A scoping review of clinical management guidelines in inborn errors of immunity.

Background: A scoping review was conducted for the European Society for Immunodeficiencies (ESID) Clinical Working Party (CWP) to evaluate clinical management guidelines for Inborn Errors of Immunity (IEIs). The goal was to identify gaps to inform future guideline development, thereby supporting improved clinical practice and patient outcomes.

Methods: A search strategy was developed in collaboration with the ESID CWP and an information specialist.

Immunophenotyping of apparently immunocompetent hosts with cryptococcosis reveals IL-17 deficiency as a unifying susceptibility factor.

Introduction: We describe the immunophenotyping and genetic analysis of HIV-uninfected apparently immunocompetent adults presenting with disseminated cryptococcosis. Cryptococci are environmentally ubiquitous fungi that may cause disseminated infection including meningitis. Cryptococcosis occurs predominantly in immunocompromised hosts and most commonly in the context of human immunodeficiency virus (HIV) infection.

Exploiting TCR Repertoire Analysis to Select Therapeutic TCRs for Cancer Immunotherapy.

Over the past decade, numerous innovative immunotherapy strategies have transformed the treatment of cancer and improved the survival of patients unresponsive to conventional chemotherapy and radiation therapy. Immune checkpoint inhibition approaches aim to block negative regulatory pathways that limit the function of endogenous T cells, while adoptive cell therapy produces therapeutic T cells with high functionality and defined cancer specificity. While CAR engineering successfully targets cancer surface antigens, TCR engineering enables targeting of the entire cancer proteome, including mutated neo-antigens.

Impaired DNA damage responses and inflammatory signaling underpin hematopoietic stem cell defects in Gata2 haploinsufficiency.

Clinical GATA2 haploinsufficiency results in immunodeficiency that evolves to leukemia. How GATA2 haploinsufficiency disrupts the functionality of hematopoietic stem/progenitor cells (HSCs/HSPCs) to facilitate pre-leukemia development is poorly defined. Using a hematopoietic-specific conditional mouse model of Gata2 haploinsufficiency, we identified pervasive defects in HSPC differentiation in young adult Gata2 haploinsufficient mice and perturbed HSC self-renewal following transplantation.

Organ-specific features of human kidney lymphatics are disrupted in chronic transplant rejection.

Lymphatic vessels maintain tissue fluid homeostasis and modulate inflammation, yet their spatial organisation and molecular identity in the healthy human kidney, and how these change during chronic transplant rejection, remain poorly defined. Here, we show that lymphatic capillaries initiate adjacent to cortical kidney tubules and lack smooth muscle coverage. These vessels exhibit an organ-specific molecular signature, enriched for CCL14, DNASE1L3, and MDK, with limited expression of canonical immune-trafficking markers found in other organ lymphatics, such as LYVE1 and CXCL8.

Tuning antibody stability and function by rational designs of framework mutations.

Artificial intelligence and machine learning models have been developed to engineer antibodies for specific recognition of antigens. These approaches, however, often focus on the antibody complementarity-determining region (CDR) whilst ignoring the immunoglobulin framework (FW), which provides structural rigidity and support for the flexible CDR loops. Here we present an integrated computational-experimental workflow, combining static structure analyses, molecular dynamics simulations and physicochemical and functional assays to generate rational designs of FW mutations for modulating antibody stability and activity.

Fusion of Complement Fragment C3d Enhances Germinal Center Responses to HIV-1 Envelope Glycoproteins.

Eliciting sustained germinal center (GC) responses is critical for the development of an effective HIV-1 vaccine, yet HIV-1 envelope glycoprotein (Env) immunogens often fail to elicit GC responses required for the maturation of cognate B cells that secrete broadly neutralizing antibodies (bNAbs). Effective antigen recognition is important for initial B cell priming, activation, and GC engagement. Since complement opsonization contributes to antigen recognition, we investigated whether C3d fusion could enhance the GC response of the stabilized HIV-1 Env immunogen based on a consensus sequence (ConM Env).

Tumor necrosis factor receptor 2 in allergen tolerance: a perspective view.

Central and peripheral tolerance are key to maintain immune homeostasis. Imbalance of these processes often leads to diseases such as allergy, cancer or autoimmune disorders. During the immune response to allergens, several regulatory immune cells play a role in the development of peripheral tolerance and maintenance of homeostasis by inhibiting the development of CD4 type 2 helper T cells, impairing the production of pro-allergenic cytokines, reducing the activation of effector cells driving allergic inflammation and generating allergen-neutralizing antibodies.

Navigating disruption in the PID landscape: embracing opportunities and anticipating threats in the next ten years.

Introduction: The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its third edition of the Global Multi-Stakeholders' Summit, gathering key primary immunodeficiencies (PID) stakeholders and experts to discuss and foment global collaboration.

Methods: This edition focused on the impact of genomic medicine in PID treatment, the role of digital health, including artificial intelligence, in PID care, and how to anticipate and minimise risks to ensure optimal patient access to care.

Results: These discussions aimed to examine current hurdles and brainstorm feasible solutions and priorities for the PID community in these areas in the next ten years.

Tissue-resident memory CD4 T cells are sustained by site-specific levels of self-renewal and continuous replacement.

Tissue-resident memory T cells (T) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new T are generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging.

Allogeneic hematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.

Signal transduction and activator of transcription 3 hyperimmunoglobulin E syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatoceles, and aspergillosis; lymphoma; and extraimmune manifestations including fractures and vasculopathy. Published data on immune and extraimmune hematopoietic stem cell transplant (HSCT) outcomes focus on case reports or small cohorts. We conducted an international multicenter retrospective study of HSCT in STAT3-HIES.

A linear ontogeny accounts for the development of naive, memory, and tumor-infiltrating regulatory T cells in mice.

