Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups.

Background: Colorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. Methods: A retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. Results: The blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. Conclusions: Our study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Impact of COVID-19 on anti-HLA antibodies in kidney transplantation.

The effects of COVID-19 on the immune profile of kidney transplant recipients are unknown. Immunosuppression adjustment during the illness can increase the risk for de novo donor-specific anti-HLA antibodies (DSA) and acute rejection episodes. This single-center retrospective study includes adult kidney transplant recipients diagnosed with COVID-19 between March 2020 and December 2022, screened for anti-HLA antibodies (AbHLA) pre-transplant and after COVID-19. Analyzed data comprised demographics, immunosuppressive therapy before and during the illness, hospitalization rate, and AbHLA specificity. Two hundred sixty-seven transplant recipients were included and divided according to the pre-transplant AbHLA profile: absent [PRA- (n = 206, 77%)], non-DSA (N = 46, 17%), and DSA+ (n = 15, 6%). The DSA+ group was younger (40.5 ± 16.5; PRA- 50.3 ± 13.4; non-DSA 49.3 ± 11.7 years; p = 0.02). The hospitalization rate was higher in groups with preformed AbHLA (DSA+ n = 8, 53%; non-DSA = 24, 52%; PRA- n = 54, 26%; p < 0.01). Immunosuppression was maintained in 222 (83%), withdrawn in 33 (12%), and reduced in 11 (4%) cases without difference among groups. Twenty-two (8%) cases of de novo DSA were observed after COVID-19 [PRA-, n = 16 (73%) and non-DSA, n = 6 (27%)]. In the DSA+ group, the AbHLA profile remained stable. There were 6 (2%) cases of post-COVID-19 antibody-mediated rejection (DSA+ n = 4, 66%; non-DSA n = 1, 17%, PRA- n = 1, 17%) without T cell-mediated rejection cases. Post-COVID-19 de novo DSA was more frequent in groups without pre-transplant AbHLA, not having association with changes in immunosuppressive therapy.

Potential Involvement of Human Leukocyte Antigen-DR/DQ Polymorphisms with Schizophrenia Among Patients with Schizophrenia in Yemen.

Objectives: To evaluate the hypothesis that human leukocyte antigens (HLAs) confer susceptibility to schizophrenic disorders, by assessing their contribution to the risk of schizophrenia in a Yemeni population. Methods: The researchers approached patients who had been diagnosed with schizophrenia at Al-Amal Hospital for Psychiatric Diseases, Sana'a. Controls were drawn randomly from the general population. The HLA class II alleles of the participants were examined. The genotypes of the HLA-DQB1 and HLA-DRB1 alleles were determined by polymerase chain reaction using sequence-specific primers. Results: The subjects comprised 110 patients with schizophrenia, matched by an equal number of controls. The prevalence of HLA-DRB1*04 was significantly higher among patients than among controls (7.3% vs. 0.0%; p =0.003), as was HLA-DRB1*07 (62.7% vs. 17.3%, odds ratio (OR) = 8.1, 95% CI: 4.3-15.1; p < 0.001). HLA-DRBI*14 was significantly less prevalent among patients (0.9% vs. 11.8%, OR = 0.06, 95% CI: 0.01-0.50, χ2 = 10.9; p < 0.001). HLA-DQB1*07 was the most common allele discovered in schizophrenia patients and was found to have a much higher incidence in patients than the control group (22.7% vs. 4.5%, OR = 6.2, 95%CI: 2.3-16.8, χ2 = 15.4; p < 0.001). Conclusions: The HLA-DQB1 and HLA-DRB1 gene loci are linked to schizophrenia in the Yemeni population, according to the current study's evidence.

Sensitive HLA antibody testing and the risk of antibody-mediated rejection and graft failure.

