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Valentin I Popa - One of the best experts on this subject based on the ideXlab platform.
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immediate hypersensitivity in adults with IgG Deficiency and recurrent respiratory infections
Annals of Allergy Asthma & Immunology, 1999Co-Authors: Valentin I Popa, Stephen M NagyAbstract:Background Little is known about the prevalence of atopy in adults with recurrent respiratory infections and IgG Deficiency. Objective and methods To elucidate this aspect, we skin-tested 95 consecutive adults with respiratory infections, subnormal levels of IgG subclasses or common variable immunoDeficiency and usually poor response to vaccination. In 50 subjects we also measured total IgE. Results We found 67 subjects with IgG subclass Deficiency, 21 subjects with mild (partial) and 5 with usual common variable immunoDeficiency, and 2 subjects with functional IgG Deficiency. Atopy was encountered in 42/95 subjects, 33/44 (75%) with asthma, 7/19 (38%) with isolated rhinosinusitis, 1/27 (4%) with chronic obstructive lung disease, and 1/5 (20%) with both the latter disease and asthma, respectively. Atopy was preferentially clustered in subjects with asthma ( P P Conclusions In adults with symptomatic IgG Deficiency, the prevalence of immediate hypersensitivity and its modulation by age and smoking are similar to the referred, non-IgG deficient population; however, total IgE may be lower in the former than in the latter. In common variable immunoDeficiency, consistent with the literature data, both the prevalence of atopy and serum total IgE are decreased.
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airway obstruction in adults with recurrent respiratory infections and IgG Deficiency
Chest, 1994Co-Authors: Valentin I PopaAbstract:In 42 adults with recurrent respiratory infections (RRI) and common variable immunoDeficiency or immunoglobulin G (IgG) subclass Deficiency, the results of pulmonary function tests were related to factors apt to produce airway obstruction: serum concentration of IgG and IgG subclasses, various features of acute RRI (number/year, time from onset to diagnosis, episodes of pneumonia, etc) and type of chronic lung disease (smoking and nonsmoking related chronic bronchitis, episodic wheezing, and bronchiectasis). Compared with nonsmokers, usually less than 40 years of age, the patients above 40 had smoking-related chronic bronchitis and had obstruction (%FEV1/forced vital capacity [FVC] 55.3 ± 8.1 vs 80.1 ± 4.5), hyperinflation (residual volume 182.7 ± 22.7 percent vs 109.7 ± 8.8 percent of pred) hypoxemia (66.6 ± 5.8 vs 83.4 ± 4.2 mm Hg) and impaired carbon monoxide transfer (65.5 ± 9.1 percent vs 93.3 ± 5.8 percent). The features of acute or chronic RRI, the time from onset to diagnosis (
Anita Chandra - One of the best experts on this subject based on the ideXlab platform.
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clinical spectrum and features of activated phosphoinositide 3 kinase δ syndrome a large patient cohort study
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Tanya Coulter, Anita Chandra, Chris M Bacon, Judith Babar, James Curtis, Nicholas Screaton, John R Goodlad, George Farmer, Cathal Steele, Timothy Ronan LeahyAbstract:Background Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunoDeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). Objective We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG Deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion APDS is a combined immunoDeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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common variable immunoDeficiency and natural killer cell lymphopenia caused by ets binding site mutation in the il 2 receptor γ il2rg gene promoter
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Anita Chandra, Fang Zhang, Kimberly Gilmour, David Webster, Vincent Plagnol, Dinakantha S Kumararatne, Siobhan O BurnsAbstract:To the Editor: Patients with severe combined immunoDeficiency (SCID) of a classical phenotype present within the first year of life with life-threatening infections and failure to thrive.1 The X-linked T−B+ natural killer (NK)− form of SCID is the most frequent type (44% to 46%) and is a consequence of mutations in the IL-2 receptor γ (IL2RG) gene (OMIM 308380), which encodes the common cytokine receptor γ chain (γc).2 The γc acts as a signal-transducing subunit of cytokine receptors that are essential in the ontogeny and function of T, B, and NK cells, namely IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The intracellular part of γc interacts with Janus kinase 3 and mediates phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins, which regulate induction of gene transcription. A number of patients with a milder form of combined immunoDeficiency, often termed “leaky” or “hypomorphic” SCID, have been described. Here we describe 2 male relatives with a novel hypomorphic mutation in the IL2RG promoter who presented with a phenotype more akin to common variable immunoDeficiency (CVID). CVID is the most common clinically and genetically heterogeneous primary immunoDeficiency, which is characterized by low IgG, IgA, and/or IgM levels, with a failure to produce specific antibodies.3 Mutations in genes encoding transmembrane activator and CAML interactor (TACI), inducible costimulator (ICOS), CD19, CD20, CD21, CD81, LRBA, CXCR4, NF-κB2, B cell–activating factor of the TNF family (BAFF) receptor, TNF-related weak inducer of apoptosis (TWEAK), phosphoinositide 3-kinase catalytic subunit δ polypeptide (PI3KCD), and PI3KR1 were shown to cause CVID-like phenotypes.3 The grandson presented at age 4 years with a history of recurrent bacterial otitis media and chronic suppurative rhinitis, rotavirus-induced gastroenteritis (age 18 months), echoviral gastroenteritis (age 2 years), and varicella zoster (age 4 years). He had IgG Deficiency (1.8 g/L) with normal IgA and IgM levels (1.0 and 0.5 g/L, respectively) and did not mount an