Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era.

Background: Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).

Methods: Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.

Results: Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes.

Entry into the lytic cycle exposes EBV-infected cells to NK cell killing via upregulation of the MICB ligand for NKG2D and activation of the CD56 and NKG2AKIRCD56 subsets.

The Epstein-Barr virus (EBV) is usually acquired during infancy as an asymptomatic infection and persists throughout life in a latent state under the control of the host immune system. However, EBV is associated with various malignant diseases that preferentially develop in immunodeficient individuals. Accumulating evidence suggests an important role for NK cells, though the mechanisms by which EBV evades or triggers NK cell responses are poorly understood.

Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for the diagnosis of inborn errors of immunity (IEI).

Background: Inborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition.

A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment.

Vasculitis and vasculopathy associated with inborn errors of immunity: an overview.

Systemic autoinflammatory diseases (SAIDs) are disorders of innate immunity, which are characterized by unprovoked recurrent flares of systemic inflammation often characterized by fever associated with clinical manifestations mainly involving the musculoskeletal, mucocutaneous, gastrointestinal, and nervous systems. Several conditions also present with varied, sometimes prominent, involvement of the vascular system, with features of vasculitis characterized by variable target vessel involvement and organ damage. Here, we report a systematic review of vasculitis and vasculopathy associated with inborn errors of immunity.

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT.

The Inborn Errors of Immunity-Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase.

Purpose: Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.

Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.

Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.

Long term longitudinal follow-up of an AD-HIES cohort: the impact of early diagnosis and enrollment to IPINet centers on the natural history of Job's syndrome.

Job's syndrome, or autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES, STAT3-Dominant Negative), is a rare inborn error of immunity (IEI) with multi-organ involvement and long-life post-infective damage. Longitudinal registries are of primary importance in improving our knowledge of the natural history and management of these rare disorders. This study aimed to describe the natural history of 30 Italian patients with AD-HIES recorded in the Italian network for primary immunodeficiency (IPINet) registry.

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement.

Inborn errors of immunity associated with atopy (IEIs-A) are a group of inherited monogenic disorders that occur with immune dysregulation and frequent skin involvement. Several pathways are involved in the pathogenesis of these conditions, including immune system defects, alterations of skin barrier and metabolism perturbations. Current technological improvements and the higher accessibility to genetic testing, recently allowed the identification of novel molecular pathways involved in IEIs-A, also informing on potential tailored therapeutic strategies.

The Role of NK Cells in EBV Infection and Related Diseases: Current Understanding and Hints for Novel Therapies.

The Epstein-Barr virus (EBV) is a ubiquitous herpesvirus most often transmitted during infancy and infecting the vast majority of human beings. Usually, EBV infection is nearly asymptomatic and results in life-long persistency of the virus in a latent state under the control of the host immune system. Yet EBV can cause an acute infectious mononucleosis (IM), particularly in adolescents, and is associated with several malignancies and severe diseases that pose a serious threat to individuals with specific inborn error of immunity (IEI).

How CD4 T Cells Transcriptional Profile Is Affected by Culture Conditions: Towards the Design of Optimal In Vitro HIV Reactivation Assays.

Unlabelled: Most of the current assays directed at the investigation of HIV reactivation are based on cultures of infected cells such as Peripheral Blood Mononuclear Cells (PBMCs) or isolated CD4 T cells, stimulated in vitro with different activator molecules. The culture media in these in vitro tests lack many age- and donor-specific immunomodulatory components normally found within the autologous plasma. This triggered our interest in understanding the impact that different matrices and cell types have on T cell transcriptional profiles following in vitro culture and stimulation.

Natural history of type 1 diabetes on an immunodysregulatory background with genetic alteration in B-cell activating factor receptor: A case report.

The immunological events leading to type 1 diabetes (T1D) are complex and heterogeneous, underscoring the necessity to study rare cases to improve our understanding. Here, we report the case of a 16-year-old patient who showed glycosuria during a regular checkup. Upon further evaluation, stage 2 T1D, autoimmune thrombocytopenic purpura (AITP), and common variable immunodeficiency (CVID) were diagnosed.

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies.

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options.

Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment.

We described the case of a patient affected by activated PI3K-kinase delta syndrome (APDS) and a long-lasting and pauci-symptomatic SARS-CoV-2 infection, treated with multiple therapeutic agents including remdesivir and SARS-CoV-2-neutralizing monoclonal antibodies. We detected the clearance of the virus 105 days from the first positive swab and 7 days after monoclonal antibody administration. At genotyping, the SARS-CoV-2 virus resulted as wild type on all samples tested.