Solid phase detection and identification of HLA antibodies in kidney transplantation currently relies on single antigen bead (Luminex®) assays, which is more sensitive than the previously used enzyme-linked immunosorbent assays (ELISA). To evaluate the impact of more sensitive HLA testing on antibody-mediated rejection (AMR) occurrence and allograft survival, we analysed 1818 renal allograft recipients transplanted between March 2004 and May 2021. In 2008, solid phase testing switched from ELISA to Luminex. We included 393 (21.6%) transplantations before and 1425 (78.4%) transplantations after transition from ELISA- to Luminex-based testing. For this study, bio-banked ELISA era samples were tested retrospectively with Luminex. Significantly less pretransplant DSA were found in patients transplanted with pre-existing HLA antibodies in the Luminex (109/387) versus the ELISA period (43/90) (28% vs. 48%, p < 0.01). Throughout histological follow-up, 169 of 1818 (9.3%) patients developed AMR. After implementing Luminex-based testing, the rate of AMR significantly decreased (p = 0.003). However, incidence of graft failure did not significantly differ between both eras. In conclusion, less patients with pretransplant DSA were transplanted since the implementation of Luminex HLA testing. Transition from ELISA- to Luminex-based HLA testing was associated with a significant decrease in AMR occurrence post-transplantation. Since the decline of AMR did not translate into improved graft survival, Luminex-based testing has the added value of preventing low-risk AMR cases. Therefore, Luminex' high sensitivity must be balanced against waiting time for a suitable organ.

HLA-DR and HLA-DQ Polymorphism Correlation with Sexually Transmitted Infection Caused by Chlamydia trachomatis.

Background and Objectives: Chlamydia trachomatis (C. trachomatis) represents one of the most prevalent bacterial sexually transmitted diseases. This study aims to explore the relationship between HLA alleles/genotypes/haplotypes and C. trachomatis infection to better understand high-risk individuals and potential complications. Materials and Methods: This prospective study recruited participants from Transylvania, Romania. Patients with positive NAAT tests for C. trachomatis from cervical/urethral secretion or urine were compared with controls regarding HLA-DR and -DQ alleles. DNA extraction for HLA typing was performed using venous blood samples. Results: Our analysis revealed that the presence of the DRB1*13 allele significantly heightened the likelihood of C. trachomatis infection (p = 0.017). Additionally, we observed that individuals carrying the DRB1*01/DRB1*13 and DQB1*03/DQB1*06 genotype had increased odds of C. trachomatis infection. Upon adjustment, the association between the DRB1*01/DRB1*13 genotype and C. trachomatis remained statistically significant. Conclusions: Our findings underscore the importance of specific HLA alleles and genotypes in influencing susceptibility to C. trachomatis infection. These results highlight the intricate relationship between host genetics and disease susceptibility, offering valuable insights for targeted prevention efforts and personalized healthcare strategies.

Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations.

BACKGROUND: Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA-matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA-matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. STUDY DESIGN AND METHODS: We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. RESULTS: We found 20 articles describing platelet transfusion policies in 483 GT-patients and 29 BSS-patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS-patients, including one child. Fifteen respondents gave preventive HLA-matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT-patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor-platelets in acute settings. CONCLUSION: Elective HLA-matching for GT and BSS-patients is already conducted by most Dutch (pediatric) hematologists. HPA-matching is mainly applied when HPA-antibodies are formed. Based on the current literature and the survey, recommendations are proposed.

HLA peptide-binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia.

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.

Relación entre la compatibilidad del HLA y la pérdida del injerto en trasplante renal de donante cadavérico: Un análisis por propensity score matching en Colombia / Relationship between HLA compatibility and graft loss in renal transplant from a deceased donor: An analysis by propensity score matching in Colombia

Introducción. En Colombia, solo un 24 % de los pacientes en lista recibieron un trasplante renal, la mayoría de donante cadavérico. Para la asignación de órganos se considera el HLA A-B-DR, pero la evidencia reciente sugiere que el HLA A-B no está asociado con los desenlaces del trasplante. El objetivo de este estudio fue evaluar la relevancia del HLA A-B-DR en la sobrevida del injerto de los receptores de trasplante renal. Métodos. Estudio de cohorte retrospectivo que incluyó pacientes trasplantados renales con donante cadavérico en Colombiana de Trasplantes, desde 2008 a 2023. Se aplicó un propensity score matching (PSM) para ajustar las covariables en grupos de comparación por compatibilidad y se evaluó la relación del HLA A-B-DR con la sobrevida del injerto renal por medio de la prueba de log rank y la regresión de Cox. Resultados. Se identificaron 1337 pacientes transplantados renales, de los cuales fueron mujeres un 38,7 %, con mediana de edad de 47 años y de índice de masa corporal de 23,8 kg/m2. Tras ajustar por PSM las covariables para los grupos de comparación, la compatibilidad del HLA A-B no se relacionó significativamente con la pérdida del injerto, con HR de 0,99 (IC95% 0,71-1,37) para HLA A y 0,75 (IC95% 0,55-1,02) para HLA B. Solo la compatibilidad por HLA DR fue significativa para pérdida del injerto con un HR de 0,67 (IC95% 0,46-0,98). Conclusión. Este estudio sugiere que la compatibilidad del HLA A-B no influye significativamente en la pérdida del injerto, mientras que la compatibilidad del HLA DR sí mejora la sobrevida del injerto en trasplante renal con donante cadavérico

