Primary immunodeficiency (PID) is a group of genetic disorders which affects immune cell development, differentiation, and function. The affected individuals are highly susceptible to infection by a diverse array of pathogens. Epstein–Barr virus (EBV) infection is ubiquitous in humans and usually involves an asymptomatic or self-limiting clinical course. In rare cases, EBV can cause not only an acute infection but also a severe exaggerated immune response and lymphoproliferative disease.Furthermore, EBV infection in patients with PID can lead to immune dysregulation and increased risk of malignancies, in addition to the severe course of the acute infection. Recognition of the different genetic defects and their effect on immunological pathways provide us with fundamental insights into the pathophysiology of EBV infection and associated disease, and may lead to developing better targeted therapies in the future. Here, we review all of PIDs with an abnormal response to EBV disease.Statement of novelty: Here we provide a review of the current knowledge of all PIDs reported to be associated with abnormal response to EBV infection and associated disease, such as hemophagocytic lymphohistiocytosis.

Background: Leukocyte adhesion deficiency (LAD) syndromes are primary immunodeficiency disorders caused by defects in adhesion molecules on leukocytes resulting in impaired migration into tissues. Common cutaneous manifestations of LAD include bacterial infections, omphalitis with delayed separation of the umbilical cord, impaired pus formation and poor wound healing. LAD is associated with significant morbidity and mortality, making early diagnosis and management integral in the care of these patients.Methods: Molecular testing and flow cytometry for expression of CD18 were performed on 2 siblings presenting with cutaneous lesions including pyoderma gangrenosum (PG).Results: We describe 2 siblings with a novel homozygous mutation in ITGB2 (c.2070del, p.Asp690Glufs*25) resulting in an atypical presentation of LAD-I with PG.Conclusion: LAD should be considered in patients presenting with unexplained PG, even in the absence of significant infections or umbilical cord complications.Statement of novelty: To the best of our knowledge, we describe a novel homozygous mutation in ITGB2 (c.2070del, p.Asp690Glufs*25) resulting in LAD-I. Patients with LAD-I may present with unexplained PG and may lack classic symptoms including umbilical cord complications.

Background: Gastrointestinal defects and immunodeficiency syndrome (GIDID) is a severe neonatal disorder usually fatal within the first months of life. We report a case presenting with intestinal atresia, combined immunodeficiency, and a novel association with hypothyroidism and cardiac malformations. The immune phenotype was remarkable for agammaglobulinemia, lymphopenia, and mildly decreased lymphocyte proliferation. We present here the unique phenotype as well as studies to determine if the agammaglobulinemia was due to an intrinsic B lymphocyte defect.Methods: Peripheral blood mononuclear cells from the patient and a healthy control were isolated by Ficoll-Hypaque centrifugation and stimulated with anti-CD40, IL-4 and IL-21 for 7 days. Total IgG production was measured by ELISA in the supernatant of the stimulated sample on day 7. Cells were stained for CD19, CD27, IgM, CD11b, CD11c, and CD14.Results: At day 7, supernatant from the patient stimulated cells contained levels of total IgG comparable to the control (755 ng/mL vs. 658 ng/mL, respectively). B cell maturation appeared impaired, as morphologically the patient sample demonstrated fewer B cell clones and cells with dendritic projections.Conclusions: Despite this typical severe clinical picture of GIDID with agammaglobulinemia, IgG production was detected under optimal stimulation for induction of plasma cells. This suggests that there may not be an inherent defect in class switching and antibody production in B cells in this disorder. It is possible that the in vivo physical or cytokine milieu may be defective for optimal B cell function. Further studies assessing the function of the immune cells as well as possible gastrointestinal loss of immunoglobulins are needed in this disease.Statement of novelty: Despite much improvement in understanding the effects of TTC7A mutations in GIDID, the root cause of hypogammaglobulinemia in these patients is still unclear. The work portrayed in this study furthers the current knowledge. It suggests that when appropriately stimulated in vitro, this patient’s B cells were capable of adequate immunoglobulin production. Moreover, to the best of our knowledge, this patient is the first with this genetic defect to be reported with hypothyroidism and cardiac malformations.

Purine nucleoside phosphorylase (PNP) is a key enzyme required for the degradation of purine nucleosides into uric acid or their salvage into nucleic acids. Patients who are deficient in PNP suffer from progressive T cell immunodeficiency, with increased susceptibility to infections, autoimmunity, and neurologic abnormalities. In the absence of successful treatment to restore immune function, these patients rarely survive to adulthood. Hematopoietic stem cell transplantation is the only known cure for PNP deficiency. Use of an HLA-matched donor is preferable as the outcome with alternative donors have been variable; however, this option is rarely available.Gene therapy represents a therapeutic option that bypasses the need for a donor, and thus associated complications. Although first generation γ-retroviral vectors have been successful in some immunodeficiencies, in others, evidence of insertional mutagenesis prompted a halt in their use. More recently, the introduction of safer lentiviral vectors holds promise in offering a viable option to treat immunodeficiency.Here, we present a clinical trial protocol utilizing self-inactivating lentiviral vectors to treat PNP deficiency. Patients will be evaluated up to 3 years post-transplantation to determine the safety of lentiviral-treated stem cell infusion, as well as the extent of immune reconstitution.Statement of novelty: This protocol describes the novel treatment of PNP deficiency using lentiviral-based gene therapy.