The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function.

Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real-world conditions. Here we have addressed the importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes. IRF9, together with phosphorylated STAT1 and STAT2, form a heterotrimer called interferon stimulated gene factor 3 (ISGF3) which promotes the expression of hundreds of IFN-stimulated genes that mediate antiviral function triggered by exposure to type I interferons.

Enrichment of Immune Dysregulation Disorders in Adult Patients with Human Inborn Errors of Immunity.

Human inborn errors of immunity (IEI) comprise a group of diseases resulting from molecular variants that compromise innate and adaptive immunity. Clinical features of IEI patients are dominated by susceptibility to a spectrum of infectious diseases, as well as autoimmune, autoinflammatory, allergic, and malignant phenotypes that usually appear in childhood, which is when the diagnosis is typically made. However, some IEI patients are identified in adulthood due to symptomatic delay of the disease or other reasons that prevent the request for a molecular study.

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

Background: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance.

Inborn Error of STAT2-Dependent IFN-I Immunity in a Patient Presented with Hemophagocytic Lymphohistiocytosis and Multisystem Inflammatory Syndrome in Children.

Human inborn errors of immunity (IEI) affecting the type I interferon (IFN-I) induction pathway have been associated with predisposition to severe viral infections. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome that has been increasingly associated with inborn errors of IFN-I-mediated innate immunity. Here is reported a novel case of complete deficiency of STAT2 in a 3-year-old child that presented with typical features of HLH after mumps, measles, and rubella vaccination at the age of 12 months.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.

Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.

Background: We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.

Methods: We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.

Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene.

Effective Natural Killer Cell Degranulation Is an Essential Key in COVID-19 Evolution.

NK degranulation plays an important role in the cytotoxic activity of innate immunity in the clearance of intracellular infections and is an important factor in the outcome of the disease. This work has studied NK degranulation and innate immunological profiles and functionalities in COVID-19 patients and its association with the severity of the disease. A prospective observational study with 99 COVID-19 patients was conducted.

An Early Th1 Response Is a Key Factor for a Favorable COVID-19 Evolution.

The Th1/Th2 balance plays a crucial role in the progression of different pathologies and is a determining factor in the evolution of infectious diseases. This work has aimed to evaluate the early, or on diagnosis, T-cell compartment response, T-helper subsets and anti-SARS-CoV-2 antibody specificity in COVID-19 patients and to classify them according to evolution based on infection severity. A unicenter, randomized group of 146 COVID-19 patients was divided into four groups in accordance with the most critical events during the course of disease.

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination.

The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination.

Clinical and Immunological Features of Human BCL10 Deficiency.

The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease.

Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored.

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management.

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders).

Next Generation Sequencing for Detecting Somatic Mutations in Patients With Autoimmune Lymphoproliferative Syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder clinically defined by chronic and benign lymphoproliferation, autoimmunity and an increased risk of lymphoma due to a genetic defect in the FAS-FASL apoptotic pathway. Genetic defects associated with ALPS are germinal and somatic mutations in gene, in addition to germinal mutations in and genes. The accumulation of CD3+TCRαβ+CD4-CD8- double negative T-cells (DNT) is a hallmark of the disease and 20-25% of ALPS patients show heterozygous somatic mutations restricted to DNT in the gene (ALPS-sFAS patients).

T-Helper Cell Subset Response Is a Determining Factor in COVID-19 Progression.

The immune response type organized against viral infection is determinant in the prognosis of some infections. This work has aimed to study Th polarization in acute COVID-19 and its possible association with the outcome through an observational prospective study. Fifty-eight COVID-19 patients were recruited in the Medicine Department of the hospital "12 de Octubre," 55 patients remaining after losses to follow-up.

Autoimmune Lymphoproliferative Syndrome in Children with Nonmalignant Organomegaly, Chronic Immune Cytopenia, and Newly Diagnosed Lymphoma.

This study investigated the frequency of and predictive factors for autoimmune lymphoproliferative syndrome (ALPS) in children with lymphoma, chronic immune cytopenia, and nonmalignant organomegaly. Thirty-four children with suspected ALPS (n=13, lymphoma; n=12, immune cytopenia; n=9, nonmalignant organomegaly) were included. Double-negative T-cells, lymphocyte apoptosis, and genetic findings were analyzed.

Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS).

Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy.

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies.

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy.