Manish Butte

Hypomorphic CARD11 mutations associated with diverse immunologic phenotypes with or without atopic disease.

J Allergy Clin Immunol. 2018 Aug 28;:

Authors: Dorjbal B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, Frey-Jakobs S, Weidinger S, Moebus L, Franke A, Schäffer AA, Bulashevska A, Fuchs S, Ehl S, Limaye S, Arkwright PD, Briggs TA, Langley C, Bethune C, Whyte AF, Alachkar H, Nejentsev S, DiMaggio T, Nelson CG, Stone KD, Nason M, Brittain EH, Oler AJ, Veltri DP, Leahy TR, Conlon N, Poli MC, Borzutzky A, Cohen JI, Davis J, Lambert MP, Romberg N, Sullivan KE, Paris K, Freeman AF, Lucas L, Chandrasakan S, Savic S, Hambleton S, Patel SY, Jordan MB, Theos A, Lebensburger J, Atkinson TP, Torgerson TR, Chinn IK, Milner JD, Grimbacher B, Cook MC, Snow AL

Abstract
BACKGROUND: CARD11 encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to NF-κB, JNK, and mTORC1. Germline CARD11 mutations cause several distinct primary immune disorders in humans, including SCID (biallelic null mutations), B cell Expansion with NF-κB and T cell Anergy (BENTA; heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by whole exome sequencing.
OBJECTIVES: To determine the molecular actions of an extended allelic series of CARD11, and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.
METHODS: Cell transfections and primary T cell assays were utilized to evaluate signaling and function of CARD11 variants.
RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in STAT3-LOF, DOCK8 deficiency, common variable immune deficiency (CVID), neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like syndrome. Pathogenic variants exhibited dominant negative activity, and were largely confined to the CARD or coiled-coil domains of the CARD11 protein.
CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in humans, and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

PMID: 30170123 [PubMed – as supplied by publisher]

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Practice Pattern Changes and Improvements in Hematopoietic Cell Transplantation for Primary Immunodeficiencies.

J Allergy Clin Immunol. 2018 Aug 28;:

Authors: Marsh R, Hebert KM, Keesler D, Boelens JJ, Dvorak C, Eckrich MJ, Kapoor N, Parikh S, Eapen M

Abstract
Allogeneic HCT practice patterns for PID changed between 1974-2016. Three-year survival improved to ≥70% for SCID and non-SCID patients after 1999, and further increased to 94% for SCID patients transplanted 2010-2016 following newborn screening diagnosis.

PMID: 30170121 [PubMed – as supplied by publisher]

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Flow Cytometry: Surface Markers and Beyond.

J Allergy Clin Immunol. 2018 Aug 28;:

Authors: Delmonte OM, Fleisher TA

Abstract
Flow cytometry is a routinely available laboratory method to study cells in suspension from a variety of human sources. The application of this technology as a clinical laboratory method has evolved from the identification of cell surface proteins to characterizing intracellular proteins and providing multiple different techniques to assess specific features of adaptive and innate immune function. This expanded menu of flow cytometry testing approaches has increased the utility of this platform in characterizing and diagnosing disorders of immune function.

PMID: 30170120 [PubMed – as supplied by publisher]

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NFkB mutations in humans: The devil is in the details.

J Allergy Clin Immunol. 2018 Aug 27;:

Authors: Fliegauf M, Grimbacher B

PMID: 30165054 [PubMed – as supplied by publisher]

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The broad spectrum of lung diseases in primary antibody deficiencies.

Eur Respir Rev. 2018 Sep 30;27(149):

Authors: Cinetto F, Scarpa R, Rattazzi M, Agostini C

Abstract
Human primary immunodeficiency diseases (PIDs) represent a heterogeneous group of more than 350 disorders. They are rare diseases, but their global incidence is more relevant than generally thought. The underlying defect may involve different branches of the innate and/or adaptive immune response. Thus, the clinical picture may range from severe phenotypes characterised by a broad spectrum of infections to milder infectious phenotypes due to more selective (and frequent) immune defects. Moreover, infections may not be the main clinical features in some PIDs that might present with autoimmunity, auto-inflammation and/or cancer. Primary antibody deficiencies (PADs) represent a small percentage of the known PIDs but they are the most frequently diagnosed, particularly in adulthood. Common variable immunodeficiency (CVID) is the most prevalent symptomatic PAD.PAD patients share a significant susceptibility to respiratory diseases that represent a relevant cause of morbidity and mortality. Pulmonary complications include acute and chronic infection-related diseases, such as pneumonia and bronchiectasis. They also include immune-mediated interstitial lung diseases, such as granulomatous-lymphocytic interstitial lung disease (GLILD) and cancer. Herein we will discuss the main pulmonary manifestations of PADs, the associated functional and imaging findings, and the relevant role of pulmonologists and chest radiologists in diagnosis and surveillance.

