Human Leukocyte Antigen Research Articles

Type 1 Diabetes Genetic Risk Scores: History, Application and Future Directions.

To review the genetics of type 1 diabetes (T1D) and T1D genetic risk scores, focusing on their development, research and clinical applications, and future directions. More than 90 genetic loci have been linked to T1D risk, with approximately half of the genetic risk attributable to the human leukocyte antigen (HLA) locus, along with non-HLA loci that have smaller effects to disease risk. The practical use of T1D genetic risk scores simplifies the complex genetic information, within the HLA and non-HLA regions, by combining the additive effect and interactions of single nucleotide polymorphisms (SNPs) associated with risk. Genetic risk scores have proven to be useful in various aspects, including classifying diabetes (e.g., distinguishing between T1D vs. neonatal, type 2 or other diabetes types), predicting the risk of developing T1D, assessing the prognosis of the clinical course (e.g., determining the risk of developing insulin dependence and glycemic control), and research into the heterogeneity of diabetes (e.g., atypical diabetes). However, there are gaps in our current knowledge including the specific sets of genes that regulate transition between preclinical stages of T1D, response to disease modifying therapies, and other outcomes of interest such as persistence of beta cell function. Several T1D genetic risk scores have been developed and shown to be valuable in various contexts, from classification of diabetes to providing insights into its etiology and predicting T1D risk across different stages of T1D. Further research is needed to develop and validate T1D genetic risk scores that are effective across all populations and ancestries. Finally, barriers such as cost, and training of medical professionals have to be addressed before the use of genetic risk scores can be incorporated into routine clinical practice.

Identification of Interleukin-Related Genes Signature for Prognosis Prediction in Head and Neck Squamous Cell Carcinoma Patients.

This study focused on identifying the interleukin (IL)-related genes that influence the head and neck squamous cell carcinoma (HNSCC) patients' prognosis and response to anticancer therapy in patients with HNSCC. We developed a risk model that included three gene signatures, IL Enhancer Binding Factor 2 (ILF2), IL 36 alpha (IL36A), and IL10, based on differential expression analysis, survival analysis, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and Cox regression analysis. We found that the low-risk group was scored with higher immune cell infiltration, higher expression of human leukocyte antigen (HLA) family genes and immune checkpoint genes, higher cytolytic activity (CYT), tertiary lymphoid structures (TLS), and CD8A/PD-L1 ratio. In contrast, the high-risk group was scored with higher tumor immune dysfunction and exclusion (TIDE), which implied worse response to immunotherapy and worse prognosis. The results above indicated that the low-risk group had stronger antitumor immunity and better responsiveness to immunotherapy. We also observed a significantly enriched pattern of cancer-related pathways and immune pathways in the comparison of the high-risk and low-risk groups. Furthermore, the high-risk group had higher sensitivity to chemotherapy drugs, which suggested that they might benefit from chemotherapy treatment. Following the results above, we confirmed in HNSCC cell lines and clinical specimens that the level of ILF2 in tumors was significantly higher than that in adjacent tumor tissues. Besides, in vivo and in vitro results both showed that silencing ILF2 might depress tumor growth, invasion, and migration. This study not only provided novel perspectives into the immunological and molecular mechanisms of HNSCC and uncovered IL-related gene signatures for predicting HNSCC patients' prognosis and response to chemotherapy and immunotherapy, but also preliminarily suggested that ILF2 might be an important target in the treatment of HNSCC.

VEGFR3 pathway in corneal transplantation.

Corneal transplantation, a common procedure in ophthalmology, faces challenges in high-risk (HR) cases due to inflammation and vascularization of the host bed, leading to graft rejection. Despite advancements in surgical techniques and therapeutics, preventing rejection in HR cases remains elusive. This study investigates the role of the vascular endothelial-derived growth factor (VEGF)-C/D-VEGFR3 pathway in corneal transplantation, focusing on its impact on inflammation and immune response. In this study, 42 eyes of 42 patients were evaluated, 24 of whom underwent corneal transplantation, with follow-up visits at 90, 180 and 360 days post-transplantation. Clinical assessments included visual acuity, corneal oedema, endothelial cell count and vascularization. Molecular analyses were performed to measure VEGFR3, VEGF-C, VEGF-D, VEGF-A and inflammatory markers. Results revealed a distinct pattern of VEGF-C/D and VEGFR3 expression in HR versus low-risk (LR) transplants, correlating with inflammatory markers and clinical outcomes. In HR cases, elevated VEGFR3 expression was associated with increased inflammatory markers (Intercellular Adhesion Molecule 1 (ICAM-1) and Human Leukocyte Antigen - DR isotype (HLA-DR)) and graft rejection risk. These findings underscore the importance of understanding the VEGF-C/D-VEGFR3 pathway in modulating immune responses and inflammation in corneal transplantation, particularly in HR cases. Targeting this pathway could offer novel therapeutic avenues to mitigate inflammation and improve graft survival. Further research is warranted to elucidate the underlying mechanisms and validate these findings, potentially enhancing transplant outcomes, especially in HR patients.

