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Background and Objectives: Antibodies to human leucocyte antigen (HLA) Class‐I antigens can lead to refractoriness to platelet transfusion. Although this can be overcome by transfusion of HLA‐compatible platelets, they are not always available. Disruption of HLA antigens on platelets by acid treatment may be a suitable alternative when no other components are available. The aim of this study was to assess the effect of HLA disruption and subsequent storage of platelet components. Materials and Methods: Platelet components were treated with 0.9% saline or citric acid solution (pH 3.0), and then stored until expiry (Day 7). HLA and platelet glycoprotein expression, platelet viability, activation and sialylation were measured by flow cytometry. Release of soluble factors was measured by ELISA and metabolism by biochemistry analyser. Reactivity to patient anti‐sera containing anti‐HLA antibodies was measured using platelet immunofluorescence tests (PIFTs) and monoclonal antibody immobilization of platelet antigen (MAIPA) assays. Platelet function was measured using aggregometry and thromboelastography (TEG). Results: Acid treatment reduced detection of HLA Class‐I on platelets by 75%, with significant reductions in reactivity to patient anti‐sera. Acid treatment reduced platelet content and viability, increased platelet activation and accelerated metabolism. Glycan cleavage was increased by acid treatment. Treatment reduced platelet activation following agonist stimulation by ADP and TRAP‐6, but platelets remained functional, displaying increased aggregation response and reduced time to clot formation by TEG. Conclusion: Although HLA disruption had some detrimental effects, acid‐treated platelets remained functional, retaining their capacity to respond to agonists and form clots, and with further development could be used to support refractory patients. [ABSTRACT FROM AUTHOR]

Solid organ transplantation has progressed dramatically over the last 50 years; however, rejection still remains one of the barriers to successful transplantation. Immunological processes underlying the mechanisms of rejection are well described and numerous pharmacological agents exist to help suppress a recipient's immune system in order to prolong graft survival. Furthermore, clinician decisions and actions during both the work-up of a potential transplant recipient and in the perioperative phase can impact upon the immunological status of an individual and the likelihood of successful solid organ transplantation. In this article we aim to describe the key processes involved in solid organ immunology and their relevance in anaesthetic practice. [ABSTRACT FROM AUTHOR]

Aims: To report the clinicopathological features of Kikuchi disease in patients with acute leukaemia, emphasising similarities among cases. Methods and results: In a cohort of 454 Kikuchi disease patients, we identified three cases of concurrent acute leukaemia. These patients shared similar clinical traits, with Kikuchi disease emerging approximately a month after induction chemotherapy onset, featuring neck‐region lymphadenopathy. Notably, two patients were middle‐aged, deviating from the typical age distribution of Kikuchi disease. Histologically, these cases aligned with typical Kikuchi disease. Negative immunohistochemical stains (CD34, CD117, ERG, TdT) indicated the absence of extramedullary leukaemic infiltration. Herpes simplex virus immunohistochemical staining was also negative. Significantly, a human leucocyte antigen (HLA) association was observed in these three cases. HLA‐B*15:01, C*04:01, and DRB1*04:06 were more prevalent in these patients compared to the general population (compared with three independent control cohorts: Taiwanese Han Chinese (n = 504), Tzu Chi Taiwanese bone marrow donors (n = 364) and Hong Kong Chinese (n = 5266)). Conclusions: Our study underscores the unique link between Kikuchi disease and acute leukaemia, characterised by specific features and HLA associations. This underlines Kikuchi disease as a possible differential diagnosis in pertinent clinical scenarios. Furthermore, this syndrome offers insights into postchemotherapy immunology in acute leukaemia, enhancing comprehension. [ABSTRACT FROM AUTHOR]

Abstract Background Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. Methods: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. Results Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2–266.8; P = 1.9 × 10− 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3–670.5 and p-value = 1.7 × 10− 27). Conclusions Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

In the past, identification of HLA alleles was limited to sequencing the region of the gene coding for the peptide binding groove, resulting in a lack of sequence information in the HLA database, challenging HLA allele assignment software programs. We investigated full-length sequences of 19 HLA class I and 7 HLA class II alleles, and we extended another 47 HLA class I alleles with sequences of 5′ and 3′ UTR regions that were all not yet available in the IPD-IMGT/HLA database. We resolved 8638 unknown nucleotides in the coding sequence of HLA class I and 2139 of HLA class II. Furthermore, with full-length sequencing of the 26 alleles, more than 90 kb of sequence information was added to the non-coding sequences, whereas extension of the 47 alleles resulted in the addition of 5.5 kb unknown nucleotides to the 5′ UTR and > 31.7 kb to the 3′ UTR region. With this information, some interesting features were observed, like possible recombination events and lineage evolutionary origins. The continuing increase in the availability of full-length sequences in the HLA database will enable the identification of the evolutionary origin and will help the community to improve the alignment and assignment accuracy of HLA alleles. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an immune disorder, that is triggered by gluten ingestion in genetically predisposed individuals. The HLA‐DQB1*02 allele is the main predisposing genetic factor and a candidate for first‐line genotyping screening. We designed and validated a simple, DNA purification‐free PCR protocol directly from crude saliva, enabling the detection of the DQB1*02 allele. This assay also distinguishes homozygous from heterozygous carriers. We propose this method for use in mass screening and/or epidemiological studies. [ABSTRACT FROM AUTHOR]

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin–clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim–sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system. [ABSTRACT FROM AUTHOR]

