ABSTRACT
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.
Subject(s)
B-Lymphocytes/metabolism , Common Variable Immunodeficiency/genetics , Genome/genetics , RNA, Messenger/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , B-Cell Activation Factor Receptor/genetics , Case-Control Studies , Child , Child, Preschool , Female , Gene Expression Profiling , Genetic Predisposition to Disease , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Middle Aged , Multifactorial Inheritance , Sequence Analysis, DNA , Sequence Analysis, RNA , Transmembrane Activator and CAML Interactor Protein/genetics , Young AdultABSTRACT
XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years.
Subject(s)
Cation Transport Proteins/genetics , Leukoencephalopathy, Progressive Multifocal/diagnosis , Leukoencephalopathy, Progressive Multifocal/etiology , Mutation , X-Linked Combined Immunodeficiency Diseases/complications , X-Linked Combined Immunodeficiency Diseases/genetics , Brain/pathology , DNA Mutational Analysis , Fluorodeoxyglucose F18 , Humans , Immunophenotyping , Lymph Nodes/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Phenotype , Positron-Emission Tomography , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tomography, X-Ray Computed , X-Linked Combined Immunodeficiency Diseases/diagnosisABSTRACT
This review of the currently available literature from more than two decades of clinical experience with self-infusions of immunoglobulin at home provides evidence to support the feasibility, safety, and efficacy in all age groups. Self-infusions at home not only increase patient confidence and their understanding of the immune deficiency but also contribute to the improvement of health-related quality of life. Such home therapy programs should be encouraged, and wherever possible, experienced centers should extend their services to include patients who require immunoglobulin therapy for immunomodulation. Home therapy programs play an important role in long-term health outcome.
Subject(s)
Home Infusion Therapy/methods , Immunization, Passive/methods , Immunologic Deficiency Syndromes/therapy , Home Infusion Therapy/economics , Home Infusion Therapy/psychology , Home Infusion Therapy/trends , Humans , Immunization, Passive/economics , Immunization, Passive/psychology , Immunization, Passive/trends , Immunologic Deficiency Syndromes/economics , Patient Education as Topic , Practice Guidelines as Topic , Program Development/economics , Program Development/methods , Quality of LifeABSTRACT
In a double-blind study, we randomly assigned 84 patients with chronic lymphocytic leukemia who were judged to be at increased risk of bacterial infection to receive intravenous immunoglobulin G (400 mg per kilogram of body weight) or a placebo every three weeks for one year. Eligible patients had hypogammaglobulinemia, a history of infection, or both. The patients receiving immunoglobulin had significantly fewer bacterial infections during the study period than those receiving placebo (23 vs. 42; P = 0.01). This reduction was most striking in the patients who completed a full year of treatment (14 vs. 36; P = 0.001). The period from study entry to the first serious bacterial infection was significantly longer in the patients receiving immunoglobulin (P = 0.026). There was no significant difference between the two groups in the incidence of nonbacterial infection. Immunoglobulin therapy was tolerated well; there were no serious adverse reactions, and the incidence of minor reactions was low. We conclude that selected patients with chronic lymphocytic leukemia who are at risk of bacterial infection can be substantially protected from this complication by the regular intravenous administration of immunoglobulin.