Introduction. In Colombia, only 24% of patients on the waiting list received a renal transplant, most of them from cadaveric donors. HLA A-B-DR is considered for organ allocation, but recent evidence suggests that HLA A-B is not associated with transplant outcomes. The objective of this study was to evaluate the relevance of HLA A-B-DR on graft survival in kidney transplant recipients. Methods. Retrospective cohort study that included kidney transplant recipients with a cadaveric donor in Colombiana de Trasplantes from 2008 to 2023. A propensity score matching (PSM) was applied to adjust the covariates in comparison groups for compatibility, and the relationship of HLA A-B-DR with kidney graft survival was evaluated using the log rank test and Cox regression. Results. A total of 1337 kidney transplant patients were identified; of those, 38.7% were female, with median age of 47 years, and BMI 23.8 kg/m2. After adjusting the covariates with PSM for the comparison groups, HLA A-B matching was not significantly related to graft loss, with HR of 0.99 (95% CI 0.71-1.37) and 0.75 (95% CI 0.55-1.02), respectively. Only HLA DR matching was significant for graft loss with an HR of 0.67 (95% CI 0.46-0.98). Conclusions. This study suggests that HLA A-B matching does not significantly influence graft loss, whereas HLA DR matching does improve graft survival in renal transplantation with a cadaveric donor.

Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada.

Background: In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival. Methods: This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and-DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders. Findings: Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17-0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10-3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77-2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders. Interpretation: Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required. Funding: None.

Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. MATERIAL AND METHODS: This retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. RESULTS: Our study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). CONCLUSION: Donor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.

Impact of predicted HLA class I immunopeptidome on viral reservoir in a cohort of people living with HIV in Italy.

The class I HLA genotype has been widely recognized as a factor influencing HIV disease progression in treatment-naïve subjects. However, little is known regarding its role in HIV disease course and how it influences the size of the viral reservoir once anti-retroviral therapy (ART) is started. Here, leveraging on cutting-edge bioinformatic tools, we explored the relationship between HLA class I and the HIV reservoir in a cohort of 90 people living with HIV (PLWH) undergoing ART and who achieved viral suppression. Analysis of HLA allele distribution among patients with high and low HIV reservoir allowed us to document a predominant role of HLA-B and -C genes in regulating the size of HIV reservoir. We then focused on the analysis of HIV antigen (Ag) repertoire, by investigating immunogenetic parameters such as the degree of homozygosity, HLA evolutionary distance and Ag load. In particular, we used two different bioinformatic algorithms, NetMHCpan and MixMHCpred, to predict HLA presentation of immunogenic HIV-derived peptides and identified HLA-B*57:01 and HLA-B*58:01 among the highest ranking HLAs in terms of total load, suggesting that their previously reported protective role against HIV disease progression might be linked to a more effective viral recognition and presentation to Cytotoxic T lymphocytes (CTLs). Further, we speculated that some peptide-HLA complexes, including those produced by the interaction between HLA-B*27 and the HIV Gag protein, might be particularly relevant for the efficient regulation of HIV replication and containment of the HIV reservoir. Last, we provide evidence of a possible synergistic effect between the CCR5 ∆32 mutation and Ag load in controlling HIV reservoir.

The impact of donor-specific anti-HLA antibody levels on primary poor graft function and graft rejection in rituximab desensitized haploidentical stem cell transplantation.