adequate response to the 23-valent pneumococcal polysaccharide vaccine (Pneumovax; Merck & Co, Whitehouse Station, NJ), although he responded appropriately to immunization with protein antigens (see Table E1 in this article's Online Repository at www.jacionline.org). He had normal numbers of T and B cells but completely absent NK cells. T-cell proliferation after stimulation with PHA, anti-CD3, and Candida species was suboptimal but not completely abrogated. He was started on immunoglobulin replacement therapy and is well, with his infections limited to recalcitrant cutaneous warts. At the time of his diagnosis, it was noted that his maternal grandfather was under treatment for CVID. The grandfather presented to an immunology team at the age of 34 years with a 20-year history of recurrent otosinopulmonary tract infections with Streptococcus pneumoniae and Haemophilus influenzae, bronchiectasis, and type 1 diabetes mellitus and celiac disease. On initial presentation, he had an IgG2 and IgG4 subclass Deficiency, absent antibody response to polysaccharide vaccine, CD4 and NK lymphopenia, and reduced proliferative responses to PHA. Immunoglobulin substitution was implemented, along with antibiotic prophylaxis, and he was managed successfully on this regimen for 25 years until he died at age 62 years after a cardiac event. Flow cytometric analysis of lymphocytes revealed a significantly diminished γc expression in both the grandson and grandfather (Fig 1, A; see the Methods section in this article's Online Repository at www.jacionline.org). Likewise, IL2RG mRNA expression in sorted T and B cells from the grandson showed a 4.2-fold reduction in T cells and a 33-fold reduction in B cells compared with healthy control subjects (Fig 1, B). The T cells were then stimulated with IL-2, IL-7, and IL-15, and phosphorylated STAT5 levels were determined by means of flow cytometric analysis (Fig 1, C). This was diminished in the patient with a fold reduction compared with healthy control samples of 3.5-, 7.5-, and 3.8-fold for IL-2, IL-7, and IL-15, respectively. Fig 1 Reduced IL2RG expression and function. A and B, Common γc expression on lymphocytes (Fig 1, A) in a control subject (CON), the grandson (GS), and the grandfather (GF), as well as IL2RG mRNA expression (Fig 1, B). C, Phosphorylated STAT5 (pSTAT5) ... X-inactivation studies performed on samples from the mother of the grandson demonstrated random X-inactivation in whole blood but apparent nonrandom X-inactivation in T cells (see Table E2 in this article's Online Repository at www.jacionline.org). Whole-exome sequencing of the grandson revealed a point mutation, C to T at position g.chrX:71,111,618 (GRCh38), which was located −13 nucleotides upstream of the transcription start site in the IL2RG gene (ENST00000374202; Fig 1, D). This is situated at an identified binding site for the transcription factor ETS, which is required for basal promoter activity in cell lines.4 For functional validation, we generated the same mutation in an IL2RG minigene (Mut.gcPRO and WT.gcPRO), and using a lentiviral vector, introduced this into γc-deficient ED7R cells. We found that γc expression from Mut.gcPRO was dramatically abrogated when compared with the wild-type sequence in a dose-dependent manner. When transduced at similar efficiency (similar vector copy numbers), there is an 8-fold difference in γc expression between the WT-gcPRO and Mut-gcPRO transduced cells (Fig 1, E). To confirm that the mutation abrogated binding of ETS, using the electrophoretic mobility shift assay, we showed that mutant oligonucleotides were unable to form a normal protein/DNA complex (Fig 2). Fig 2 Electrophoretic mobility shift assay. Biotin-labeled wild-type or mutant oligonucleotides incubated without nuclear extracts (lanes 1 and 4), with nuclear extracts (lanes 2, 3, 5, and 6), and in the absence (lanes 2 and 5) or presence (lanes 3 and 6) ... More than 100 mutations in IL2RG have been described extending across all of its 8 exons, intron/exon boundaries, and 3′ regulatory regions.4 Although most of the known mutations result in a classical immunophenotype of T−B+NK− SCID, variants leading to a T−B+NK+ SCID and TlowB+NK+ have been described.5, 6 Attenuated SCID phenotypes have also been observed as a result of splice-site mutations resulting in diminished expression of truncated γc protein or as a result of somatic reversion.5, 6, 7 Here we identified a novel point mutation at nucleotide −13 upstream of the transcription start site in a putative ETS-binding site.3 ETS transcription factors comprise a large evolutionarily conserved family characterized by sequence homology within their DNA-binding domain that bind to sequences containing a consensus GGAA/T motif.8 The ETS transcription factors have been linked with diverse biological processes, including hematopoiesis, T-cell survival, and NK cell production.9 Previous studies have shown that an ETS-binding site in a 1053-bp fragment 5′ to the IL2RG transcription initiation site is essential for tissue-specific basal promoter activity of IL2RG.3 Our data indicate that a point mutation within the ETS-binding site of the proximal IL2RG promoter has a significant detrimental effect on its activity in human subjects. The residual expression of γc appears to differentially affect signaling through the cytokine receptors leading to normal T-cell development, with minimal reduction in T-cell function and absent NK cell development. In this family this resulted in an initial presentation akin to CVID, manifesting with recurrent bacterial and viral infections. This scenario should be considered in male patients with antibody Deficiency, particularly if accompanied by NK lymphopenia. These patients should also be monitored closely for more serious manifestations because this defect is amenable to correction by means of hematopoietic stem cell transplantation or gene therapy. Furthermore, our finding highlights the potential role of mutations in gene regulatory regions as a cause of significant primary immunodeficiencies.