Regulatory T cells (T cells) are critical regulators of adaptive immunity and the pathophysiology of antitumoral immunity. T cells are both generated during thymic development and induced from peripheral conventional T cells. How these distinct pathways contribute to the homeostasis of circulating T cells in health and disease remains unclear.

CD28 and TCR differentially impact naïve and memory T cell responses.

Manipulating CD28 co-stimulation is a key element of anti-tumour immune responses and treating autoimmune diseases. CD28 can reduce the T cell activation threshold but has a complex relationship with T cell receptor (TCR) signalling and an unclear role in specific T cell subsets. Using a series of stimulation assays, we have studied the relative contribution of CD28 and TCR signals in human CD4 + T cell responses.

Developing a Vaccine Against Human Cytomegalovirus: Identifying and Targeting HCMV's Immunological Achilles' Heel.

Human cytomegalovirus (HCMV) is a critical pathogen in immunocompromised populations, such as organ transplant recipients as well as congenitally infected neonates with immature immune systems. Despite decades of research and the growing financial burden associated with the management of HCMV, there is no licensed vaccine to date. In this review, we aim to outline the complexity of HCMV and the antigens it presents and the journey and challenges of developing an effective HCMV vaccine, as well as further highlight the recent analyses of the most successful vaccine candidate so far-gB/MF59.

Skin Manifestations in Adults With Chronic Granulomatous Disease in the United Kingdom.

Background: Chronic granulomatous disease (CGD) is a rare inborn error of immunity caused by mutations affecting individual components of the nicotinamide adenine dinucleotide phosphate oxidase complex. Resultant defective neutrophil function leads to infectious and inflammatory complications, resulting in reduced quality of life and survival. Although hematopoietic stem cell transplantation is a curative option, a significant proportion of patients are managed conservatively into adulthood.

Long-term effects of COVID-19 in patients with primary immunodeficiency: An IPOPI worldwide survey.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, many individuals developed persistent symptoms after COVID-19. The data on these long-term effects in the primary immunodeficiency (PID) community are limited.

Objective: This study aimed to understand long-term symptoms after COVID-19 in patients with PID, focusing on prevalence, risk factors, viral persistence, and the impact of COVID-19 on their health-related quality of life (HR-QoL).

Safety and Diagnostic Utility of Brain Biopsy and Metagenomics in Decision-Making for Patients with Inborn Errors of Immunity (IEI) and Unexplained Neurological Manifestations.

Unexplained neurological symptoms can pose a diagnostic challenge in patients with inborn errors of immunity (IEI) where the aetiology can be varied, and diverse pathologies may require contrasting treatments. Brain biopsy, the process of sampling brain tissue directly, has historically provided histological and microbiological information and can now be exploited for deep metagenomic next generation analysis (mNGS). We conducted a retrospective analysis of clinical and diagnostic data on paediatric patients with IEI who had a brain biopsy between 2010 and 2022 at a UK tertiary centre where 14 patients fulfilled our search criteria.

Heat shock protein 90 is a chaperone regulator of HIV-1 latency.

An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but therapy interruption results in viral rebound from a latent reservoir mainly found in memory CD4+ T cells. Treatment is therefore lifelong and not curative.

Microvascular aberrations found in human polycystic kidneys are an early feature in a Pkd1 mutant mouse model.

Therapies targeting blood vessels hold promise for autosomal dominant polycystic kidney disease (ADPKD), the most common inherited disorder causing kidney failure. However, the onset and nature of kidney vascular abnormalities in ADPKD are poorly defined. Accordingly, we employed a combination of single-cell transcriptomics; three-dimensional imaging with geometric, topological and fractal analyses; and multimodal magnetic resonance imaging with arterial spin labelling to investigate aberrant microvasculature in ADPKD kidneys.

Severe acute respiratory syndrome coronavirus-2 antibody prevalence in adults with HIV.

Objectives: To measure severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibody seroprevalence within a cohort of adults with HIV and correlate demographics with response rates to SARS CoV-2 vaccination.

Design: Initial vaccine trials for SARS CoV-2 did not examine efficacy in people with HIV. We undertook the SCAPE-HIV study from April 2021 to November 2022 to focus on vaccine response in this population to guide future vaccine scheduling.

Guidance for stem cell therapy for juvenile systemic sclerosis patients.

Introduction: Autologous stem cell transplantation (ASCT) and cellular therapies (CTs) are emerging therapeutic options for both adult and juvenile-onset systemic sclerosis (jSSc) patients. However, most efficacy data are derived from adult studies, and it remains unclear whether adult stem cell transplant criteria are fully applicable to pediatric patients with jSSc. Given pediatric patients' unique potential for recovery and tissue remodeling, the stringent criteria used in adults need adaptation for children.

High-Resolution Imaging of Intracellular Trafficking of B Cell Receptor Using Specific Hybridization Internalization Probe (SHIP).

Recent advancements in microscopy have greatly expanded our understanding of intracellular traffic. Yet, due to the inherent characteristics of B cells, such as their small size and high receptor density on the plasma membrane, visualization of internalized cargo or receptors remains challenging. This challenge is particularly pronounced in the case of the B cell receptor (BCR), where accurate detection of internalized, antigen-bound BCR molecules can be strongly hindered by the signal from the plasma membrane-bound pool of the same molecules.

Memory CD4+ T cells sequentially restructure their 3D genome during stepwise activation.

Background: CD4+ T cells are a highly differentiated cell type that maintain enough transcriptomic plasticity to cycle between activated and memory statuses. How the 1D chromatin state and 3D chromatin architecture support this plasticity is under intensive investigation.

Methods: Here, we wished to test a commercially available Hi-C kit (Arima Genomics Inc.