Understanding HLA-DQ in renal transplantation: a mini-review

Human leukocyte antigen (HLA) mismatching, particularly with HLA-DQ, significantly impacts the development of donor-specific antibodies (DSA) and transplant outcomes. HLA-DQ antibodies are highly immunogenic and detrimental, necessitating advanced high-resolution HLA typing to improve mismatch assessment and clinical risk evaluation. Traditional serological or low-resolution typing often misclassifies mismatches, leading to inaccuracies in assessing immunogenicity and predicting outcomes. Emerging molecular mismatch algorithms refine immunogenicity assessments by analyzing amino acid differences and structural interactions. These tools show promise for personalizing transplant protocols but have limitations, such as variability in predicting individual patient outcomes. Immunogenicity of mismatches also depends on evolutionary divergence and specific amino acid differences, with studies revealing that certain evolutionary lineages and polymorphisms influence T-cell alloreactivity and DSA development. Complexities in HLA-DQ protein expression, including combinatorial diversity of heterodimers and inter-isotypic heterodimers, further complicate risk evaluation. Expression levels, influenced by tissue specificity and inflammatory stimuli, and alternative splicing of HLA-DQ transcripts add additional layers of variability. Future clinical applications, enabled by high-resolution HLA typing, may include refined graft selection, improved DSA monitoring, and individualized therapy. However, understanding the precise mechanisms of HLA-DQ immunogenicity remains a priority for advancing transplantation science and enhancing patient outcomes.

Constructing a potential HLA haplo-homozygous induced pluripotent stem cell haplobank using data from an umbilical cord blood bank

BackgroundInduced pluripotent stem cells (iPSCs) can differentiate into any type of cell and have potential uses in regenerative medicine for the treatment of many diseases. However, reducing immune rejection is a key problem in the application of iPSCs that can be solved by the development of haplobanks containing specially selected iPSC lines.MethodsTo study the feasibility of constructing an HLA (human leukocyte antigen)-matched induced pluripotent stem cell haplobank in China, 5421 umbilical cord blood samples were randomly collected from the Umbilical Cord Blood Bank of Zhejiang Province, China. The HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci were genotyped using next-generation sequencing. Using HLA genotype data at the high-resolution level, the number of HLA homozygous donors needed to cover a certain percentage of the Chinese population and the feasibility of constructing a high-matching iPSC haplobank were estimated.ResultsThirteen HLA-A, -B, and -DRB1 and 11 HLA-A, -B, -C, -DRB1, and -DQB1 haplotype homozygotes were observed among the stored umbilical CB units which were as HLA zero-mismatched iPSC donors cumulatively matched 37.01% and 32.99% of 5421 potential patients respectively. The analysis showed that 100 distinct HLA-A, -B, and -DRB1 and HLA-A, -B, -C, -DRB1, and -DQB1 homozygous haplotypes would cover 72.74% and 67.87% of Chinese populations, respectively, and 600 HLA-A, -B, -C, -DRB1, and -DQB1 homozygous haplotypes would cover more than 90% of Chinese populations. PCA (principal component analysis) of published HLA data from different populations revealed that the frequency of these haplotypes in Asian populations is different from those in European populations.ConclusionThe results suggested that at least some HLA-homozygous iPSC lines developed from Chinese individuals will not only be useful for covering the Chinese population but will also cover other Asian populations. A high-matching iPSC haplobank generated from umbilical CB units may be an economical and effective option in an allogeneic model of iPSC therapy.