Tertiary lymphoid structures (TLSs) are increasingly recognized as pivotal formations in antitumor immunity, with many mature TLSs relating to favorable prognosis in a variety of cancers. Analysis of the transcriptome data provided an opportunity to investigate the relationship between TLSs and the clinical outcomes of patients. We performed transcriptome analysis to examine the expression patterns of 79 TLS-related genes within 32 cancers from The Cancer Genome Atlas, correlating these patterns to the clinical outcomes of patients. To improve the analysis, we developed a novel prognostic signature (TLSig) and validated its robust performance via multiple independent cancer cohorts. Our results demonstrated that the expression of TLS-related genes exhibited significant heterogeneity across cancers; and that TLSig was significantly associated with patient prognosis within most cancer types. Specifically, TLSig expressed potential prediction of whether patients would benefit from immunotherapy and presented significant interactions with epithelial to mesenchymal transition (EMT) and the cell cycle. Moreover, a difference in the distribution of TLSs between tumor and nontumor tissues was observed, which was validated in hepatocellular carcinoma (HCC) samples. We further investigated the potential mechanism for the difference in the distribution of TLSs between tumor and nontumor tissues of HCC, and observed the connection between TLSs and human leucocyte antigen (HLA). In summary, our results demonstrated the prognostic value of TLSs in predicting patient prognosis and provided new insights into the molecular mechanism of TLSs in cancer. [ABSTRACT FROM AUTHOR]

Background: Persistent human papillomavirus (HPV) infection is a necessary cause for development of cervical precancerous lesions and cervical cancer, however, only a small percentage of women progress to cervical cancer. The local immune response, determined, among other factors, by Human Leucocyte Antigen (HLA) genes, is thought to be significant. Still the results of genome studies are inconsistent and differ between ethnical populations. The aim of the study was to assess an association between HLA-DQA1*; DQB1*; DRB1* allele’s genetic variants between women with cervical precancerous lesions and healthy controls in Latvia.Materials and methods: From January until April 2017 we enrolled 84 consecutive patients referred for colposcopy to Riga East University Hospital (Latvia) due to abnormal cervical cytology results. 57 women who came for a regular check-up and had normal cytology smears were included in the control group. Material from the cervix was taken for subsequent HLA genotyping of 13 DRB1*, 8 DQA1*, and 12 DQB1* alleles. Colposcopy was performed on all participants. In case of visual suspicion for CIN cervical biopsy was done.Results: There were 57 “no CIN” patients, 23 histologically proven CIN 1 and 61 CIN2+ cases in the study population. CIN2+ was more often associated with DQA1*0401 (OR 6.68, 95% CI 1.47-30.29, p=0.014), DRB*15 (OR 2.99, 95% CI 1.22-7.39, p=0.017), DQB1*0401 (OR 2.91, 95%CI 1.11-7.68, p=0.03), DQA1*0103 (OR 2.72, 95% CI 1.02-7.21, p=0.045), DRB1*11 (OR 2.42, 95% CI 1.10-5.33, p=0.029) and DQB1*0301 (OR 1.94, 95% CI 1.12-3.38, p=0.018). Women with “no CIN” more often had DQB1*0501 (OR 0.17, 95% CI 0.04-0.81, p=0.026), DRB1*16 (OR 0.21, 95% CI 0.06-0.78, p=0.019), DQA1*0301 (OR 0.35, 95% CI 0.14-0.87, p=0.024) and DRB1*14 (OR 0.59, 95% CI 0.01-0.46, p=0.007).Conclusions: In the current study we have demonstrated a strong association with risk and protective HLA class II alleles that are determined by the HLA-DRB1*; DQA1*; DQB1*.

Introduction: Rheumatic fever and RHD constitutes an important public health problem in India. The relatively low attack rate of RF, the high concordance rate for RF in monozygotic twins (19%) compared to dizygotic twins (2.5%), and the high familial incidence of RF suggest the involvement of host genetic factors in susceptibility to RF with consequential progression to RHD. Objective: To study the association of HLA CLASS II DR/DQ alleles in children and adolescents with RHD from a tertiary care center in North India. Methods: 30 RHD patients and 30 age and sex-matched controls were included in our study and blood samples for HLA typing were processed through LAB Type™ reverse SSO DNA typing method. The assignment of the HLA typing was based on a comparison with already published HLA gene sequences. Results: The mean age of RHD patients and matched control groups were 12.97 ± 2.95 and 11.93 ± 3.23, respectively. In the cases and control group, males accounted for 63.3% and 50% of the patients respectively. A significant difference was found between the cases and controls for HLA DR∗ 15 (p-value 0.002), HLA DR∗ B4 (p-value 0.045), HLA DR∗ B5 (p-value 0.017), and HLA DQB1∗ 02 (p-value 0.005). Conclusion: Our study suggests that HLA class II haplotypes may provide insight into the molecular mechanism of RHD and be a useful tool in predicting the clinical outcome in RF patients, thereby affording new means of intervention or vaccine design. Larger studies are needed to address this in our population.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10−304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10−33; OR = 4.26) and rs7765379 (p = 5.08 × 10−18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Background: Perioperative anaphylaxis (POA) can lead to severe consequences. Identifying clinical risk factors and genetic loci associated with POA through pre-prescription screening may help reduce its incidence. Methods: Using univariate regression and covariate-adjusted multivariate regression, we retrospectively analyzed the association between clinical characteristics and POA in 72 POA patients and 72 non-POA individuals. The discovery study of whole-exome association relied on whole-exome sequencing of 73 POA cases and 1339 healthy individuals. A replication study involving an independent set of 16 POA cases and 1339 healthy individuals confirmed this association. The accurate typing of human leucocyte antigen through exome sequencing (ATHLATES) algorithm and the whole-exome sequencing data were used for genotyping the human leucocyte antigen G (HLA-G) of 73 POA patients. The HLA-G of 16 POA cases and 122 non-POA patients were genotyped through Sanger sequencing. We used Fisher's exact probability method to compare the allele and carrier frequencies between POA patients and healthy individuals or non-POA patients. A Pc (P/Bonferroni correction coefficient)

