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Manish Butte

EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders.

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EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders.

JIMD Rep. 2017 Nov 21;:

Authors: Balasubramaniam S, Riley LG, Vasudevan A, Cowley MJ, Gayevskiy V, Sue CM, Edwards C, Edkins E, Junckerstorff R, Kiraly-Borri C, Rowe P, Christodoulou J

Abstract
Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described.Autosomal recessive mutations in EPG5 encoding ectopic P-granules autophagy protein 5 (EPG5), a key autophagy regulator implicated in the formation of autolysosomes, were identified as the genetic cause of Vici syndrome. The eight key features outlined above are highly predictive of EPG5 involvement, with pathogenic EPG5 mutations identified in >90% of cases where six or more of these features are present. The manifestation of all eight features has a specificity of 97% and sensitivity of 89% for EPG5-related Vici syndrome. Nevertheless, substantial clinical overlap exists with other multisystem disorders, in particular congenital disorders of glycosylation and mitochondrial disorders. Clinical and pathological findings suggest Vici syndrome as a paradigm of congenital disorders of autophagy, a novel group of inherited neurometabolic conditions linking neurodevelopment and neurodegeneration due to primary autophagy defects.Here we describe the diagnostic odyssey in a 4-year-old boy whose clinical presentation with multisystem manifestations including skeletal myopathy mimicked a mitochondrial disorder. A genetic diagnosis of Vici syndrome was made through whole genome sequencing which identified compound heterozygous variants in EPG5. We also review the myopathic presentation and morphological characterisation of previously reported cases.

PMID: 29159459 [PubMed – as supplied by publisher]

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Liver transplantation in adults with liver disease due to common variable immunodeficiency leads to early recurrent disease and poor outcome.

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Liver transplantation in adults with liver disease due to common variable immunodeficiency leads to early recurrent disease and poor outcome.

Liver Transpl. 2017 Nov 20;:

Authors: Azzu V, Elias JE, Duckworth A, Davies S, Brais R, Kumararatne DS, Gimson AES, Griffiths WJH

Abstract
Common variable immunodeficiency (CVID) is the commonest from of primary immunodeficiency characterized by antibody deficiency, recurrent bacterial infections and autoimmunity. Advanced chronic liver disease occurs in a subset of patients with CVID and manifests with various histological features such as nodular regenerative hyperplasia, inflammation, fibrosis and cholangiopathy. We present a case series characterizing the outcomes in adult patients transplanted for primary CVID-related liver disease. We discuss the unique transplantation challenges faced in this primary immunodeficiency group including susceptibility to infections and early disease recurrence. There is a statistically significant decrease in 3-year and 5-year survival post-liver transplantation in those with CVID related liver disease (55% at 3 and 5 years) compared to all-comers (89% at 3 years, 81% at 5 years), prompting a need for discussion of suitability of transplantation in this group of patients as well as methods for reducing post-transplantation risk such as scrupulous search for infectious agents and reduction of immunosuppression. This article is protected by copyright. All rights reserved.

PMID: 29156507 [PubMed – as supplied by publisher]

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Treosulfan, Fludarabine Conditioning for HSCT in Children with Primary Immunodeficiency: UK Experience.

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Treosulfan, Fludarabine Conditioning for HSCT in Children with Primary Immunodeficiency: UK Experience.

Biol Blood Marrow Transplant. 2017 Nov 16;:

Authors: Slatter MA, Rao K, Abd Hamid IJ, Nademi Z, Chiesa R, Elfeky R, Pearce MS, Amrolia P, Worth A, Flood T, Abinun M, Hambleton S, Qasim W, Gaspar HB, Cant AJ, Gennery AR, Veys P

Abstract
We previously published results of 70 children who received treosulfan with cyclophosphamide (30) or fludarabine (40) before haematopoietic stem cell transplantation (HSCT) for Primary Immunodeficiency (PID). Toxicity was lower and T cell chimerism better in those receiving fludarabine, but numbers were relatively small and follow-up short. We now report outcome of 160 children who received homogeneous conditioning with treosulfan, fludarabine mostly with alemtuzumab (n=124). Median age at transplant was 1.36 years (0.09-18.25). Donors were: matched unrelated, 73; 1-3 antigen mismatched unrelated, 54; matched sibling, 12; other matched family, 17; haploidentical, 4. Stem cell source was: peripheral blood stem cells (PBSCs), 70; Bone marrow, 49; Cord Blood, 41. Median follow up was 4.3 years (0.8-9.4). Overall survival was 83%. There was no veno- occlusive disease. Seventy-four (46%) had acute GVHD, but only 14(9%) greater than grade II. Four patients were successfully retransplanted for graft loss or poor immune reconstitution. One further patient who rejected the graft, died. There was no association between T cell chimerism > 95% and stem cell source, but a significant association with myeloid chimerism > 95% and use of PBSC without an increased risk of significant GVHD compared to other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth are alive with up to 8.7 years follow up. Long-term studies are required to determine late gonadotoxic effects and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine and alemtuzumab gives excellent results in HSCT for PID.

PMID: 29155317 [PubMed – as supplied by publisher]

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RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.

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RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, Ni K, Lv M, Liu C, Huang H, Chan KW, Pui-Wah Lee P, Tu W, Fischer A, Lau YL

Abstract
BACKGROUND: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of ALPS patients, but around one third of such patients remain undefined genetically.
OBJECTIVE: We described two siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype.
METHODS: Whole exome sequencing, molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported.
RESULTS: The two patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, presence of ANA and other autoantibodies, but normal double negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the two siblings. The mutations impaired TCR signaling, leading to defective T cell activation and proliferation, as well as impaired activation-induced cell death of T cells.
CONCLUSION: This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the TCR signaling pathway in similar patients but with unknown genetic cause.