This study investigates the influence of donor-specific anti-HLA antibodies (DSA) levels on primary poor graft function (PGF) and graft rejection (GR) after haploidentical stem cell transplantation (haplo-SCT) with rituximab desensitization. A total of 155 DSA-positive haplo-SCT candidates with mean fluorescence intensity (MFI) between 2000 and 10,000 were enrolled in this prospective clinical trial. Receiver operating characteristic (ROC) curves determined the optimal DSA MFI cutoff for identifying high-risk patients. Patients were categorized into two groups: DSA low-level group (2000 ≤ DSA MFI < 5000, Group A) and high-level group (5000 ≤ DSA MFI ≤ 10,000, Group B). The incidence of primary PGF was 6.5% (2.6%-10.3%), while GR incidence was 0.6% (0.0%-1.9%). Group A had significantly lower primary PGF rates than Group B (2.3% [0.0%-5.7%] vs. 12.9% [4.8%-21.0%], p = 0.017). Only one patient in Group B experienced GR. High DSA levels (5000 ≤ MFI ≤ 10,000) were identified as the sole independent risk factor for primary PGF and GR after haplo-SCT with rituximab desensitization (HR = 7.282, 95% CI 1.517-34.953, p = 0.013). The 4-year cumulative incidence of relapse, non-relapse mortality, disease-free survival, and overall survival were 14.7% (11.6%-17.8%), 16.3% (13.1%-19.4%), 69.0% (65.9%-76.2%), and 70.6% (66.4%-74.8%), respectively. DSA levels have an impact on efficiency of rituximab desensitization, and a DSA MFI threshold is provided for predicting primary PGF and GR.

Current status of research on the genetic susceptibility of primary biliary cholangitis / 临床肝胆病杂志

Primary biliary cholangitis （PBC） is a liver autoimmune disease with a strong genetic tendency characterized by the degeneration and necrosis of bile duct epithelial cells， and it is often observed in middle-aged and elderly women. With the continuous development of genome-wide association studies， the genetic susceptibility of PBC has attracted more and more attention. This article elaborates on the research advances in the genetic susceptibility genes closely associated with PBC， in order to provide effective targets for the treatment of PBC.

Selection and Interpretation of Molecular Diagnostics in Heart Transplantation.

The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation.

Immune surveillance and humoral immune responses in kidney transplantation - A look back at T follicular helper cells.

T follicular helper cells comprise a specialized, heterogeneous subset of immune-competent T helper cells capable of influencing B cell responses in lymphoid tissues. In physiology, for example in response to microbial challenges or vaccination, this interaction chiefly results in the production of protecting antibodies and humoral memory. In the context of kidney transplantation, however, immune surveillance provided by T follicular helper cells can take a life of its own despite matching of human leukocyte antigens and employing the latest immunosuppressive regiments. This puts kidney transplant recipients at risk of subclinical and clinical rejection episodes with a potential risk for allograft loss. In this review, the current understanding of immune surveillance provided by T follicular helper cells is briefly described in physiological responses to contrast those pathological responses observed after kidney transplantation. Sensitization of T follicular helper cells with the subsequent emergence of detectable donor-specific human leukocyte antigen antibodies, non-human leukocyte antigen antibodies their implication for kidney transplantation and lessons learnt from other transplantation "settings" with special attention to antibody-mediated rejection will be addressed.

Accuracy of Serological Screening for the Diagnosis of Celiac Disease in Type 1 Diabetes Children.

Background and Objectives: Patients with type 1 diabetes (T1D) are considered at high-risk for developing celiac disease (CD). The purpose of our study was to determine the prevalence of CD among children who were followed in our unit for T1D using the latest ESPGHAN guidelines, and avoiding intestinal biopsies in some of the children. Materials and Methods: We performed a prospective monocentric study, which included 663 T1D children between June 2014 and June 2016. We considered CD according to serological (tissue transglutaminase (TGAs) and endomysium antibodies) results. Children were included either at the time of T1D diagnosis or during their follow up. We looked for clinical and biochemical signs of CD, and for T1D characteristics. Results: The children's ages ranged from 11 months to 18 years. CD was confirmed in 32 out of 663 patients with T1D, with a prevalence of 4.8%. CD was excluded in 619 children and remained uncertain for 12 children, who had positive TGAs without the required criteria. We found that 95% of T1D children express HLA-DQ2 and/or -DQ8, which was 2.4 times higher than in the general population. Conclusions: An intestinal biopsy could be avoided to confirm CD in the majority of T1D children. Silent forms of CD are frequent and screening is recommended for all patients. Importantly, repeated TGA assessment is required in HLA genetically predisposed T1D patients, while it is unnecessary in the 5% who are HLA-DQ2 and -DQ8 negative.

Vascular and Non-HLA autoantibody profiles in hospitalized patients with COVID-19.