PMID: 30158276 [PubMed – in process]

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Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report.

BMC Pediatr. 2018 Aug 29;18(1):285

Authors: Lundin KE, Wang Q, Hamasy A, Marits P, Uzunel M, Wirta V, Wikström AC, Fasth A, Ekwall O, Smith CIE

Abstract
BACKGROUND: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 + 3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations.
CASE PRESENTATION: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naïve CD4+ and CD8+ T-cells, increased number of activated effector memory CD8+ T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient’s cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age.
CONCLUSIONS: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.

PMID: 30157810 [PubMed – in process]

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SCID genotype and 6-month post-transplant CD4 count predict survival and immune recovery: a PIDTC retrospective study.

Blood. 2018 Aug 28;:

Authors: Haddad E, Logan BR, Griffith LM, Buckley RH, Parrot RE, Prockop SE, Small TN, Chaisson J, Dvorak CC, Murnane M, Kapoor N, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJH, Chandra S, Smith AR, Cavanaugh ME, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-Smith S, Haight AE, Tumlin AG, Quigg TC, Taylor C, Dávila Saldaña BJ, Keller MD, Seroogy CM, Desantes KB, Petrovic A, Leiding JW, Shyr DC, Decaluwe H, Teira P, Gillio AP, Knutsen A, Moore TB, Kletzel M, Craddock JA, Aquino V, Davis JH, Yu LC, Cuvelier GDE, Bednarski JJ, Goldman FD, Kang EM, Shereck E, Porteus MH, Connelly JA, Fleisher TA, Malech HL, Shearer WT, Szabolcs P, Thakar MS, Vander Lugt MT, Heimall J, Yin Z, Pulsipher MA, Pai SY, Kohn DB, Puck JM, Cowan MJ, O’Reilly RJ, Notarangelo LD

Abstract
The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 662 patients with Severe Combined Immunodeficiency (SCID) who received an Hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched sibling donors (MSD). Among recipients of non-MSD HCT, multivariate analysis showed that SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG or JAK3 defects, and was significantly better compared to patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced intensity or myeloablative conditioning had a lower incidence of treatment failure and better T and B cell reconstitution, but higher risk of graft versus host disease compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were each associated with improved survival. Typical SCID, leaky SCID and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

PMID: 30154114 [PubMed – as supplied by publisher]

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Gastrointestinal Manifestations in Children with Primary Immunodeficiencies: Single Center: 12 Years Experience.

Dig Dis. 2018 Aug 28;:1-8

Authors: Akkelle BS, Tutar E, Volkan B, Sengul OK, Ozen A, Celikel CA, Ertem D

Abstract
BACKGROUND: It has been reported that 5-50% of patients with primary immune deficiencies (PID) may present with or develop gastrointestinal (GI) manifestations.
OBJECTIVE: This study was aimed at analyzing GI and related endoscopic, histopathological findings in children with PID.
METHODS: Children with PID who were evaluated by endoscopy between 2005 and 2016 were enrolled in this study. Demographic data, growth parameters, signs and symptoms at diagnosis were obtained.
RESULTS: Of 425 children with PID, 195 had GI manifestations. Forty-seven of 195 children required endoscopic investigation, 30 (63.8%) were male, and the mean age was 7.7 ± 5 years. The rate of consanguinity was 61.7%, and the most common symptom was chronic diarrhea (57.4%). Seventy-two percent of the patients were malnourished. Giardia intestinalis was detected in 4, and Helicobacter pylori was confirmed in 8/45 (17.7%) patients. Non-celiac villous flatting was discovered in 15.5% of patients. Twelve patients were diagnosed as having immunodeficiency associated inflammatory bowel disease (IBD)-like colitis.
CONCLUSIONS: PID may present with GI manifestations or develop during the course of the disease. Investigating immunodeficiency in patients with atypical GI symptoms can provide an appropriate therapeutic option, and an improved quality of life, particularly in populations with a high rate of consanguinity.