Immunogenetics of longevity and its association with human endogenous retrovirus K

IntroductionThe human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality.MethodsWe utilized high-resolution genotyping to characterize HLA and apolipoprotein E in a large sample (N = 986) of participants (469 men, 517 women) ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. Since each individual carries 12 classical HLA alleles (6 alleles of each Class I and Class II), we determined in silico the median predicted binding affinity for each individual (across the 12 HLA alleles) and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW). Next, we performed a stepwise multiple linear regression where the age of the participant was the dependent variable and the 13 median predicted HLA-virus binding affinities were the independent variables.ResultsThe analyses yielded only one statistically significant effect–namely, a positive association between age and HERVK (P = 0.005). Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses (P < 0.001). ApoE genotypes did not differ significantly between older and younger groups.DiscussionTaken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.

Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics.

Medulloblastoma is the most frequent malignant primary brain tumor in children. Despite recent advances in integrated genomics, the prognosis in children with high-risk medulloblastoma remains devastating, and new tumor-specific therapeutic approaches are needed. Here, we present an atlas of naturally presented T cell antigens in medulloblastoma. We map the human leukocyte antigen (HLA)-presented peptidomes of 28 tumors and perform comparative immunopeptidome profiling against an in-house benign database. Medulloblastoma is shown to be a rich source of tumor-associated antigens, naturally presented on HLA class I and II molecules. Remarkably, most tumor-associated peptides and proteins are subgroup-specific, whereas shared presentation among all subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) is rare. Functional testing of top-ranking novel candidate antigens demonstrates the induction of peptide-specific T cell responses, supporting their potential for T cell immunotherapy. This study is an in-depth mapping of naturally presented T cell antigens in medulloblastoma. Integration of immunopeptidomics, transcriptomics, and epigenetic data leads to the identification of a large set of actionable targets that can be further used for the translation into the clinical setting by facilitating the informed design of immunotherapeutic approaches to children with medulloblastoma.

Frequent detection of anti-nuclear antibodies and low-titer rheumatoid factor in female patients with undifferentiated peripheral spondyloarthritis in Japan: a prospective observational study.

Studies on the clinical features of undifferentiated peripheral spondyloarthritis (upSpA) are limited. This study explores sex-based manifestations of upSpA and compares upSpA with rheumatoid arthritis (RA) under conditions of low human leukocyte antigen B27 positivity in Japan. In this multicenter prospective observational study, physical and laboratory findings from 29 upSpA cases (19 females, 10 males) were collected to investigate sex differences. Fourteen patients with RA were also enrolled as a control group to evaluate clinical parameters distinguishing upSpA and RA. Tenderness at the humeral epicondyles and the Achilles tendon were more common in female patients with upSpA than in males. Serum C-reactive protein (CRP) levels were lower in female patients with upSpA than in male patients. Serum rheumatoid factor (RF) levels were lower in upSpA cases than in RA, with a cut-off value of 84 IU/mL differentiating RA from upSpA. An anti-nuclear antibodies (ANA) test at a dilution of ≥1:160 was detected in about half of the female upSpA cases but not in male cases. Among upSpA and RA cases, female patients with upSpA frequently present with multiple enthesitis, low serum CRP levels, low-titer RF positivity, and a high incidence of ANA positivity.

Transvitreal Retinochoroidal Biopsies of Primary Uveal Melanoma Reveal an Association of Low HLA Class I and High NK Cell Abundance in Low-Risk Disease.

Immune cells in primary uveal melanoma (PUM) have mostly been studied in enucleated tissue, thereby precluding material from thinner, low-risk PUM tumors for research purposes. Here, we investigated the feasibility of using tumor tissue acquired by transvitreal retinochoroidal (TVRC) tumor biopsies to study the tumor immune microenvironment and relation to genetic risk class. Collected tumor biopsies of 41 patients were tested for genetic aberrations to determine high-risk (n = 19), medium-risk (n = 12), and low-risk (n = 9) tumors and were digested for flow cytometry analysis of immune cell and tumor markers. In addition, 13 patient-matched enucleated tumors were stained using multiplex immunohistochemistry. Tumor biopsies showed a high variability in the degree of immune infiltration. The tumor-specific lymphocyte infiltration pattern correlated well with the infiltration pattern in patient-matched enucleations. High-risk tumors tended to have a higher abundance of CD8 T cells, which expressed activation markers CD39, CD69, and PD-1, with reduced CD127 expression. In general, low-risk tumors exhibited decreased human leukocyte antigen (HLA) class I expression, coinciding with a higher abundance of natural killer (NK) cells (P = 0.0049), indicating a different lymphocyte infiltration pattern between low-, medium- and high-risk tumors. TVRC biopsies are a suitable and valuable source of PUM tissue for research purposes. An abundance of CD8 T cells was found in high-risk PUM tumors. Further, medium- and low-risk PUM tumors are characterized by decreased HLA class I expression with a concomitant increase in NK cell infiltration as compared to high-risk PUM tumors, correlating with decreased risk of disease recurrence.