Introduction: Severe COVID-19 illness is characterized by an overwhelming immune hyperactivation. Autoantibodies against vascular, tissue, and cytokine antigens have been detected across the spectrum of COVID-19. How these autoantibodies correlate with COVID-19 severity is not fully defined. Methods: We performed an exploratory study to investigate the expression of vascular and non-HLA autoantibodies in 110 hospitalized patients with COVID-19 ranging from moderate to critically ill. Relationships between autoantibodies and COVID- 19 severity and clinical risk factors were examined using logistic regression analysis. Results: There were no absolute differences in levels of expression of autoantibodies against angiotensin II receptor type 1 (AT1R) or endothelial cell proteins between COVID-19 severity groups. AT1R autoantibody expression also did not differ by age, sex, or diabetes status. Using a multiplex panel of 60 non- HLA autoantigens we did identify seven autoantibodies that differed by COVID-19 severity including myosin (myosin; p=0.02), SHC-transforming protein 3 (shc3; p=0.07), peroxisome proliferator-activated receptor gamma coactivator 1-beta (perc; p=0.05), glial-cell derived neurotrophic factor (gdnf; p=0.07), enolase 1 (eno1; p=0.08), latrophilin-1 (lphn1; p=0.08), and collagen VI (coll6; p=0.05) with greater breadth and higher expression levels seen in less severe COVID-19. Discussion: Overall, we found that patients hospitalized with COVID-19 demonstrate evidence of auto-reactive antibodies targeting endothelial cells, angiotensin II receptors, and numerous structural proteins including collagens. Phenotypic severity did not correlate with specific autoantibodies. This exploratory study underscores the importance of better understanding of the role of autoimmunity in COVID-19 disease and sequelae.

Relevance of Pharmacogenomics to the Safe Use of Antimicrobials.

There has been widespread implementation of pharmacogenomic testing to inform drug prescribing in medical specialties such as oncology and cardiology. Progress in using pharmacogenomic tests when prescribing antimicrobials has been more limited, though a relatively large number of pharmacogenomic studies on aspects such as idiosyncratic adverse drug reactions have now been performed for this drug class. Currently, there are recommendations in place from either National Regulatory Agencies and/or specialist Pharmacogenomics Advisory Groups concerning genotyping for specific variants in MT-RNR1 and CYP2C19 before prescribing aminoglycosides and voriconazole, respectively. Numerous additional pharmacogenomic associations have been reported concerning antimicrobial-related idiosyncratic adverse drug reactions, particularly involving specific HLA alleles, but, to date, the cost-effectiveness of genotyping prior to prescription has not been confirmed. Polygenic risk score determination has been investigated to a more limited extent but currently suffers from important limitations. Despite limited progress to date, the future widespread adoption of preemptive genotyping and genome sequencing may provide pharmacogenomic data to prescribers that can be used to inform prescribing and increase the safe use of antimicrobials.

HLA B27 in Ankylosing Spondylitis: Differences in Frequency and Relative Risk in American Blacks and Caucasians.

Twenty-eight HLA alleles of the A and B loci were determined in 23 American Blacks and 50 Caucasians with primary ankylosing spondylitis (AS). The prevalence of HLA B27 was significantly increased in American Black patients (48 per cent) vs Black controls (two per cent), but was much less than the 94 per cent found in Caucasian patients (controls eight per cent). The lower prevalence of B27 in American Black patients vs Caucasian patients was significant (p < 0.001), and indicated that susceptibility to AS is not as closely associated with B27 in Blacks as in Caucasians. No other HLA antigen was significantly associated with AS in either racial group. Among B27 positive individuals, the relative risk of developing AS was significantly lower in American Blacks than in Caucasians. These data indicate that for diagnostic purposes, the absence of B27 is less important in ruling out AS in Blacks than in Caucasians.

Comparative analysis of the variability of the human leukocyte antigen peptide-binding pockets in patients with acute leukaemia.

The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide-binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide-binding pockets and/or their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the Eurocord/European Blood and Marrow Transplant registry. The HLA peptide-binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA-DRB1, and P4 and P9 for HLA-DQB1. The motif RFDRAY in P4 of HLA-DRB1*16:01/02/03/05 alleles and the motif YYVSY in P9 of HLA-DQB1*05:02/04/05 alleles, were statistically associated with ALL (corrected p value [pc ] = 0.001 and pc  = 0.035 respectively). The frequency of serine 57 in the P9 of HLA-DQB1 was higher in ALL (odds ratio 2.09, 95% confidence interval: 1.27-3.44; pc  = 0.037). Our analysis suggests that specific motifs in terms of HLA class II pockets and amino acids might be unique to ALL. The associations identified in this study encourage further investigation oF the role of HLA peptide-binding pockets and their amino acids in immune processes underpinning acute leukaemia and ultimately in immunotherapy settings.