Background: Preeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed. Methods: Single-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte. Results: A total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation. Conclusions: We revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Chronic subdural hematoma (CSDH) pathophysiology has undergone a paradigm shift from being regarded as solely traumatic to be driven mainly by inflammation. Human leucocyte antigen (HLA) is a gene complex involved in antigen processing and presentation to T lymphocytes, thereby mediating the adaptive immune responses. As specific HLA profiles are associated with inflammatory diseases, patients with a specific HLA profile may have a lower threshold for subdural inflammation, and therefore are predisposed for CSDH development. We hypothesized that (1) CSDH patients have a specific HLA profile compared to a Danish background population, and (2) patients with recurrent CSDH have a specific HLA profile compared to CSDH patients without recurrent CSDH. Methods: Three specific HLA class II haplotypes known to drive inflammatory-mediated diseases were determined in 68 patients with CSDH. The distribution of these three haplotypes in our CSDH population was compared to a Danish population of blood donors using Monte Carlo Pearson's chi-square test. Furthermore, the distribution of the haplotypes was compared between CSDH patients with and without recurrent CSDH. Results: We found no significant association between either of the haplotypes and the risk of CSDH, and neither of the haplotypes were associated with increased risk of CSDH recurrence. Conclusion: This study did not show an association between selected HLA class II haplotypes and the risk of CSDH or recurrence of CSDH compared with a healthy background population. [ABSTRACT FROM AUTHOR]

Aims: Idiopathic type 1 diabetes (T1D) is a neglected subtype of T1D. Our aim was to investigate the frequency, clinical characteristics, and human leucocyte antigen (HLA) genotypes of idiopathic T1D. Methods: We enrolled 1205 newly diagnosed T1D patients in our analysis. To exclude monogenic diabetes in autoantibody‐negative patients, we utilised a custom monogenic diabetes gene panel. Individuals negative for autoantibodies and subsequently excluded for monogenic diabetes were diagnosed with idiopathic T1D. We collected clinical characteristics, measured islet autoantibodies by radioligand assay and obtained HLA data. Results: After excluding 11 patients with monogenic diabetes, 284 cases were diagnosed with idiopathic T1D, accounting for 23.8% (284/1194) of all newly diagnosed T1D cases. When compared with autoimmune T1D, idiopathic T1D patients showed an older onset age, higher body mass index among adults, lower haemoglobin A1c, higher levels of fasting C‐peptide and 2‐h postprandial C‐peptide, and were likely to have type 2 diabetes (T2D) family history and carry 0 susceptible HLA haplotype (all p < 0.01). A lower proportion of individuals carrying 2 susceptible HLA haplotypes in idiopathic T1D was observed in the adult‐onset subgroup (15.7% vs. 38.0% in child‐onset subgroup, p < 0.001) and in subgroup with preserved beta‐cell function (11.0% vs. 30.1% in subgroup with poor beta‐cell function, p < 0.001). Multivariable correlation analyses indicated that being overweight, having T2D family history and lacking susceptible HLA haplotypes were associated with negative autoantibodies. Conclusions: Idiopathic T1D represents about 1/4 of newly diagnosed T1D, with adult‐onset and preserved beta‐cell function patients showing lower HLA susceptibility and more insulin resistance. [ABSTRACT FROM AUTHOR]

Aims: Hip resurfacing remains a potentially valuable surgical procedure for appropriately-selected patients with optimised implant choices. However, concern regarding high early failure rates continues to undermine confidence in use. A large contributor to failure is adverse local tissue reactions around metal-on-metal (MoM) bearing surfaces. Such phenomena have been well-explored around MoM total hip arthroplasties, but comparable data in equivalent hip resurfacing procedures is lacking. In order to define genetic predisposition, we performed a case-control study investigating the role of human leucocyte antigen (HLA) genotype in the development of pseudotumours around MoM hip resurfacings. Methods: A matched case-control study was performed using the prospectively-collected database at the host institution. In all, 16 MoM hip resurfacing 'cases' were identified as having symptomatic periprosthetic pseudotumours on preoperative metal artefact reduction sequence (MARS) MRI, and were subsequently histologically confirmed as high-grade aseptic lymphocyte-dominated vasculitis-associated lesions (ALVALs) at revision surgery. ‘Controls’ were matched by implant type in the absence of evidence of pseudotumour. Blood samples from all cases and controls were collected prospectively for high resolution genetic a nalysis targeting 11 separate HLA loci. Statistical significance was set at 0.10 a priori to determine the association between HLA genotype and pseudotumour formation, given the small sample size. Results: Using a previously-reported ALVAL classification, the majority of pseudotumour-positive caseswere found to have intermediate-grade group 2 (n = 10; 63%) or group 3 (n = 4; 25%) histological findings. Two further patients (13%) had high-grade group 4 lesions. HLA-DQB1*05:03:01 (p = 0.0676) and HLA-DRB1*14:54:01 (p = 0.0676) alleles were significantly associated with a higher risk of pseudotumour formation, while HLA-DQA1*03:01:01 (p = 0.0240), HLA-DRB1*04:04:01 (p = 0.0453), HLA-C*01:02:01 (p = 0.0453), and HLA-B*27:05:02 (p = 0.0855) were noted to confer risk reduction. Conclusion: These findings confirm the association between specific HLA genotypes and the risk of pseudotumour development around MoM hip resurfacings. Specifically, the two ‘at risk’ alleles (DQB1*05:03:01 and DRB1*14:54:01) may hold clinical value in preoperative screening and prospective surgical decision-making. Cite this article: Bone Jt Open 2023;4(3):182–187.

