Manish Butte

Disseminated cryptococcosis in two boys with novel mutation of CD40 Ligand-Associated X-linked hyper-IgM syndrome.

Asian Pac J Allergy Immunol. 2018 Oct 15;:

Authors: Pacharn P, Phongsamart W, Boonyawat B, Jirapongsananuruk O, Visitsunthorn N, Chokephaibulkit K

Abstract
X-linked hyper-IgM syndrome (XHIM) caused by CD40L mutations is a primary immunodeficiency condition that increases susceptibility to opportunistic infections. Disseminated cryptococcosis in XHIM is rarely reported in children. Here, we report two related boys who have a novel hemizygous frameshift c.208delC mutation of CD40L. They live in the western region of Thailand and developed disseminated cryptococcosis while receiving regular intravenous immunoglobulin supplementation.

PMID: 30447657 [PubMed – as supplied by publisher]

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Gastrointestinal Presentations of Common Variable Immunodeficiency: Hiding in Plain Sight.

Arch Pathol Lab Med. 2018 Nov 16;:

Authors: Odetola O, Ananthanarayanan V

Abstract
Primary immunodeficiency disorders typically have an onset in childhood. The suspicion for these conditions usually arises from a history of recurrent respiratory, gastrointestinal, or cutaneous infections with a history often dating back to infancy or early childhood. However, adults can also be affected. Common variable immunodeficiency, which usually has an onset/diagnosis in adulthood, is the most common symptomatic primary immunodeficiency. However, as its presentation could be manifold, its diagnosis is often delayed. The gastrointestinal tract is the second most affected system after the respiratory tract; symptoms associated with the gastrointestinal tract are often intractable. As patients with common variable immunodeficiency are often misdiagnosed, a high index of suspicion and clinical correlation is required for the appropriate diagnosis of this potentially debilitating condition.

PMID: 30444437 [PubMed – as supplied by publisher]

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Genes at the Crossroad of Primary Immunodeficiencies and Cancer.

Front Immunol. 2018;9:2544

Authors: Derpoorter C, Bordon V, Laureys G, Haerynck F, Lammens T

Abstract
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients.

PMID: 30443258 [PubMed – in process]

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Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

Front Immunol. 2018;9:2411

Authors: Gambineri E, Ciullini Mannurita S, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, Segundo GRS, Allenspach EJ, Favre C, Ochs HD, Torgerson TR

Abstract
Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of “Primary Immune Deficiency (PID-related) genes.” Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.

PMID: 30443250 [PubMed – in process]

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An Adult Fatal Case with a STAT1 Gain-of-function Mutation Associated with Multiple Autoimmune Diseases.

J Rheumatol. 2018 Nov 15;:

Authors: Maeshima K, Ishii K, Shibata H

Abstract
Primary immunodeficiency diseases (PID) are a heterogeneous group of diseases with variable genetic etiologies. Although immunodeficiency is a hallmark of susceptibility to infection, autoimmunity is clearly a prevalent feature.

PMID: 30442829 [PubMed – as supplied by publisher]

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The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management.

Clin Immunol. 2018 Nov 12;:

Authors: Yazdani R, Fekrvand S, Shahkarami S, Azizi G, Moazzami B, Abolhassani H, Aghamohammadi A

Abstract
Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed.

PMID: 30439505 [PubMed – as supplied by publisher]

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Primary Immunodeficiency: The Israeli Connection.

Isr Med Assoc J. 2018 Nov;20(11):703-706

Authors: Etzioni A

Abstract

PMID: 30430801 [PubMed – in process]

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Measles antibody trough levels after treatment with immunoglobulin products and predicted levels assuming lower measles antibody specifications.

Transfusion. 2018 Nov 15;:

Authors: Vandeberg P, Cruz MC, Griffin R

Abstract
BACKGROUND: Widespread vaccination against measles has resulted in decreasing measles antibody levels in human immune globulin (IG) products. As levels continue to decline, it needs to be determined whether the release specifications for measles antibody levels in IG products can be lowered and still provide protection against infection for patients who receive IG treatment for primary immunodeficiency disease.
STUDY DESIGN AND METHODS: Trough level measles neutralizing antibodies were measured in 10 pediatric patients with primary immunodeficiency disease (ages 2-16) treated with IG administered both by intravenous and subcutaneous infusion. The results were used to model worst-case (lowest) serum measles antibody levels in two cases: 1) the current case with intravenous dosage at 300 mg/kg at a measles antibody level of 0.48× Center for Biologics Evaluation and Research Reference 176 and 2) a future case with intravenous dosage at 400 mg/kg and 0.30× Center for Biologics Evaluation and Research Reference 176.
RESULTS: Serum trough measles neutralizing antibody levels were an average of 11-fold or greater above minimum protective levels for immunocompetent individuals of 0.12 IU/mL in both the intravenous and subcutaneous phases of the study. Modeling using both the current worst-case dose and future case shows average levels for IG intravenous/subcutaneous infusion of 3.9/4.8- and 3.2/4.0-fold above 0.12 IU/mL for the two cases, respectively.
CONCLUSION: Lowering the measles antibody level specification to 0.30× Center for Biologics Evaluation and Research Reference 176 in IG products will still provide trough serum antibody levels against measles infection of greater than 0.12 IU/mL when dosed at 400 mg/kg or higher.

