseases in the Chinese population, Benjamini–Hochberg correction to adjust for multiple testing. HLA genotypes were also analyzed in patients with EBV‐associated diseases showing EBV‐infected lymphocyte subpopulations.ResultsWe found that individuals carrying the following alleles showed the following levels of risks: HLA‐DRB1*11 allele, reduced risk of EBV‐related disease (OR [odds ratio]: 0.56; 95% confidence interval [95% CI]: 0.32–0.99; p < .05; Adjust p = .71); HLA‐DQB1*06:02 allele, reduced risk (OR: 0.5699; 95% CI: 0.3486–0.9317; p < .05; Adjust p = .57); and HLA‐B*15:01 allele, increased risk (OR: 1.763; 95% CI: 0.3486–0.9317; p < .05; Adjust p = .57). Patients with EBV‐associated diseases showing the B*15:01 genotype had a higher risk of T‐cell, NK‐cell, and multicell infections than those with other genotype subgroups.ConclusionsThese findings highlight the importance of HLA genotype for assessing EBV infectivity.

Abstract 6258: Development of humanized patient-derived xenograft models for triple negative breast cancer

Abstract As a new promising in vivo platform for personalized treatment in the field of cancer research, the most improved way has been adopted by far is grafting patient-derived xenograft (PDX) to humanized mouse models which represent the unique features of interaction with human immune system and tumor microenvironment (TME). Here, we engineered triple negative breast cancer (TNBC) humanized PDX mouse (Hu-PDX) model to observe human immune system and tumor growth in TME. In addition, we analyzed gene ontology of PDX isolated from hu or non-humanized mouse model. Method: Human CD34+hematopoietic stem cells (HSCs) derived from cord blood is reconstructed into mature human leukocytes (hCD45+) in NOD.Cg-PrkdcscidIL2γgtm1 Sug (NOG) mice. TNBC PDX tumors are established it with unmatched human leukocyte antigen (HLA) genotypes, confirmed by that hCD45+ engraftment levels did not exceed 20-30% in the peripheral blood of mice. To be repopulated functional human T cells in xenograft models with severely depleted thymus, hCD34-PBMC cells are directly intravenously injected into tail vein of humanized mice followed by hCD34+cells injected without the onset of graft-versus-host disease (GVHD). The growth and gene expression of TNBC PDX tumors, as well as engrafted human immune population including T, B, natural killer (NK) cells and myeloid cells in TME, are monitored and investigated in both hu and non-hu-mice model. Results: Human immune reconstruction of cells, of the lymphoid as well as myeloid lineages, has been successfully accomplished in peripheral blood, spleen, and bone marrow over time in TME. Although the number of human mature leukocytes was gradually decreased in mice by 17 weeks, humanized mice have enabled studies of human immunity and TME in limitation period. Also, one of remaining limitations is unable to positive and negative selection of human T cells in the humanized mouse thymus and required to human major histocompatibility complex (MHC) molecules in humanized mice. To overcome this barrier, additional stimulation factor for generating functional T cells have successfully engrafted by transferring hCD34-PBMC cells. Moreover, tumor infiltrating human lymphocytes (TILs) have obviously detected in Hu-PDX model, although the differences tumor growth rate was not significantly monitored, compared with non-humanized mice. Interestingly, the analysis of gene ontology; biological process, cellular component and molecular function, ribosomal relevant proteins, not immune related genes, were highly up-regulated in TNBC PDX humanized in comparison to non-humanized mouse model. Conclusion: Humanized PDX model will contribute to studies more efficiently for the machinery underlying immunological response in breast tumor microenvironment. Furthermore, it might be an important unknown mechanism that the effect of elevated cancer-related ribosomal proteins expression within hu immune-TME. Citation Format: Yujeong Her, Hye Yeon Son, Ju Hee Kim, Woo Hang Heo, Mingji Quan, Songbin Li, Hyeong Gon Moon. Development of humanized patient-derived xenograft models for triple negative breast cancer [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 6258.

Month of birth and the risk of developing type 1 diabetes among children in the Swedish national Better Diabetes Diagnosis Study.

Previous studies have reported an association between month of birth and incidence of type 1 diabetes. Using population-based data, including almost all newly diagnosed children with type 1 diabetes in Sweden, we tested whether month of birth influences the risk of type 1 diabetes. For 8761 children diagnosed with type 1 diabetes between May 2005 and December 2016 in the Better Diabetes Diagnosis study, month of birth, sex and age were compared. Human leucocyte antigen (HLA) genotype and autoantibodies at diagnosis were analysed for a subset of the cohort (n=3647). Comparisons with the general population used data from Statistics Sweden. We found no association between month of birth or season and the incidence of type 1 diabetes in the cohort as a whole. However, boys diagnosed before 5 years were more often born in May (p=0.004). We found no correlation between month of birth and HLA or antibodies. In this large nationwide study, the impact of month of birth on type 1 diabetes diagnosis was weak, except for boys diagnosed before 5 years of age, who were more likely born in May. This may suggest different triggers for different subgroups of patients with type 1 diabetes.

HLA class II variants defined by next generation sequencing are associated with sarcoidosis in Korean patients

Polymorphic genes with immune functions, namely those of the human leukocyte antigen (HLA) system, have been implicated in sarcoidosis pathogenesis. As HLA polymorphisms in sarcoidosis have not been yet investigated in the Korean population, we used next-generation sequencing (NGS), allowing detailed characterization of HLA alleles to investigate the role of HLA variation in Korean sarcoidosis patients. We enrolled 103 patients diagnosed by the ATS/ERS/WASOG guidelines at Asan Medical Centre, Seoul, Korea. Among those, genotyping of 7 HLA loci (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -DPB1) was performed using Omixon Holotype™ kit and HLATwin software™. HLA allele frequencies were compared with frequency data on healthy Koreans from the allelic frequency databases, and 4-digit characteristics of HLA genotyping were used. Associations were assessed by two-tailed Fischer’s exact test with correction for multiple comparisons. Variants previously associated with sarcoidosis risk (HLA-C*03:04, HLA-DRB1*12:01, HLA-DRB1*14:54) and a known protective variant HLA-DPB1*04:01, were associated with sarcoidosis in Koreans. Further, we suggest new HLA variants associated with sarcoidosis risk (e.g., HLA-DQA1*05:08) and novel protective variants HLA-DQB1*03:02 and HLA-DQA1*01:02 in Koreans. This first study of HLA variation in Korean patients with sarcoidosis by precise genotyping methodology reports data that could serve future meta-analyses on HLA variation’s role in sarcoidosis.