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin–clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim–sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

Introduction: In this study, we evaluated whether SARS‐CoV‐2 mRNA vaccines induce anti‐human leukocyte antigen (HLA) antibodies and anti‐ ABO blood type antibodies (ABOAb) in kidney transplant recipients (KTRs). Methods: Sixty‐three adult KTRs with functioning grafts who received two doses of the SARS‐CoV‐2 mRNA vaccine were enrolled in this cohort. Changes in anti‐ABO blood type immunoglobulin IgM and IgG antibody titers, flow panel reactive antibody (PRA), de novo donor‐specific anti‐human leukocyte antigen antibodies (DSA), and kidney allograft function before and after vaccination were evaluated. Results: Only one patient experienced conversion from negative to positive flow PRA after vaccination. However, there was no DSA in single antigen flow‐bead assays. The mean fluorescence intensity (MFI) in the eight DSA‐positive recipients did not significantly change before and after vaccination (p =.383), and no additional DSA was produced after vaccination in those patients. No significant elevation of ABOAb titer was observed for either IgM (p =.438) or IgG (p =.526) after vaccination. There was no significant deterioration in estimated glomerular filtration rate (eGFR) after vaccination (p =.877) or elevation of the urine protein‐to‐creatinine ratio (p =.209) after vaccination. One episode of AMR was observed in addition to a preexisting acute cellular rejection. Conclusions: The SARS‐CoV‐2 mRNA vaccine did not induce anti‐HLA antibody or ABOAb production in KTRs. [ABSTRACT FROM AUTHOR]

Objective To analyze the correlation between internal iliac artery calcification and delayed graft function (DGF) and short-term prognosis of kidney transplant recipients. Methods Clinical data of 222 kidney transplant recipients were retrospectively analyzed. According to the recovery of renal function, all recipients were divided into the DGF group (n=50) and immediate graft function (IGF) group (n=172). According to whether the recipients were complicated with severe internal iliac artery calcification, DGF and IGF groups were further divided into the high-risk DGF (n=22), low-risk DGF (n=28), high-risk IGF (n=41) and low-risk IGF(n=131) subgroups, respectively. Clinical data of donors and recipients were statistically compared between two groups. The incidences of postoperative DGF and internal iliac artery calcification were recorded. The risk factors of DGF after kidney transplantation, and the correlation between internal iliac artery calcification and clinical parameters were analyzed. Short-term prognosis of recipients with DGF complicated with severe internal iliac artery calcification was evaluated. Results The incidence of DGF was 22.5% (50/222). Among all recipients, 28.4% (63/222) were complicated with severe internal iliac artery calcification. In the DGF group, 44% (22/50) of the recipients were complicated with severe internal iliac artery calcification, higher than 23.8% (41/172) in the IGF group (P<0.05). Univariate analysis showed that high serum creatinine (Scr) level of donors, male donor, high triglyceride level and severe internal iliac artery calcification of recipients were the risk factors for DGF after kidney transplantation (all P<0.05). Multivariate logistic regression analysis revealed that Scr≥143 μmol/L of donors and severe internal iliac artery calcification of recipients were the independent risk factors for DGF after kidney transplantation (both P<0.05). Correlation analysis indicated that internal iliac artery calcification was weakly correlated with the age of recipients and renal artery anastomosis (both P<0.05). In the DGF group, the Scr level at postoperative 1 month was significantly higher, whereas the estimated glomerular filtration rate (eGFR) was significantly lower than those in the IGF group (both P<0.05). The eGFR at postoperative 12 months in the high-risk DGF subgroup was significantly lower than those in the low-risk DGF, high-risk IGF and low-risk IGF subgroups (all P<0.05). Conclusions Internal iliac artery calcification is not only a risk factor for recovery of renal allograft function, but also negatively affects short-term prognosis of renal allograft function. [ABSTRACT FROM AUTHOR]

Abstract Background Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilaginous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves’ disease (GD) and Hashimoto thyroiditis (HT). However, there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed the clinical and genetic profiles of patients in whom these diseases co-occur. Methods We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1, and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD. Results The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p = 2.44 × 10–7, binomial test). RP patients with GD tended to have nasal involvement (p = 0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p = 0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP. Conclusions Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 characterize the subset of RP patients with GD, which may guide attempts to characterize a distinct subtype of RP for precision medicine.

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells recognize and eliminate cancer cells. However, immune evasion, downregulation of immune function by the tumour microenvironment and resistance of cancer cells are major problems. Although CTL and NK cells are both important to eliminate cancer, most studies address them individually. We quantified sequential primary human CTL and NK cell cytotoxicity against the melanoma cell line SK‐Mel‐5. At high effector‐to‐target ratios, NK cells or melan‐A (MART‐1)‐specific CTL eliminated all SK‐Mel‐5 cells within 24 h, indicating that SK‐Mel‐5 cells are not resistant initially. However, at lower effector‐to‐target ratios, which resemble numbers of the immune contexture in human cancer, a substantial number of SK‐Mel‐5 cells survived. Pre‐exposure to CTL induced resistance in surviving SK‐Mel‐5 cells to subsequent CTL or NK cell cytotoxicity, and pre‐exposure to NK cells induced resistance in surviving SK‐Mel‐5 cells to NK cells. Higher human leucocyte antigen class I expression or interleukin‐6 levels were correlated with resistance to NK cells, whereas reduction in MART‐1 antigen expression was correlated with reduced CTL cytotoxicity. The CTL cytotoxicity was rescued beyond control levels by exogenous MART‐1 antigen. In contrast to the other three combinations, CTL cytotoxicity against SK‐Mel‐5 cells was enhanced following NK cell pre‐exposure. Our assay allows quantification of sequential CTL and NK cell cytotoxicity and might guide strategies for efficient CTL–NK cell anti‐melanoma therapies. Key points: Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells eliminate cancer cells. Both CTL and NK cells attack the same targets, but most studies address them individually.In a sequential cytotoxicity model, the interdependence of antigen‐specific CTL and NK cell cytotoxicity against melanoma is quantified.High numbers of antigen‐specific CTL and NK cells eliminate all melanoma cells. However, lower numbers induce resistance if secondary CTL or NK cell exposure follows initial CTL exposure or if secondary NK cell exposure follows initial NK cell exposure. On the contrary, if secondary CTL exposure follows initial NK cell exposure, cytotoxicity is enhanced.Alterations in human leucocyte antigen class I expression and interleukin‐6 levels are correlated with resistance to NK cells, whereas a reduction in antigen expression is correlated with reduced CTL cytotoxicity; CTL cytotoxicity is rescued beyond control levels by exogenous antigen.This assay and the results on interdependencies will help us to understand and optimize immune therapies against cancer. [ABSTRACT FROM AUTHOR]