PMID: 30153682 [PubMed – as supplied by publisher]

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Targeted next-generation sequencing for genetic diagnosis of 160 patients with primary immunodeficiency in South China.

Pediatr Allergy Immunol. 2018 Aug 28;:

Authors: Xia Y, He T, Luo Y, Li C, Lim CK, Abolhassani H, Yang J, Hammarström L

Abstract
BACKGROUND: Primary immunodeficiency disorders (PID) is a group of heterogeneous diseases mainly characterized by severe and recurrent infections and an increased susceptibility to lymphoproliferative, atopic and autoimmune conditions. The clinical diagnosis should preferably be complemented by a genetic diagnosis. To date, PID-related reports from China seldom attempt to make a genetic test for their patients.
METHODS: Our study aims to evaluate demographic data, clinical manifestations and molecular diagnosis of PID patients from southern China. Moreover, by comparison with previous reports, we provide a picture of the current status of PID in mainland China. A total number of 160 pediatric PID patients (106 males and 54 females) were enrolled and targeted next-generation sequencing was conducted using 269 PID related genes and subsequently confirmed by Sanger sequencing and familial segregation analysis.
RESULT: The autoinflammatory disease group was the most common subcategory of PID (20%), followed by immune dysregulation (17.5%) and combined immunodeficiencies (16.2%). Antibody deficiency disorders were identified in only 11.9% of the cohort. The putative causative gene was identified in 70 patients (43.8%) and an X-linked pattern was found in 45.7% of the genetically diagnosed patients.
CONCLUSION: The current study provides the first collective study of PID phenotypes and genotypes in south China, and provides a strong argument for the diagnostic application of targeted next generation sequencing panels in patients with suspected PID. This article is protected by copyright. All rights reserved.

PMID: 30152884 [PubMed – as supplied by publisher]

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Allogeneic Hematopoietic Cell Transplantation in Patients with Primary Immunodeficiencies in Korea: Eleven-Year Experience in a Single Center.

J Clin Immunol. 2018 Aug 27;:

Authors: Yi ES, Choi YB, Lee NH, Lee JW, Sung KW, Koo HH, Kang ES, Kim YJ, Yoo KH

Abstract
PURPOSE: We aimed to report our single-center experience of allogeneic hematopoietic cell transplantation (HCT), which has been the only curative option for certain patients with lethal primary immunodeficiencies (PIDs).
METHODS: We summarized the results of HCT performed for patients with PIDs for 11 consecutive years from 2006 to 2016 at Samsung Medical Center, Seoul, Korea. Twenty-six patients with PIDs received HCT. Most had chronic granulomatous disease (42.3%), Wiskott Aldrich syndrome (15.4%), or severe combined immunodeficiency (11.5%).
RESULTS: Nine patients (34.6%) received HCT during the former half period and 17 patients (65.4%) during the latter half period. Donor types were categorized as: matched sibling donor (n = 5), unrelated donor (n = 17), and familial mismatched donor (FMMD) (n = 4). Unrelated HCT and FMMD transplantation were increasingly performed in the latter half period compared to the first (5 vs. 16, P = 0.034). Five patients experienced initial engraftment failure, but all of them were eventually engrafted after additional HCTs. The 3-year probability of overall survival was 72.0%. Seven patients (26.9%) died, and the causes of death were bacterial sepsis (n = 4), pneumonia (n = 1), chronic graft-versus-host disease (GVHD) (n = 1), and diffuse alveolar hemorrhage (n = 1). Two patients with bacterial sepsis and a patient with pneumonia also had chronic GVHD. Unrelated HCT and use of methotrexate were associated with poor outcome. Complete chimerism was attained in 85.0% at 1 year after HCT.
CONCLUSION: PID candidates have been increasingly identified for allogeneic HCT in Korea, and the majority of them could be cured by HCT. Establishment of a systematic registry of PID patients for HCT is needed.

PMID: 30151618 [PubMed – as supplied by publisher]

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