Explore the vast range of titles available.

Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL −/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.

Hyper-IgM syndrome (HIGM) is a genetic immunodeficiency characterized by elevated to normal IgM levels and decreased IgG, IgA, and IgE. The overlapping clinical presentations of different gene mutations complicate diagnosis and management. This study aims to elucidate the clinical implications of concurrent and homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome. We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the and genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of and mutations and to provide a definitive diagnosis and appropriate management. Genetic analysis identified two homozygous variants: (p.W80S) and (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation. The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the p.W80S variant is pathogenic, while the p.R77Q variant is likely benign.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.In this Expert Recommendation, Uhlig and colleagues review the therapeutic landscape for monogenic inflammatory bowel disease and propose recommendations for standardized reporting of clinical outcomes.

MAIT cells have been shown to be activated upon several viral infections in a TCR-independent manner by responding to inflammatory cytokines secreted by antigen-presenting cells. Recently, a few studies have shown a similar activation of MAIT cells in response to severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. In this study, we investigate the effect of SARS-CoV-2 infection on the frequency and phenotype of MAIT cells by flow cytometry, and we test in vitro stimulation conditions on the capacity to enhance or rescue the antiviral function of MAIT cells from patients with coronavirus disease 2019 (COVID-19). Our study, in agreement with recently published studies, confirmed the decline in MAIT cell frequency of hospitalized donors in comparison to healthy donors. MAIT cells of COVID-19 patients also had lower expression levels of TNF-alpha, perforin and granzyme B upon stimulation with IL-12 + IL-18. 24 h’ incubation with IL-7 successfully restored perforin expression levels in COVID-19 patients. Combined, our findings support the growing evidence that SARS-CoV-2 is dysregulating MAIT cells and that IL-7 treatment might improve their function, rendering them more effective in protecting the body against the virus.

Colorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial to devise effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation. In this study, we sought to elucidate the relationship between MUC2 expression and immune infiltration within CRC using models involving two well-established cell lines, HT-29 and LS-174T. By employing CRISPR-mediated MUC2 knockout, we investigated the influence of MUC2 on tumor immune infiltration and its interplay with T cells and NK cells enriched peripheral blood mononuclear cells (PBMCs) in 3D spheroid cultures. While MUC2 was more abundant in LS-174T cell line compared to HT-29, its knockout resulted in increased immune infiltration solely in the HT-29 cell line, but not in the LS-174T cell line. We revealed that the removal of MUC2 protein was compensated in LS-174T by the expression of other gel-forming mucin proteins (MUC6, MUC5B) commonly expressed in the gastrointestinal epithelium, while this was not observed in HT-29 cell line. Our study is the first to demonstrate that MUC2 functions as a physical barrier to immune infiltration in colorectal cancer (CRC) . In HT-29 cells, MUC2 knockout increased immune infiltration, while in LS-174T cells, compensatory expression of other mucins (MUC6, MUC5B) maintained the barrier. These findings reveal the complexity of mucin biology in CRC and suggest that targeting mucin pathways could be a novel therapeutic approach.

CD19 is an essential component of a membrane protein complex on B cells, which also includes complement receptor 2 (CD21), CD81, and CD225. It amplifies B cell receptor (BCR) signaling by recruiting regulatory molecules and facilitating the phosphorylation of key kinases. Mutations in the gene disrupt the integrity of this complex and impair BCR signaling, ultimately leading to antibody deficiency. we report here a novel mutation in the gene in two patients from consanguineous Algerian kindred. We conducted a comprehensive analysis of the clinical, genetic, and immunological characteristics of two siblings with CD19 deficiency. Both siblings began experiencing upper and lower respiratory tract infections in early childhood. Over time, the older sibling developed recurrent fungal and viral skin infections, as well as episodes of pyelonephritis. Whole exome sequencing identified a novel homozygous mutation in the gene, leading to an out-of-frame translation predicted to trigger nonsense-mediated decay and result in absent gene expression. Flow cytometry revealed a complete absence of CD19 and reduced CD21 expression on CD20 B cells in both siblings, while CD81 expression remained normal. Despite normal total peripheral B cell counts, the older patient exhibited reduced memory B cells. Additionally, both patients displayed circulating autoantibodies and an increased frequency of circulating follicular helper T cells. These findings highlight the critical role of CD19 not only in the initial activation of B lymphocytes by T-dependent antigens, but also in the maturation and/or selection of activated B cells within the memory compartment.

Secondary hypogammaglobulinaemia or antibody deficiency (SAD) is an under-recognised complication of B cell-targeted therapies (BCTTs) in both autoimmune diseases (AIDs) and haematological malignancy. In 2019, UK recommendations were published for SAD in patients receiving BCTT,1 while, in 2022, the American Academy of Allergy, Asthma, and Immunology (AAAAI) produced guidance.2 Both publications recommend baseline immunoglobulin (Ig) measurements, followed by at 6–12-monthly intervals. Our aims here were to (1) describe Ig monitoring in our paediatric cohort receiving BCTT; and (2) audit our practice as per the 2019 UK and 2022 AAAAI guidance. Pharmacy records were screened for AID and malignancy patients receiving BCTT at Sidra Medicine between 2016 and 2024. Patients were between 0 and 18 years of age at the time of starting BCTT. Frequency and results of Ig testing were extracted from electronic medical records. These findings were audited against monitoring guidance from the 2019 and 2022 publications. Hypogammaglobulinaemia was defined as IgG below the lower limit of age-related reference range (irrespective of IgA and IgM levels). Values of IgG and the prevalence of hypogammaglobulinaemia were recorded at baseline and during follow-up. 98 patients were identified and 92 included with a minimum of 6 months’ follow-up duration (Fig 1);•Pre-BCTT baseline IgG results were available in 82/92 patients (89.1%);•19/82 patients (23.2%) had low IgG levels at baseline;•73/92 patients (79.3%) had IgG testing post-BCTTs;•Range of IgG measurements per patient: 1–14 timepoints over median follow-up of 0–72 months. Baseline IgG tests were almost always performed as per the guidance (Table 1). Baseline IgG was low in 23.2% patients, confirming the importance of this timepoint. However, post-BCTT IgG monitoring followed the guidance less strictly. Only 79.3% of patients had IgG measured post-BCTT, with variation in monitoring between specialties. Adherence to guidance was relatively lower in patients seen under neurology and nephrology. One systemic lupus erythematous (SLE) patient developed persistent low IgG after a solitary BCTT cycle. Further testing revealed an underlying primary immune deficiency disorder/inborn error of immunity. Baseline IgG tests were almost always performed as per the guidance, illustrating close adherence by clinicians. Furthermore, baseline IgG was low in 23.2% of patients, showing the clinical importance of baseline measurements, otherwise, low IgG during follow-up might be incorrectly attributed to BCTT. However, IgG measurement post-BCTT did not follow the guidance as closely. Overall, only 79.3% of patients had IgG measured post-BCTT, with clear variation in monitoring between specialties: haematology/oncology and rheumatology showed closer adherence compared with neurology and nephrology. The importance of baseline testing and monitoring was demonstrated by unmasking of a primary immune deficiency disorder in an SLE patient after a solitary BCTT cycle.3 (1)Protocol-driven approach to standardise IgG collection timepoints and improve monitoring;(2)Automation of IgG monitoring by including IgG orders as part of combined pharmacy–pathology rituximab order set;(3)Clinical Immunology review if persistent antibody deficiency and/or recurrent/severe infections develop after BCTT.

Background Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. Methods Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. Results We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. Conclusions This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.