PMID: 30430616 [PubMed – as supplied by publisher]

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A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation.

Front Immunol. 2018;9:2366

Authors: De Bruyne M, Hoste L, Bogaert DJ, Van den Bossche L, Tavernier SJ, Parthoens E, Migaud M, Konopnicki D, Yombi JC, Lambrecht BN, van Daele S, Alves de Medeiros AK, Brochez L, Beyaert R, De Baere E, Puel A, Casanova JL, Goffard JC, Savvides SN, Haerynck F, Staal J, Dullaers M

Abstract
Background: Inherited CARD9 deficiency constitutes a primary immunodeficiency predisposing uniquely to chronic and invasive fungal infections. Certain mutations are shown to negatively impact CARD9 protein expression and/or NF-κB activation, but the underlying biochemical mechanism remains to be fully understood. Objectives: To investigate a possible founder origin of a known CARD9 R70W mutation in five families of Turkish origin. To explore the biochemical mechanism of immunodeficiency by R70W CARD9. Methods: We performed haplotype analysis using microsatellite markers and SNPs. We designed a model system exploiting a gain-of-function (GOF) CARD9 L213LI mutant that triggers constitutive NF-κB activation, analogous to an oncogenic CARD11 mutant, to study NF-κB signaling and signalosome formation. We performed reporter assays, immunoprecipitation and confocal imaging on HEK cells overexpressing different CARD9 variants. Results: We identified a common haplotype, thus providing evidence for a common Turkish founder. CARD9 R70W failed to activate NF-κB and abrogated NF-κB activation by WT CARD9 and by GOF CARD9. Notably, R70W CARD9 also exerted negative effects on NF-κB activation by CARD10, CARD11, and CARD14. Consistent with the NF-κB results, the R70W mutation prevented GOF CARD9 to pull down the signalosome partner proteins BCL10 and MALT1. This reflected into drastic reduction of BCL10 filamentous assemblies in a cellular context. Indeed, structural analysis revealed that position R70 in CARD9 maps at the putative interface between successive CARD domains in CARD9 filaments. Conclusions: The R70W mutation in CARD9 prevents NF-κB activation by inhibiting productive interactions with downstream BCL10 and MALT1, necessary for assembly of the filamentous CARD9-BCL10-MALT1 signalosome.

PMID: 30429846 [PubMed – in process]

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Pre-filled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience from other disease settings.

Expert Opin Drug Deliv. 2018 Nov 13;:

Authors: Kafal AR, Vinh DC, Langelier MJ

Abstract
INTRODUCTION: Ready-to-use pre-filled syringes for drug delivery are increasingly used across a broad spectrum of clinical specialties. For patients with primary immunodeficiencies manifesting as antibody deficiencies, immunoglobulin G (IgG) replacement therapy (IgRT) by subcutaneous administration is an established treatment modality. Expanding IgRT administration options through the introduction of pre-filled syringes may further improve its utility. Areas covered: Here, we collate experience with pre-filled syringes from other clinical settings to inform on their practicality and suitability for IgRT. In addition to discussing drug characteristics such as stability, pharmacokinetics, and efficacy, we focus on treatment delivery, physician/patient experience, costs, and the importance of education for the use of pre-filled syringes. Expert opinion: Perceived benefits of pre-filled syringes include accurate dosing, sterility, and reduced treatment time, while offering patients greater choice, convenience, and ease-of-use. Our review of clinical experience with pre-filled syringes supports this consensus. Relatively few studies directly compare pre-filled syringes with conventional administration, and robust studies of cost-effectiveness and health-related quality of life are needed on a drug-by-drug basis. Growth in the availability of pre-filled syringes will continue, encouraged by the importance of patient choice and treatment convenience, toward the goal of individualized treatment regimens and improved quality of life.

PMID: 30422015 [PubMed – as supplied by publisher]

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