Trisomy 8‐Positive Atypical Neuro‐Behçet's Disease With Recurrent Fever Attacks and Meningitis Over 17 Years

ABSTRACTTrisomy 8 very rarely causes atypical Behçet's disease without myelodysplastic syndrome (MDS). We report the case of 75‐year‐old woman with trisomy 8 who developed an atypical neuro‐Behçet's disease (NBD) without MDS. She developed aseptic meningitis and ileal ulcers after 17 years of recurrent fever attacks with high C‐reactive protein levels. Despite steroid treatment, her condition deteriorated. Laboratory tests showed human leukocyte antigen (HLA)‐B54, HLA‐Cw1, and a heterozygous E148Q mutation in the MEFV gene. She had no MDS complications. Colchicine and adalimumab were effective. Two years later, pathergy and genital ulcers appeared. We diagnosed NBD based on the symptoms. Chromosomal abnormalities, genetic factors, and HLA typing could influence symptoms and treatment responsiveness.

Disulfidptosis-related immune patterns predict prognosis and characterize the tumor microenvironment in oral squamous cell carcinoma

BackgroundEstablishing a prognostic risk model based on immunological and disulfidptosis signatures enables precise prognosis prediction of oral squamous cell carcinoma (OSCC).MethodsDifferentially expressed immune and disulfidptosis genes were identified in OSCC and normal tissues. We examined the model’s clinical applicability and its relationship to immune cell infiltration. Additionally, the risk score, ssGSEA, ESTIMATE, and CIBERSORT were used to evaluate the intrinsic molecular subtypes, immunological checkpoints, abundances of tumor-infiltrating immune cell types and proportions between the two risk groups. GO-KEGG and GSVA analyses were performed to identify enriched pathways.ResultsWe analyzed the correlation immune genes based on the 14 disulfidptosis-related genes, and found 379 disulfidptosis-related immune genes (DRIGs). After univariate Cox regression we obtained 30 DRIGs and least absolute shrinkage and selection operator (LASSO) regression to reduce the number of genes to 16. Finally we created a nine-DRIGs risk model, of which four were upregulated and five were downregulated. The analysis results showed that disulfidptosis was tightly related to immune cells, immunological-related pathways, the tumor microenvironment (TME), immune checkpoints, human leukocyte antigen (HLA), and tumor mutational burden (TMB). The nomogram, integrating the risk score and clinical factors, accurately predicted overall survival.ConclusionsThis novel risk model highlights the role of disulfidptosis-related immune genes in OSCC prognosis. With this model, we can more accurately predict the prognosis of patients with OSCC, as well as assess the potential effects of their TME and immunotherapy.

Correlation of HLA-A and HLA-B/C Expression With ESR1 Expression in Patients With Metastatic Breast Cancer as a Potential Prognosticator of Favorable Distant Disease-free Survival.

The loss of breast cancer cell differentiation during metastatic progression leads to a down-regulation of class 1 human leukocyte antigen (HLA) expression, which in turn hinders cytotoxic T lymphocytes from effectively preventing tumor cell proliferation. Consequently, one would expect that decreased HLA expression would correlate with decreased 5-year survival. However, estrogen receptor alpha (ESR1) is known to be positively associated with overall survival. The study aimed to determine the expression levels of HLA-A, HLA-B/C, and ESR1 and to assess their influence on distant disease-free survival (DDFS). This retrospective subgroup analysis of the initial prospective, single-center, double-blind cohort study included a total of 34 patients who underwent a new treatment line for metastatic breast cancer (MBC). The MBC cells were examined using RT-qPCR. The acquired data and the subsequent survival and ROC analyses indicated a positive association of reduced expression of HLA-A and HLA-B/C with DDFS. A statistically significant association of ESR1 with DDFS could not be shown. A potential positive association between reduced expression of HLA-A and HLA-B/C and DDFS is observed. This contrasts with the generally observed association between HLA expression loss and poor prognosis, as reported in previous protein-based studies. In metastatic settings, reduced expression of particular HLA subsets, measured at the mRNA level, might have a protective effect against disease progression.

EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with pancreatic cancer (PANC) or other mesothelin (MSLN)-expressing solid tumors and human leukocyte antigen (HLA)–A*02 loss of heterozygosity (LOH).

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .

Allogeneic Hematopoietic Cell Transplantation in Elderly Patients in a Latin American Country: Analysis of 11 Year of Data from the Brazilian Registry SBTMO/CIBMTR.

This study analyzed recent changes in the utilization of allogeneic hematopoietic cell transplantation (HCT) for treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative diseases (MPDs) and the survival of HCT recipients ≥60 years of age in Brazil. This retrospective registry study included patients who received a first allogeneic HCT from any donor between 2012 and 2023. Of the 6657 patients, 444 (7%) were 60 years of age or older who received grafts from human leukocyte antigen (HLA)-matched related (42%) or unrelated (20%) donors or HLA-haploidentical donors (32%). The proportion of HCT recipients 60 years of age or older increased gradually from 3.2% in 2012 to 16% in 2023 mostly due to the increased use of HLA-haploidentical donors since 2018. Overall survival (OS) at day 100 was 77%, and estimated OS at 12 months was 53% (95% CI, 48%-58%). OS at 12 months was higher for transplants during 2015 to 2017 (58%) and 2018 to 2020 (68%) compared with 2012 to 2014 (45%), but it did not differ for those during 2021 to 2023 (49%). Mortality with HLA-haploidentical donors (HR, 2.35; 95% CI, 1.65-3.34 [P < .001]) and cord blood donors (HR, 4.68; 95%,CI, 1.29-16.9 [P = .01]) was higher than with HLA-matched related donors. Mortality was lower for patients with transplants during the 2015 to 2020 period (HR, 0.57; 95% CI, .34-.96 [.037]) than for those during 2012 to 2014.This study revealed a gradual increase in the use of allogeneic HCT in individuals aged 60 years and older in Brazil. While use of haploidentical donors has increased worldwide, its association with increased mortality in the elderly population warrants caution when considering this treatment.

Peripheral monocyte subsets are altered during gestation in oocyte donation pregnancy complicated with pre-eclampsia.

Oocyte donation (OD) pregnancies show a higher fetal-maternal incompatibility and a higher risk of developing pre-eclampsia (PE) than autologous pregnancies. As maternal monocytes play a role in the tolerization of the allogeneic fetus, the aim of this study was to analyse monocyte phenotypes in healthy and PE OD pregnancies. We collected maternal peripheral blood at different gestational time points in healthy (n = 10) and PE (n = 5) OD pregnancies. Fetal-maternal human leukocyte antigen (HLA) mismatches were calculated. We used a 35-colour antibody panel for Aurora spectral flow cytometry to analyse the composition and surface marker expression of monocyte subsets. Expression of CD38 on intermediate monocytes significantly increased throughout gestation in healthy OD pregnancies. Compared with the healthy group, the PE group exhibited even higher CD38 expression on monocyte subsets, with statistical significance. Immune inhibiting receptors CD85j (LILRB1) and CD85d (LILRB2), as well as monocyte recruitment regulating molecules CCR2 and CD91, also showed significantly enhanced expression on monocyte subsets during PE. When comparing healthy and PE OD only in pregnancies with high HLA mismatches, the different CD38 and CD85j expression in monocyte subsets was still significant. In conclusion, in healthy OD pregnancies, the upregulated CD38 expression might reflect a proinflammatory condition specifically at the third trimester. In PE OD pregnancies, expression of both inflammatory and immune regulatory markers is increased in maternal peripheral monocyte subsets. The elevated expression of CCR2 and CD91 on these subsets might reflect monocyte chemotaxis and the effect from systemic vascular dysfunction at the late stage of PE.

What is new in the management of coeliac disease?