Harold Merle,1 Laurence Béral,2 Maxime Rocher,3 Mitta Pierre,1 Albert Jean-Charles,1 Odile Béra,4 Laurie-Anne Rosamont,4 Pierre-Yves Robert,3 Agnes Lézin4 1Department of Ophthalmology, University Hospital of Martinique, Fort de France, French West Indies, France; 2Department of Ophthalmology, University Hospital of Guadeloupe, Pointe à Pitre, French West Indies, France; 3Department of Ophthalmology, University Hospital of Limoges, France; 4Department of Genetics, University Hospital of Martinique, Fort de France, French West Indies, FranceCorrespondence: Harold Merle, Department of Ophthalmology, University Hospital of Martinique, Hôpital Pierre Zobda Quitman, BP 632, Martinique, Fort de France, 97261 Cedex, French West Indies, France, Tel +596 596 552 251, Fax +596 596 758 447, Email harold.merle@chu-martinique.frPurpose: To evaluate how the HLA genotype is associated to the polypoidal choroidal vasculopathy (PCV) in a population of patients of Afro-Caribbean descent.Methods: Forty-seven patients were diagnosed with PCV. The number of control patients was 457. All affected patients and control patients were of Afro-Caribbean descent and natives to Martinique. HLA typing was based on blood sample, using the polymerase chain reaction technique. Comparison of HLA alleles between the 2 groups was done using chi-2 test, odds ratio (OR) and confidence interval using Woolf’s method. The Bonferroni correction was considered significant when p-value ≤ 0.05. Alleles frequency was analyzed for DRB1 and DQB1 locus.Results: HLA-DRB1&ast;13 allele was significantly associated to PCV (OR = 2.02, CI = [1.3; 3.13], p = 0.003). In group DRB1, the Bonferroni correction significance threshold was < 0.004. HLA-DQB1&ast;04 allele was significantly associated to PCV (OR = 3.5, CI = [1.48; 8.3], p = 0.006). In group DQB1, the Bonferroni correction significance threshold was < 0.006.Conclusion: Two HLA alleles are positively associated to PCV. The possible association between PCV and certain alleles suggest HLA implication in PCV pathogeny, most likely by modeling the immune system response.Keywords: polypoidal choroidal vasculopathy, major histocompatibility complex, human leucocyte antigen, genetic predisposition

Cellular and humoral responses are required for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication. Antigen-presenting cells load SARS-CoV-2 peptides on human leukocyte antigen (HLA) with different avidities and present to T- and B-cells for imposing humoral and cellular responses. Due to immunosuppression, renal transplant recipient (RTR) patients are speculated to poorly form the antibody against the SARS-CoV-2. Therefore, determining the association of specific HLA alleles with anti-SARS-CoV-2 spike protein antibody formation will be helpful in managing the RTR having specific HLA alleles from SARS-CoV-2 infection and vaccination. Materials and Methods: In this study, anti-SARS-CoV-2 spike protein antibody in 161 RTRs was determined by the chemiluminescent microparticle immunoassay methods, and HLA alleles were determined by the polymerase chain reaction-single-strand oligonucleotide methods and analyzed to study the HLA allele association with anti-SARS-CoV-2 spike protein-specific humoral response and severity of COVID-19 symptoms in recently SARS-CoV-2-infected RTRs. Results: The anti-SARS-CoV-2 spike protein specific antibody seroconversion rate in RTRs was 90.06% with a median titer of 751.80 AU/ml. The HLA class I alleles, A*11 in 22.1%, A*24 in 21.37%, A*33 in 20.68%, HLA B*15 in 11%, B*07 in 8.27%, HLA-C*30 in 20.93%, C*70 in 23.25% and HLA Class II alleles, DRB1*07 in 18.62%, DRB1*04 in 13.8%, HLA-DRB1*10 in 14.48%, HLA-DQA1*50 in 32.55% of RTRs were associated with the seroconversion. The mean SARS-CoV-2 clearance time was 18.25 ± 8.14 days. Conclusions: RTRs with SARS-CoV-2 infection developed a robust seroconversion rate of 90.0% and different alleles of HLA-B, DRB1, and DQA1 were significantly associated with the seroconversion.

The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.10.1093/brain/awy109_video1awy109media15796480660001.

Cellular and humoral responses are required for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) eradication. Antigen-presenting cells load SARS-CoV-2 peptides on human leukocyte antigen (HLA) with different avidities and present to T- and B-cells for imposing humoral and cellular responses. Due to immunosuppression, renal transplant recipient (RTR) patients are speculated to poorly form the antibody against the SARS-CoV-2. Therefore, determining the association of specific HLA alleles with anti-SARS-CoV-2 spike protein antibody formation will be helpful in managing the RTR having specific HLA alleles from SARS-CoV-2 infection and vaccination. Materials and Methods: In this study, anti-SARS-CoV-2 spike protein antibody in 161 RTRs was determined by the chemiluminescent microparticle immunoassay methods, and HLA alleles were determined by the polymerase chain reaction-single-strand oligonucleotide methods and analyzed to study the HLA allele association with anti-SARS-CoV-2 spike protein-specific humoral response and severity of COVID-19 symptoms in recently SARS-CoV-2-infected RTRs. Results: The anti-SARS-CoV-2 spike protein specific antibody seroconversion rate in RTRs was 90.06% with a median titer of 751.80 AU/ml. The HLA class I alleles, A*11 in 22.1%, A*24 in 21.37%, A*33 in 20.68%, HLA B*15 in 11%, B*07 in 8.27%, HLA-C*30 in 20.93%, C*70 in 23.25% and HLA Class II alleles, DRB1*07 in 18.62%, DRB1*04 in 13.8%, HLA-DRB1*10 in 14.48%, HLA-DQA1*50 in 32.55% of RTRs were associated with the seroconversion. The mean SARS-CoV-2 clearance time was 18.25 ± 8.14 days. Conclusions: RTRs with SARS-CoV-2 infection developed a robust seroconversion rate of 90.0% and different alleles of HLA-B, DRB1, and DQA1 were significantly associated with the seroconversion. [ABSTRACT FROM AUTHOR]

