A standardized protocol for assessing immunodeficiency in mouse models.

Immunodeficient mouse strains are widely used in several fields of biomedical research. Despite that, no standardized system for evaluating immunodeficiency in mice currently exists, and an unbiased comparison of various immunodeficient mouse strains is difficult. The aim of our study was to develop a standardized multi-disciplinary protocol for the morpho-phenotypical assessment of immunodeficient mouse models.

TCF1 and LEF1 promote B-1a cell homeostasis and regulatory function.

B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial. The CD5 B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal.

Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.

STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice.

Further Personalizing Medicine in Immune Disorders: Genomic Findings and Hematopoietic Cell Transplantation Survival.

Background: Hematopoietic cell transplantation (HCT) provides effective long-term management for some inborn errors of immunity. Genetic findings can inform donor selection, considerations in conditioning intensity and agents, and graft-versus-host disease prophylaxis. Exome/genome sequencing is increasingly accessible but of uncertain clinical utility.

Restoration of the human skin microbiome following immune recovery after hematopoietic stem cell transplantation.

The human skin microbiome is intricately intertwined with host immunity. While studies have elucidated microbial influences on immunity, understanding how immune alterations modulate this equilibrium remains limited. We investigated the dual impact of immune deficiency and hematopoietic stem cell transplantation (HSCT) on the skin microbiome in 24 patients with dedicator of cytokinesis 8 (DOCK8) deficiency, a rare inborn error of immunity.

Factors associated with and kinetics of anti-IFN-α autoantibodies in deficiency.

Background: Autoantibodies against IFN-α (anti-IFN-α) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined.

Objective: We described the clinical and immunologic findings linked to anti-IFN-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation.

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.

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients.

The patient registry (ESID-R), established in 1994, is one of the world's largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy.

A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 () causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS).

Mutations in , a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis.

Long-term outcome in Wiskott-Aldrich syndrome and X-linked thrombocytopenia patients: an observational -prospective multi-center study of the Italian Primary Immune Deficiency Network (IPINET).

Background: Wiskott-Aldrich Syndrome (WAS) is characterized by eczema, infections, and severe bleeding, but may also include autoimmunity and malignancy. Subjects with X-linked thrombocytopenia (XLT) can display a mild phenotype, although severe complications may occur at any age. WAS and XLT are caused by mutations of the gene.

Human LY9 governs CD4 T cell IFN-γ immunity to .

CD4 T cells are indispensable for optimal immunity to (), a pathogen that triggers tuberculosis (TB) in humans. -specific human CD4 T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4CCR6CXCR3T-betRORγT T helper 1* cell (T1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10 individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T1* cells.

A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis.

ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.

Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature.

Prior SARS-CoV-2 infection affects adaptive immune responses to Omicron BA.4/BA.5 mRNA booster.

Background: Bivalent coronavirus disease 2019 (COVID) mRNA vaccines encoding Wuhan-1 and Omicron BA.4/BA.5 spike proteins (S) can prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the quality of adaptive immune responses and the importance of hybrid immunity are not well documented.

A large-scale database of T-cell receptor beta sequences and binding associations from natural and synthetic exposure to SARS-CoV-2.

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 160,000 high-confidence SARS-CoV-2-associated TCRs. This database is made freely available, and the data contained in it can be used to assist with global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.

The ClinGen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications for classification of variants in , , , , , , and .

Purpose: This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: , , , , , , and .

Methods: The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines.

Magnitude and dynamics of the T-cell response to SARS-CoV-2 infection at both individual and population levels.

Introduction: T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.

Methods: Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2.

Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Thymic and T-cell intrinsic critical roles associated with severe combined immunodeficiency and Omenn syndrome due to a heterozygous variant (G201R) in PSMB10.

Background: Heterozygous immunoproteasome 20 S subunit beta 10 (PSMB10) mutations can cause severe combined immunodeficiency and Omenn syndrome. Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death.

Objective: We sought to perform immunologic and molecular characterization of an infant with a PSMB10 heterozygous variant.

A spatial human thymus cell atlas mapped to a continuous tissue axis.

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus-the Cortico-Medullary Axis-and used it to perform a spatially resolved analysis.

Thymic inborn errors of immunity.

The thymus is crucial for optimal T-cell development by facilitating the generation and selection of a diverse repertoire of T cells that can recognize foreign antigens while promoting tolerance to self-antigens. A number of inborn errors of immunity causing complete or partial defects in thymic development (athymia) and/or impaired thymic function have been increasingly recognized that manifest clinically with a combination of life-threatening infections, severe multiorgan autoimmunity, and/or cardiac, craniofacial, ectodermal, and endocrine abnormalities. The introduction of newborn screening programs and the advent of thymic transplantation show promise for early detection and improving the outcomes of patients with certain thymic inborn errors of immunity.