Coeliac disease is the most common immune-mediated enteropathy, affecting approximately 1 % of the population worldwide. Currently, the vast majority of individuals remain undiagnosed. Coeliac disease is triggered by gluten ingestion in genetically predisposed individuals carrying the human leukocyte antigen (HLA) genes; HLA-DQ2 and HLA-DQ8. Patients with coeliac disease present with a wide spectrum of gastrointestinal and extraintestinal manifestations and, in some cases, without any symptoms. The diagnosis of coeliac disease in adults is based on a combination of clinical suspicion, positive serological markers and histological evidence of small intestinal atrophy on duodenal biopsies. The only effective treatment is a strict, lifelong gluten-free diet. However, up to 20 % of patients report persistent or recurrent symptoms. In this review, we provide a comprehensive update on coeliac disease, focusing on its relevance to the different medical specialities and highlighting the need for a multidisciplinary approach to its diagnosis and management. Clinicians practicing internal medicine have a unique opportunity to diagnose this multisystem autoimmune disease. By doing so, they would avoid delays in diagnosis for these patients. A low threshold for serological testing is recommended.

Correlation of mesothelin (MSLN) expression measured by RNA sequencing (RNASeq) and immunohistochemistry (IHC) in MSLN-expressing tumors.

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P &lt;0.001). MSLN expression by RNAseq and IHC were correlated overall ( P &lt;0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

Screening for immunodominant epitopes of SARS-CoV-2 based on CD8+ T cell responses from individuals with HLA-A homozygous alleles.

SARS-CoV-2-specific CD8+ cytotoxic T lymphocytes (CTLs) are crucial in viral clearance, disease progression, and reinfection control. However, numerous SARS-CoV-2 immunodominant CTL epitopes theoretically are still unidentified due to the genetic polymorphism of human leukocyte antigen class I (HLA-I) molecules. The CTL epitopes of SARS-CoV-2 were predicted by the epitope affinity and immunogenicity prediction platforms: the NetMHCpan and the PromPPD. Individuals with HLA-A homozygous alleles were screened from 252 COVID-19 vaccinees, including the Ad5-nCoV vaccine (CanSino, n = 183) and the CoronaVac inactivated vaccine (Sinovac, n = 69) using MiSeqDx™ generation sequencing, and their PBMCs were further stimulated by the predicted peptides to screen the immunodominant epitopes according to the secretion of IFN-γ from CD8+ T cells. Peptide-MHC tetramers were constructed and used to detect the frequency of antigen specific CTLs in vivo. Individuals with HLA-A homozygous alleles including HLA-A*01 (n = 1), -A*02 (n = 9), - A*03 and -A*11 (n = 12), and -A*24 (n = 7) supertypes were selected. Twelve immunodominant CTL epitopes for these HLA-A allotypes were finally screened based on the frequency of IFN-γ+CD8+ T cells in homozygous individuals. The SARS-CoV-2 specific CTLs from Omicron variant infected patients were successfully evaluated by these novel peptide-HLA tetramers. A set of immunodominant CTL epitopes of SARS-CoV-2 was identified, and the antigen-specific CD8+ T cells in viral infected patients or COVID-19 vaccinees could be rapidly detected by a mixture of the peptide-MHC tetramers.

Multiple classes of antigen contribute to the antigenic landscape of mesothelioma.

Mesothelioma is an incurable, asbestos-exposure related cancer that typically affects the lining or pleura of the lungs. Symptoms typically develop many decades after initial exposure to asbestos, leaving an enduring legacy of disease. Current disease burden is peaking worldwide and thus there is a massive unmet clinical need for curative therapies. Recently, immune checkpoint blockade-based therapy has been adopted as a first-line of treatment for mesothelioma. Vaccine-induced augmentation of immune responses unleashed during checkpoint blockade may provide further clinical benefit in mesothelioma. In this study we explore the human leukocyte antigen class I landscape (or immunopeptidome) of mesothelioma in patient derived cell line and clinical material (pleural effusion samples). We identify a range of peptide antigens derived from targets including cancer testis antigens, endogenous retroviruses as well as novel post-translational modification of peptides. This information will facilitate the characterization of the immune response to these antigens to determine which class of antigen is most immunogenic and has the potential to be tested in future vaccine studies.

Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange.

Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.