Varying HLA allele-specific expression levels are associated with human diseases, such as graft versus host disease (GvHD) in hematopoietic stem cell transplantation (HSCT), cytotoxic T cell response and viral load in HIV infection, and the risk of Crohn’s disease. Only recently, RNA-based next generation sequencing (NGS) methodologies with accompanying bioinformatics tools have emerged to quantify HLA allele-specific expression replacing the quantitative PCR (qPCR) -based methods. These novel NGS approaches enable the systematic analysis of the HLA allele-specific expression changes between individuals and between normal and disease phenotypes. Additionally, analyzing HLA allele-specific expression and allele-specific expression loss provide important information for predicting efficacies of novel immune cell therapies. Here, we review available RNA sequencing-based approaches and computational tools for NGS to quantify HLA allele-specific expression. Moreover, we explore recent studies reporting disease associations with differential HLA expression. Finally, we discuss the role of allele-specific expression in HSCT and how considering the expression quantification in recipient-donor matching could improve the outcome of HSCT. [ABSTRACT FROM AUTHOR]

Varying HLA allele-specific expression levels are associated with human diseases, such as graft versus host disease (GvHD) in hematopoietic stem cell transplantation (HSCT), cytotoxic T cell response and viral load in HIV infection, and the risk of Crohn’s disease. Only recently, RNA-based next generation sequencing (NGS) methodologies with accompanying bioinformatics tools have emerged to quantify HLA allele-specific expression replacing the quantitative PCR (qPCR) -based methods. These novel NGS approaches enable the systematic analysis of the HLA allele-specific expression changes between individuals and between normal and disease phenotypes. Additionally, analyzing HLA allele-specific expression and allele-specific expression loss provide important information for predicting efficacies of novel immune cell therapies. Here, we review available RNA sequencing-based approaches and computational tools for NGS to quantify HLA allele-specific expression. Moreover, we explore recent studies reporting disease associations with differential HLA expression. Finally, we discuss the role of allele-specific expression in HSCT and how considering the expression quantification in recipient-donor matching could improve the outcome of HSCT.

Aplastic Anaemia (AA) is an immune mediated, primary haematopoietic disorder characterised by pancytopenia with significant morbidity and mortality. Allogeneic Haematopoietic Stem Cell Transplant (HSCT) is the treatment of choice in younger patients whenever Human Leucocyte Antigen (HLA) matched donor is available. For older patients and those in whom matched donor is not available, immunosuppressive therapy is the frontline treatment. With the long survivals of AA patients, clonal evolution into Myelodysplastic Syndrome (MDS) and clinically evident Paraoxysmal Nocturnal Haemoglobinuria (PNH) is frequently seen over a period of 5-10 years. The prognosis and overall survival of post AA, MDS is poor and the only treatment of choice is Allogeneic HSCT. The overall survival of post AA, MDS is however comparable to de novo MDS post-transplant. The authors hereby discuss a case of 26-year-old male patient, known case of AA who evolved into MDS with Excess Blasts 1 (MDS-EB-1) and type III PNH clone over a period of six years.

Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 ± 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population. [ABSTRACT FROM AUTHOR]

Background: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilaginous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves' disease (GD) and Hashimoto thyroiditis (HT). However, there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed the clinical and genetic profiles of patients in whom these diseases co-occur.Methods: We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1, and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD.Results: The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p = 2.44 × 10-7, binomial test). RP patients with GD tended to have nasal involvement (p = 0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p = 0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP.Conclusions: Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 characterize the subset of RP patients with GD, which may guide attempts to characterize a distinct subtype of RP for precision medicine. [ABSTRACT FROM AUTHOR]

Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds. [Display omitted] • Effective decellularization achieved following Crapo's criteria. • Some decellularized scaffolds led to immunization. • Only HLA content <1 % scaffold permitted immune tolerance. • New guideline for decellularization success: minimal residual MHC-I content (<1 %). • 3 standardized criteria to develop safer scaffolds for clinical applications. [ABSTRACT FROM AUTHOR]

Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 ± 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population.

Aim: Paediatric acute-onset neuropsychiatric syndrome (PANS) is defined by an acute onset of obsessive-compulsive disorder and/or eating restrictions and at least two other severe neuropsychiatric symptoms. The condition is suspected to have an immune-mediated pathophysiology, but reliable biomarkers have not been identified.Methods: We hypothesised that PANS, like narcolepsy, might have a human leucocyte antigen (HLA) association, as found in 95% of children developing narcolepsy after H1N1 immunisation. Low resolution genotyping of the MHC class II antigens HLA-DRB1 and HLA-DQB1 was performed using two different PCR-based methods. In addition, parents were interviewed regarding a detailed family history of autoimmune diseases in first-degree relatives. A total of 18 children, aged 5-14 (mean 8.2) years at onset of PANS met symptom criteria.Results: No evident association between PANS and the specific HLA alleles examined was observed. In first-degree relatives of 10 of the 18 children, an autoimmune disease had been diagnosed, and three of the 18 children themselves had an autoimmune disease.Conclusion: No HLA allele association such as seen in children with narcolepsy after H1N1 immunisation could be confirmed in this group of children with PANS. However, more than half the group had a first-degree relative with a diagnosed autoimmune disease. [ABSTRACT FROM AUTHOR]

