The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform
Andrew W Lindsley - One of the best experts on this subject based on the ideXlab platform.
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defects of b cell terminal differentiation in patients with type 1 kabuki syndrome
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Andrew W Lindsley, Howard M Saal, Thomas A Burrow, Robert J Hopkin, Oleg A Shchelochkov, Pooja KhandelwalAbstract:Background Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by Humoral Immune Deficiency and autoImmune disease, yet no detailed molecular characterization of the KS-associated Immune phenotype has been reported. Objective We sought to characterize the Humoral Immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. Methods We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). Results Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D Mut/+ ) , hypogammaglobulinemia was detected in all but 1 patient, with IgA Deficiency affecting 90% of patients and a Deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27 + ) and class-switched memory B cells (IgM − ) were significantly reduced in patients with KMT2D Mut/+ mutations compared with numbers in control subjects ( P KMT2D Mut/+ mutations also had significantly reduced rates of somatic hypermutation in IgG ( P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D Mut/+ mutations. AutoImmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. Conclusions In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to Humoral Immune Deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical Immune evaluations.
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combined Immune Deficiency in a patient with a novel nfkb2 mutation
Journal of Clinical Immunology, 2014Co-Authors: Andrew W Lindsley, Yaping Qian, Alexander C Valencia, Kara N Shah, Kejian Zhang, Amal AssaadAbstract:NFKB2 encodes the p100/p52 protein, a critical mediator of the canonical and noncanonical NFkB signaling pathways. Here we report the comprehensive Immune evaluation of a child with a novel NFKB2 mutation and provide evidence that aberrant NFKB2 signaling not only causes Humoral Immune Deficiency, but also interferes with the TCR-mediated proliferation of T cells. These observations expand the known phenotype associated with NFKB2 mutations.
Michel Moutschen - One of the best experts on this subject based on the ideXlab platform.
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deleterious mutations in lrba are associated with a syndrome of Immune Deficiency and autoimmunity
American Journal of Human Genetics, 2012Co-Authors: G Lopezherrera, Giacomo Tampella, Qiang Panhammarstrom, Peer Herholz, Claudia M Trujillovargas, Kanchan Phadwal, Anna Katharina Simon, Michel MoutschenAbstract:Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset Humoral Immune Deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an Immune Deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
Anna Katharina Simon - One of the best experts on this subject based on the ideXlab platform.
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deleterious mutations in lrba are associated with a syndrome of Immune Deficiency and autoimmunity
American Journal of Human Genetics, 2012Co-Authors: G Lopezherrera, Giacomo Tampella, Qiang Panhammarstrom, Peer Herholz, Claudia M Trujillovargas, Kanchan Phadwal, Anna Katharina Simon, Michel MoutschenAbstract:Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset Humoral Immune Deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an Immune Deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
Claudia M Trujillovargas - One of the best experts on this subject based on the ideXlab platform.
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deleterious mutations in lrba are associated with a syndrome of Immune Deficiency and autoimmunity
American Journal of Human Genetics, 2012Co-Authors: G Lopezherrera, Giacomo Tampella, Qiang Panhammarstrom, Peer Herholz, Claudia M Trujillovargas, Kanchan Phadwal, Anna Katharina Simon, Michel MoutschenAbstract:Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset Humoral Immune Deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an Immune Deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
P J Tutschka - One of the best experts on this subject based on the ideXlab platform.
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late bacterial infections in Humoral Immune Deficiency
Recent results in cancer research, 1993Co-Authors: P J TutschkaAbstract:Between 2 and 3 months after allogeneic marrow transplantation, once past the hurdles of acute GVHD, opportunistic viral infections, and fungal and bacterial superinfections, the cellular Immune system is slowly progressing toward full immunocompetence, a process that will not be completed until close to 2 years after transplantation when finally delayed-type hypersensitivity response is normalized. Equally, T helper function for B cell production of immunoglobulins starts to return, normal immunoglobulin levels being reached not before 4 months after transplantation (Atkinson 1990b; Lum 1987). This state of relative calm can be interrupted by an important complication of allogeneic bone marrow transplantation, chronic graft-versus-host disease which, as more and more patients survive the early post-transplant complications, is becoming an ever-increasing problem (Atkinson 1990a). This syndrome, a chronic, severe and often relentlessly progressing complication, now affects more than half of the transplanted patients and is associated with a number of distinct immunobiological features. Clinically chronic GVHD resembles autoImmune diseases and most often includes a Sjogren’s syndrome with xerophthalmia and xerostomia, poikiloderma and cutaneous sclerosis, and hepatic dysfunction with features of cholestasis.