ABSTRACT
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).
Subject(s)
B-Lymphocytes , Common Variable Immunodeficiency/genetics , Ikaros Transcription Factor/genetics , Mutation , Adolescent , Adult , Antigens, CD/analysis , Bone Marrow/immunology , Bone Marrow Examination , Child , Child, Preschool , Chromosomes, Human, Pair 7 , Common Variable Immunodeficiency/immunology , Exome , Female , Heterozygote , Humans , Immunoglobulin G/blood , Lymphocyte Count , Male , Pedigree , Sequence Analysis, DNA/methodsABSTRACT
BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).
Subject(s)
Inflammation/genetics , Membrane Proteins/genetics , Mutation , Skin Diseases, Vascular/genetics , Age of Onset , Cytokines/genetics , Cytokines/metabolism , Female , Fibroblasts/metabolism , Genes, Dominant , Humans , Infant , Infant, Newborn , Inflammation/metabolism , Interferon-gamma/genetics , Interferon-gamma/metabolism , Janus Kinases/antagonists & inhibitors , Lung Diseases/genetics , Male , Pedigree , Phosphorylation , STAT1 Transcription Factor/metabolism , Sequence Analysis, DNA , Skin Diseases, Vascular/metabolism , Syndrome , Transcription, Genetic , Up-RegulationABSTRACT
Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients' elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.
Subject(s)
Class I Phosphatidylinositol 3-Kinases/genetics , Genetic Predisposition to Disease , Hyper-IgM Immunodeficiency Syndrome/complications , Hyper-IgM Immunodeficiency Syndrome/genetics , Mutation , Neoplasms/etiology , Adult , Biopsy , Child , Female , Heterozygote , Humans , Hyper-IgM Immunodeficiency Syndrome/diagnosis , Lymph Nodes/pathology , Male , Neoplasms/diagnosis , Pedigree , Young AdultABSTRACT
Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany; 1 from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12Rbeta1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12Rbeta1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established.
Subject(s)
Founder Effect , Genetic Predisposition to Disease , Mycobacterium Infections/genetics , Receptors, Interleukin-12/genetics , Animals , Argentina , BCG Vaccine/administration & dosage , BCG Vaccine/adverse effects , Humans , Linkage Disequilibrium , Models, Genetic , Mutation , Mycobacterium bovis/isolation & purification , White People/geneticsABSTRACT
Herein, we describe a combination of clinical, microbiologic, and histopathologic findings significantly associated with osteomyelitis in chronic granulomatous disease. When present, these features should raise the suspicion of underlying chronic granulomatous disease. In patients with these findings, anti-infective prophylactic measures aiming to cover highly prevalent microorganisms, as well as aggressive therapeutic measures, should be strongly encouraged.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Chemoprevention , Granulomatous Disease, Chronic/complications , Granulomatous Disease, Chronic/microbiology , Osteomyelitis/microbiology , Osteomyelitis/pathology , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillosis/pathology , Aspergillosis/physiopathology , Aspergillus/isolation & purification , Bone and Bones/pathology , Case-Control Studies , Child , Child, Preschool , Granulomatous Disease, Chronic/pathology , Granulomatous Disease, Chronic/physiopathology , Humans , Infant , Mycoses/drug therapy , Mycoses/microbiology , Mycoses/pathology , Mycoses/physiopathology , Osteomyelitis/drug therapy , Osteomyelitis/physiopathology , Penicillium/isolation & purification , Serratia Infections/drug therapy , Serratia Infections/microbiology , Serratia Infections/pathology , Serratia Infections/physiopathology , Serratia marcescens/isolation & purificationABSTRACT
Chronic granulomatous disease (CGD) is a genetically heterogeneous disease characterized by recurrent life-threatening infections with bacteria and fungi as well as dysregulated inflammatory mechanisms. CGD is caused by defects in the NADPH oxidase, the enzyme complex responsible for generation of superoxide and other reactive oxygen species (ROS) in phagocytic cells. In this review we will focus our attention on those particular inflammatory manifestations associated with CGD, their frequencies and the underlying immunologic mechanisms favoring it occurrence.
Subject(s)
Granulomatous Disease, Chronic/immunology , NADPH Oxidases/genetics , Autoimmunity/genetics , Female , Gene Expression Profiling , Genes, X-Linked , Granulomatous Disease, Chronic/genetics , Granulomatous Disease, Chronic/physiopathology , Humans , Inflammation/genetics , Inflammation/immunology , Male , Mutation , NADPH Oxidases/immunology , Phagocytes/immunologyABSTRACT
Infections due to Penicillium species other than P.marneffei are rare. We identified a boy with X-linked chronic granulomatous disease (X-CGD) with a pulmonary nodule and adjacent rib osteomyelitis caused by Penicillium piceum. The only sign of infection was an elevated sedimentation rate. P. piceum was isolated by fine needle aspirate and from excised infected tissues. Surgical removal and one year of voriconazole treatment were very well tolerated and led to complete recovery. Microbiological, microscopic and molecular studies support the fungal diagnosis. P. piceum should be considered as a relevant pathogen in immunocompromised patients.
Subject(s)
Genetic Diseases, X-Linked/complications , Granulomatous Disease, Chronic/complications , Mycoses/diagnosis , Mycoses/drug therapy , Osteomyelitis/drug therapy , Osteomyelitis/microbiology , Penicillium/isolation & purification , Antifungal Agents/therapeutic use , Biopsy, Fine-Needle , Blood Sedimentation , Child , DNA, Fungal/chemistry , DNA, Fungal/genetics , Humans , Male , Microscopy , Molecular Sequence Data , Mycoses/microbiology , Pyrimidines/therapeutic use , Radiography, Thoracic , Sequence Analysis, DNA , Triazoles/therapeutic use , VoriconazoleABSTRACT
Patients with mutations in the IFNgamma/IL-12 pathway show an exquisite susceptibility to mycobacterial diseases. An IL-12Rbeta1 deficient patient with impaired intestinal absorption suffered from a 13 year culture-positive Mycobacterium bovis-BCG infection with acquired multidrug resistance. A combined parenteral and enteral anti-mycobacterial treatment, including recombinant IFNgamma, helped to clear his infection.
Subject(s)
Antitubercular Agents/therapeutic use , Mycobacterium bovis/isolation & purification , Receptors, Interleukin-12/deficiency , Tuberculosis/drug therapy , Tuberculosis/genetics , Adolescent , Antitubercular Agents/adverse effects , Genetic Predisposition to Disease , Humans , Male , Receptors, Interleukin-12/genetics , Tuberculosis/microbiologyABSTRACT
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease (8q21) from the family of the genetically determined chromosomal instability syndromes. The disorder is characterized by microcephaly, growth retardation, immunodeficiency, and high incidence of cancer. Several noninflammatory anomalies of the musculoskeletal system have been described in patients with this syndrome. We describe an Argentinian girl with all the clinical, immunological, and cytogenic characteristics described for NBS plus a juvenile rheumatoid arthritis-like syndrome. To our knowledge this is the first report of a patient with the NBS who presented with a symmetric chronic polyarthritis resembling JRA.