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

Introduction: human leukocyte antigen (HLA) class II alleles play an important role in the early immune response to tuberculosis (TB) by presenting antigenic peptides to CD4+ T cells, hence polymorphisms in those genes can influence the efficiency of the immune response to infection and progression to active disease. Methods: an analytical cross-sectional study of adult pulmonary tuberculosis (PTB) patients at Mbagathi County Hospital, Nairobi and their HHCs. Sociodemographic data were captured on questionnaires and clinical data extracted from patient files. Intravenous blood samples were drawn for interferon-gamma release assay (IGRA) to determine latent tuberculosis infection (LTBI) among HHCs, and for extraction of DNA used in typing of HLA-DQB1 and HLA-DRB1 alleles by PCR sequence specific primer amplification. Chi-square and Fisher's exact test were used to compare the HLA type II allele frequencies of LTBI negative HHCs, LTBI positive HHCs and active TB patients. Logistic regression was used to adjust for HIV status. Results: the HLA-DQB1 and HLA-DRB1 alleles were analyzed in 17 PTB and 37 HHCs. Nineteen (19) HHCs were LTBI positive, while 18 were LTBI negative. The frequency of DRB3*1 was 0.17-fold lower [95% CI=0.03-0.83] among PTB patients compared to HHCs before adjustment for HIV status (p=0.048). The frequency of the DRB5*2 allele was significantly higher (p=0.013) among PTB patients (23.5%) compared to HHCS (0.00%). After adjusting for HIV status, the frequency of DRB1*14 was 12fold higher [95% CI=1.11-138.2] among PTB patients compared to HHCs (p=0.040). Conclusion: the higher frequencies of HLA-DRB5*2 and HLA-DRB1*14 alleles in PTB patients suggest a likely association with progression to active PTB. The higher frequency of HLA-DRB3*1 allele among LTBI negative HHCs shows its likely protective role against M. tuberculosis infection in this population. [ABSTRACT FROM AUTHOR]

Background: Human leucocyte antigen (HLA) class I genes and haplotypes correlate with hepatitis B virus (HBV) infection. Occult HBV infection (OBI), a special type of chronic HBV infection, is defined as HBV surface antigen negative patients with or those without serologic markers by the means of HBV DNA detection in human plasma or in liver tissue by a diagnostic test. So far, the associations of HLA I haplotypes with OBI have not been reported previously in China. Methods: A case–control study between 107 OBI subjects and 280 healthy controls from blood donors in the Blood Center of the Shaanxi Province was conducted in the present association analysis. The HLA‐A, ‐B and ‐C loci of case–control subjects were detected and genotyped by polymerase chain reaction‐sequence based typing. The HLA‐A, ‐B and ‐C haplotypic frequencies were calculated by the maximum likelihood method. Results: The HLA‐A*33:03‐C*07:01G (pc = 0.039, odds ratio [OR] = 8.996, 95% confidence interval [CI] = 1.825–44.338), B*44:03‐C*07:01G (pc = 0.0069, OR = 12.000, 95% CI = 2.507–57.436) and A*33:03‐B*44:03‐C*07:01G (pc = 0.04, OR = 7.094, 95% CI = 1.387–36.288) haplotypes showed a a significant positive association with OBI. Independent effects demonstrated that HLA‐B*44:03 and HLA‐C*07:01G gave the main contribution to risk, whereas HLA‐A*33:03 was associated only by linkage disequilibrium. Conclusions: This present study is the first to demonstrate that HLA I haplotypes are associated with OBI in the Shaanxi Han population. The present results suggest that HLA‐B*44:03‐C*07:01G might be a potential risk factor for OBI. Comparisons of the frequencies of HLA I haplotypes at high resolution were made between OBI from northern Chinese Han and controls. Frequencies of HLA‐A‐B, A‐C, B‐C, A‐B‐C between the OBI group (gray column) and the control group (blank column) were compared. Haplotypes with p < 0.05 in either group were shown. p values for multiple comparisons (pc) were corrected by Bonferroni correction (*pc < 0.05). [ABSTRACT FROM AUTHOR]

Aplastic Anaemia (AA) is an immune mediated, primary haematopoietic disorder characterized by pancytopenia with significant morbidity and mortality. Allogeneic Haematopoietic Stem Cell Transplant (HSCT) is the treatment of choice in younger patients whenever Human Leucocyte Antigen (HLA) matched donor is available. For older patients and those in whom matched donor is not available, immunosuppressive therapy is the frontline treatment. With the long survivals of AA patients, clonal evolution into Myelodysplastic Syndrome (MDS) and clinically evident Paraoxysmal Nocturnal Haemoglobinuria (PNH) is frequently seen over a period of 5-10 years. The prognosis and overall survival of post AA, MDS is poor and the only treatment of choice is Allogeneic HSCT. The overall survival of post AA, MDS is however comparable to de novo MDS post-transplant. The authors hereby discuss a case of 26 years old male patient, known case of AA who evolved into MDS with Excess Blasts 1 (MDS-EB-1) and type III PNH clone over a period of six years. [ABSTRACT FROM AUTHOR]

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48-94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8-47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9-42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5-52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8-57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy. [ABSTRACT FROM AUTHOR]

Solid organ transplantation has progressed dramatically over the last 50 years; however, rejection still remains one of the barriers to successful transplantation. Immunological processes underlying the mechanisms of rejection are well described and numerous pharmacological agents exist to help suppress a recipient's immune system in order to prolong graft survival. Furthermore, clinician decisions and actions during both the work-up of a potential transplant recipient and in the perioperative phase can impact upon the immunological status of an individual and the likelihood of successful solid organ transplantation. In this article we aim to describe the key processes involved in solid organ immunology and their relevance in anaesthetic practice. [ABSTRACT FROM AUTHOR]