J Leroy - One of the best experts on this subject based on the ideXlab platform.
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IgG subclass Deficiency in children with recurrent bronchitis
European Journal of Pediatrics, 1992Co-Authors: F De Baets, J Kint, Romain Pauwels, J LeroyAbstract:We studied the incidence of IgG subclass Deficiency in children with recurrent bronchitis. Recurrent bronchitis was defined as three or more episodes a year during at least 2 consecutive years, of bronchopulmonary infection, productive cough with or without fever and/or diffuse râles by physical examination in the absence of asthma or atopy. Fifty three children were selected, of whom 30 (57%) were deficient in one of the IgG subclasses. None had an IgG1 Deficiency. Nine (17%) were deficient in IgG2, 9 (17%) in IgG3 and 20 (38%) in IgG4. Isolated IgG subclass deficiencies were most frequently seen for IgG4 (14, 26%), less for IgG3 (6, 12%) and even less for IgG2 (4, 7%). Nine (17%) children were IgA deficient and 8 (15%) IgG deficient with a combined IgG subclass Deficiency in 8 and 7 of them respectively. By subdivision into different age groups most patients were encountered in the youngest group. The mean content of IgG2, IgG3 and IgG4 in 3- to 4-year-old children with recurrent bronchitis was significantly lower than in the age matched controls. The mean value for IgG4 in the 5- to 6-year-olds was significantly lower than in the control group. This study demonstrates the correlation between recurrent bronchitis in childhood and IgG subclass Deficiency. IgG subclass Deficiency and recurrent bronchitis are both quite prominent phenomena in young children but rare in older children, suggesting a transient immaturity of the immune system as one of the possible pathogenetic factors. An IgA or an IgG Deficiency is highly suggestive for the existence of a combined IgG subclass Deficiency.
Timothy Ronan Leahy - One of the best experts on this subject based on the ideXlab platform.
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clinical spectrum and features of activated phosphoinositide 3 kinase δ syndrome a large patient cohort study
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Tanya Coulter, Anita Chandra, Chris M Bacon, Judith Babar, James Curtis, Nicholas Screaton, John R Goodlad, George Farmer, Cathal Steele, Timothy Ronan LeahyAbstract:Background Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunoDeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). Objective We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. Methods We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Results Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG Deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. Conclusion APDS is a combined immunoDeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
Stephen M Nagy - One of the best experts on this subject based on the ideXlab platform.
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immediate hypersensitivity in adults with IgG Deficiency and recurrent respiratory infections
Annals of Allergy Asthma & Immunology, 1999Co-Authors: Valentin I Popa, Stephen M NagyAbstract:Background Little is known about the prevalence of atopy in adults with recurrent respiratory infections and IgG Deficiency. Objective and methods To elucidate this aspect, we skin-tested 95 consecutive adults with respiratory infections, subnormal levels of IgG subclasses or common variable immunoDeficiency and usually poor response to vaccination. In 50 subjects we also measured total IgE. Results We found 67 subjects with IgG subclass Deficiency, 21 subjects with mild (partial) and 5 with usual common variable immunoDeficiency, and 2 subjects with functional IgG Deficiency. Atopy was encountered in 42/95 subjects, 33/44 (75%) with asthma, 7/19 (38%) with isolated rhinosinusitis, 1/27 (4%) with chronic obstructive lung disease, and 1/5 (20%) with both the latter disease and asthma, respectively. Atopy was preferentially clustered in subjects with asthma ( P P Conclusions In adults with symptomatic IgG Deficiency, the prevalence of immediate hypersensitivity and its modulation by age and smoking are similar to the referred, non-IgG deficient population; however, total IgE may be lower in the former than in the latter. In common variable immunoDeficiency, consistent with the literature data, both the prevalence of atopy and serum total IgE are decreased.