PMID: 29155103 [PubMed – as supplied by publisher]

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ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

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ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Lian J, Cuk M, Kahlfuss S, Kozhaya L, Vaeth M, Rieux-Laucat F, Picard C, Benson MJ, Jakovcevic A, Bilic K, Martinac I, Stathopulos P, Kacskovics I, Vraetz T, Speckmann C, Ehl S, Issekutz T, Unutmaz D, Feske S

Abstract
BACKGROUND: Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is an essential signaling pathway in many cell types. CRAC channels are formed by ORAI1, ORAI2 and ORAI3 proteins and activated by stromal interaction molecule 1 (STIM1) and STIM2. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and non-immunological symptoms.
OBJECTIVE: Molecular and immunological analysis of patients with CID, anhidrosis and ectodermal dysplasia of unknown etiology.
METHODS: DNA sequencing of ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, measurements of SOCE, immunological analysis of peripheral blood lymphocyte populations by flow cytometry, histological and ultrastructural analysis of patient tissues.
RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis (EDA) and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients’ lymphocytes and fibroblasts. Besides impaired T cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer (iNKT) and regulatory T (Treg) cells, and altered composition of γδ T cell and NK cell subsets.
CONCLUSION: ORAI1 null mutations are associated with reduced numbers of iNKT and Treg cells that likely contribute to the patients’ immunodeficiency and autoimmunity. ORAI1 deficient patients suffer from dental enamel defects and anhidrosis representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) that is distinct from previously reported patients with EDA-ID due to mutations in the NF-kB signaling pathway (IKBKG and NFKBIA).

PMID: 29155098 [PubMed – as supplied by publisher]

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Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.

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Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.

Nat Commun. 2017 Nov 17;8(1):1576

Authors: Lee PP, Lobato-Márquez D, Pramanik N, Sirianni A, Daza-Cajigal V, Rivers E, Cavazza A, Bouma G, Moulding D, Hultenby K, Westerberg LS, Hollinshead M, Lau YL, Burns SO, Mostowy S, Bajaj-Elliott M, Thrasher AJ

Abstract
Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.

PMID: 29146903 [PubMed – in process]

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Interaction between Merkel cell carcinoma and the immune system: Pathogenetic and therapeutic implications.

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Interaction between Merkel cell carcinoma and the immune system: Pathogenetic and therapeutic implications.

Mol Clin Oncol. 2017 Nov;7(5):729-732

Authors: Zanetti I, Coati I, Alaibac M

Abstract
Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma. It usually appears on the face and neck of elderly Caucasian people as a flesh-colored, erythematous or violaceous dome-shaped, non-tender nodule with a smooth surface. In immunocompromised patients with T-cell dysfunction, such as patients with acquired immunodeficiency syndrome (AIDS) or solid organ transplant recipients, the incidence of this disease is markedly increased. This suggests a link between the development of MCC and the immune system. Merkel cell polyolmavirus (MCPyV) is clonally integrated into the majority of MCCs, suggesting its causative role in the pathogenesis of the majority of these tumors. Despite wide local excision, sentinel lymph node biopsy, and eventually, adjuvant radiation therapy, which remains the first-line treatment for MCC, the identification of MCPyV has opened novel therapeutic insights. Novel therapeutic strategies could be to inhibit MCPyV oncoproteins and to stimulate immune responses against virus-infected tumor cells by immunostimulatory cytokines, including interferons and interleukin-2.

PMID: 29142746 [PubMed]

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B-cell receptor repertoire sequencing in patients with primary immunodeficiency: a review.

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B-cell receptor repertoire sequencing in patients with primary immunodeficiency: a review.

Immunology. 2017 Nov 15;:

Authors: Ghraichy M, Galson JD, Kelly DF, Trück J

Abstract
The advent of next-generation sequencing now allows a detailed assessment of the adaptive immune system in health and disease. In particular, high-throughput B-cell receptor (BCR) repertoire sequencing provides detailed information about the functionality and abnormalities of the B-cell system. However, it is mostly unknown how the BCR repertoire is altered in the context of primary immunodeficiencies (PID) and whether findings are consistent across phenotypes and genotypes. We have performed an extensive literature search of the published work on BCR repertoire sequencing in PID patients, including several forms of predominantly antibody disorders and combined immunodeficiencies. It is somewhat surprising that BCR repertoires even from severe clinical phenotypes often show only mild abnormalities and that diversity or immunoglobulin gene segment usage is generally preserved to some extent. Despite the great variety of wet lab and analytical methods that were used in the different studies, several findings are common to most investigated PIDs such as the increased usage of gene segments that are associated with self-reactivity. These findings suggest that BCR repertoire characteristics may be used to assess the functionality of the B-cell compartment irrespective of the underlying defect. With the use of NGS approaches, there is now the opportunity to apply BCR repertoire sequencing to multiple patients and explore the PID BCR repertoire in more detail. Ultimately, using BCR repertoire sequencing in translational research could aid the management of PID patients by improving diagnosis, estimating functionality of the immune system and improving assessment of prognosis. This article is protected by copyright. All rights reserved.

PMID: 29140551 [PubMed – as supplied by publisher]

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