Human leucocyte antigens (HLAs) are highly polymorphic glycoproteins expressed at the surface of all nucleated cells. It is required for the SARS-CoV-2 peptide antigen presentation to immune cells for their effector response. However, polymorphism in HLA significantly impacts the binding of SARS-CoV-2 antigenic peptide to the HLA pocket and regulates immune activation. In this study, 514 renal transplant recipients (RTRs) were recruited from the outpatient department and categorized either into symptomatic (n = 173) or asymptomatic groups (n = 341) based on Coronavirus disease-19 (COVID-19) symptoms. The anti-SARS-CoV-2 spike protein-specific IgG antibody titer was measured by chemiluminescent microparticle immune-assay methods in 310 RTRs. The HLA details of 514 patients were retrieved from the electronic medical records and analyzed retrospectively. We found that HLA antigen allele A*24 was significantly associated with asymptomatic infection in 22.78%, HLA C*02 in 4.51%, DRB1*12 in 10.85%, and HLA DQA1*02 in 27.74% of RTRs. Whereas HLA A*29 in 3.46%, A*33 in 26.01%, B*13 in 10.40%, DRB1*10 in 4.62%, DRB1*15 in 39.30%, DRB1*30 in 1.15%, and DQA1*60 in 3.57% of RTRs were associated with symptomatic infection. HLA DRB1*13 and DRB1*15 were associated with moderate to severe degrees of COVID-19 disease. The seroconversion rate in asymptomatic patients was 118/137 (86.13%), had a median titer of 647.80 au/mL, compared to symptomatic patients 148/173 (85.54%) with a median titer of 400.00 au/mL, which was not significant between the two groups (p = 0.88 and 0.13). In conclusion, HLA alleles A*24, C*02, DRB1*12, and DQA1*02 were significantly associated with asymptomatic infection, and A*29, A*33, B*13, DRB1*10, DRB*15, and DRB1*30 were significantly associated with symptomatic infection. HLA DRB1*13 and DRB1*15 were associated with moderate to severe degrees of COVID-19 disease.

The genetic factors of tuberculosis (TB) susceptibility have been widely recognized. Here we performed a two-stage study in 616 TB patients and 709 healthy controls to systematically identify the genetic markers of TB susceptibility. In the discovery stage, we identified 93 single nucleotide polymorphisms (SNPs) and 3 human leucocyte antigen (HLA) class II alleles that had potential associations with TB susceptibility. In the validation stage, we confirmed that 6 nominally significant SNPs, including 2 novel missense variants at RAB17 and DCTN4 (odds ratio (OR) = 1.40, P = 4.98 × 10−3 and OR = 2.30, P = 3.17 × 10−2 respectively), were associated with the predisposition to TB. Moreover, our study found that HLA-II allele DQA1*05:05 (P = 0.0011, OR = 1.44, 95%CI = 1.15–1.77) was a TB susceptibility locus for the first time. This study comprehensively investigated the genetic variants that were associated with TB susceptibility and provided insight into the tuberculosis pathogenesis. • We found RAB17 and DCTN4 showing evidence of tuberculosis (TB) susceptibility risk. • HLA DQA1*05:05 allele reflected predisposition to TB for the first time. • These novel TB susceptibility loci might activate the immune system of the host. • NGS combined GWAS method is an effective solution for disease susceptibility studies. [ABSTRACT FROM AUTHOR]

• Multifocal motor neuropathy is associated with the HLA class II HLA-DRB1*15:01-DQB1*06:02 and HLA-DRB1*12:01-DQB1*03:01 haplotypes. • Patients with MMN carrying either of these haplotypes do not have a distinct disease course. • The associations could serve as a genetic tag for other disease associated regions on chromosome 6, including the MHC class III region. • Though a direct link though antigen presentation seems unlikely, these associations imply the role of T cells in the specific inflammation underlying MMN. To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data. We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population. The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1–2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2–5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies. MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN. [ABSTRACT FROM AUTHOR]

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

Summary: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV)‐infected individuals may have a faster progression of liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development when influenced by host, viral and environmental factors. Hepatitis C virus disease progression is also associated with genetic variants of specific killer cell immunoglobulin‐like receptors (KIRs) and genes of the major histocompatibility complex (MHC). The aim of the present study was to correlate clinical, virologic and biochemical parameters and to evaluate the possible influence of KIR genes and their HLA class I ligands in patients infected with hepatitis C virus. The present study analysed a total of 127 chronic HCV‐infected patients for various biochemical and genetics factors that can influence disease progression and prognosis. Liver function parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyl transferase (GGT), direct bilirubin (DB), alpha‐fetoprotein (AFP), HCV RNA levels and fibrosis indices were analysed using well‐established biochemical methods. At the same time, KIR and HLA genotyping was performed using a polymerase chain reaction sequence‐specific primer technique. Analysis of HLA class I and HLA ligands revealed that HLA‐C*12:02 and HLA‐A3 and HLA‐A11 were positively associated with the F3‐F4 fibrosis group (p =.026; OR = 8.717, CI = 1.040–73.077; respectively, p =.047; OR = 2.187; 95% CI = 1.066–4.486). KIR2DL2‐positive patients had high median levels of AST after treatment and direct bilirubin levels when compared to KIR2DL2‐negative patients (p =.013, respectively, p =.028). KIR2DL2/KIR2DL2‐C1C1 genotype was associated with increased AST, ALT and GGT levels. A higher GGT level was also observed in KIR2DS2‐C1‐positive patients when compared to KIR2DS2‐C1‐negative patients. The present research demonstrates several links between specific clinical, virologic and biochemical parameters and the expression of KIR genes and their HLA ligands in HCV‐infected patients. These connections should be taken into account when considering disease development and treatment. [ABSTRACT FROM AUTHOR]

This review attempts to collate all the studies performed in India or comprising a population originating from India and to find out if there is an association between the HLA (human leucocyte antigen) type of individual and development of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) subsequent to medication use. The authors performed a PubMed search of all articles published in English from 2009 to 2019 for articles that studied HLA type in patients who developed SJS/TEN after intake of a specific drug in the Asian Indian population or in individuals of Asian Indian origin. The selection criteria were satisfied by a total of 11 studies that reported HLA associations with specific drugs, which induced SJS/TEN, mainly anti-epileptic drugs, and cold medicine/non-steroidal anti-inflammatory drugs. These studies involved a small number of patients, and hence, there is limited evidence to conclude if these associations can be extrapolated to a larger population of the same ethnicity. Similar multi-center studies need to be conducted with a larger sample size to confirm these associations. This would have implications in policy making and for understanding the potential of using genetic markers as a screening tool before prescribing a drug to a patient, which might make them susceptible to developing a potentially life-threatening disease such as SJS/TEN. This is possibly the only mode of primary prevention for this potentially fatal severe cutaneous adverse drug reaction.