Manish Butte

Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics.

October 28, 2017 By Manish Butte

Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics.

Clin Genet. 2017 Oct 27;:

Authors: Rae W, Ward D, Mattocks C, Pengelly RJ, Eren E, Patel SV, Faust SN, Hunt D, Williams AP

Abstract
Primary immunodeficiencies (PIDs) are rare monogenic inborn errors of immunity that result in impairment of functions of the human immune system. PIDs have a broad phenotype with increased morbidity and mortality and treatment choices are often complex. With increased accessibility of next-generation sequencing the rate of discovery of genetic causes for PID has increased exponentially. Identification of an underlying monogenic diagnosis provides important clinical benefits for patients with the potential to alter treatments, facilitate genetic counselling, and pre-implantation diagnostics. We investigated a next-generation sequencing PID panel of 242 genes within clinical care across a range of PID phenotypes. We also evaluated Phenomizer to predict causal genes from human phenotype ontology (HPO) terms. 27 participants were recruited and a total of 15 reportable variants were identified in 48% (13/27) of the participants. The panel results had implications for treatment in 37% (10/27) of participants. Phenomizer identified the genes harbouring variants from HPO terms in 33% (9/27) of participants. This study demonstrates the clinical efficacy that genetic testing has in the care of PID. However, it also highlights some of the disadvantages of gene panels in the rapidly moving field of PID genomics and current challenges in HPO term assignment for PID.

PMID: 29077208 [PubMed – as supplied by publisher]

Population Pharmacokinetics of Intravenous Busulfan in Japanese Pediatric Patients With Primary Immunodeficiency Diseases.

October 28, 2017 By Manish Butte

Population Pharmacokinetics of Intravenous Busulfan in Japanese Pediatric Patients With Primary Immunodeficiency Diseases.

J Clin Pharmacol. 2017 Oct 27;:

Authors: Ishiwata Y, Nagata M, Tsuge K, Takahashi H, Suzuki S, Imai K, Takagi M, Kanegane H, Morio T, Yasuhara M

PMID: 29077206 [PubMed – as supplied by publisher]

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies.

October 28, 2017 By Manish Butte

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies.

J Allergy Clin Immunol Pract. 2016 Nov – Dec;4(6):1089-1100

Authors: Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA

Abstract
A broad spectrum of autoimmunity is now well described in patients with primary immunodeficiencies (PIDs). Management of autoimmune disease in the background of PID is particularly challenging given the seemingly discordant goals of immune support and immune suppression. Our growing ability to define the molecular underpinnings of immune dysregulation has facilitated novel targeted therapeutics. This review focuses on mechanism-based treatment strategies for the most common autoimmune and inflammatory complications of PID including autoimmune cytopenias, rheumatologic disease, and gastrointestinal disease. We aim to provide guidance regarding the rational use of these agents in the complex PID patient population.

PMID: 27836058 [PubMed – indexed for MEDLINE]

Flow Cytometry Assays in Primary Immunodeficiency Diseases.

October 27, 2017 By Manish Butte

Flow Cytometry Assays in Primary Immunodeficiency Diseases.

Methods Mol Biol. 2018;1678:321-345

Authors: O’Gorman MRG

Abstract
Inborn errors of immunity are the cause of the primary immunodeficiency diseases, an extremely diverse group of genetic defects that are inherited in Mendelian fashion and result in the impairment of development and/or function of key components of the immune system. Since the last publication of this chapter in 2011, there have been approximately 100 new primary immunodeficiency diseases officially classified by the “Expert Committee for Primary Immunodeficiency” who met in 2015 and the numbers will continue to rise with the continued evolution and widespread adoption of genomic technologies. The ultimate diagnostic modality involves the identification of a mutation in a gene whose product is known to be involved in immunity. DNA sequencing is however still a rather time-consuming technology. Flow cytometry applications have evolved that are rapid, specific, and relatively inexpensive to screen for abnormalities associated with primary immunodeficiency diseases. The numerous flow cytometry procedures that have been developed to detect abnormalities in peripheral blood cells of primary immunodeficiency patients can barely be covered in an entire book, let alone one chapter. Instead of attempting to cover each disease with a specific assay or test, we will review four procedures each covering one of the three following broad forms of immune abnormalities observed in primary immunodeficiency, i.e., immune subset abnormalities, immune marker abnormalities, and immune function abnormalities.

PMID: 29071685 [PubMed – in process]

Primary immunodeficiencies due to abnormalities of the actin cytoskeleton.

October 27, 2017 By Manish Butte

Primary immunodeficiencies due to abnormalities of the actin cytoskeleton.

Curr Opin Hematol. 2017 Jan;24(1):16-22

Authors: Burns SO, Zarafov A, Thrasher AJ

Abstract
PURPOSE OF REVIEW: Primary immunodeficiencies (PIDs) are inherited conditions where components of the immune system are missing or dysfunctional. Over 300 genes have been causally linked to monogenic forms of PID, including a number that regulate the actin cytoskeleton. The majority of cytoskeletal defects disrupt assembly and disassembly of filamentous actin in multiple immune cell lineages impacting functions such as cell migration and adhesion, pathogen uptake, intercellular communication, intracellular signalling, and cell division.
RECENT FINDINGS: In the past 24 months, new actin defects have been identified through next generation sequencing technologies. Substantial progress has also been made in understanding the pathogenic mechanisms that contribute to immunological dysfunction, and also how the cytoskeleton participates in normal physiological immune processes.
SUMMARY: This review summarises recent advances in the field, raising awareness of these conditions and our current understanding of their presentation. Description of further cases and new conditions will extend the clinical phenotype of actin-related disorders, and will promote the development of more effective and targeted therapies.

PMID: 27749373 [PubMed – indexed for MEDLINE]

Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies.

October 25, 2017 By Manish Butte

Frequency of Mycobacterium bovis and mycobacteria in primary immunodeficiencies.

Turk Pediatri Ars. 2017 Sep;52(3):138-144

Authors: Ulusoy E, Karaca NE, Aksu G, Çavuşoğlu C, Kütükçüler N

Abstract
AIM: Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases.
MATERIAL AND METHODS: Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/ interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests.
RESULTS: A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients including Mycobacterium bovis, Mycobacterium chelonea, Mycobacterium elephantis, Mycobacterium fortuitum, and Mycobacterium tuberculosis. All patients were treated with anti-tuberculosis therapy. Thirty-six percent of these 25 patients underwent hematopoietic stem cell transplantation. Eight patients (five before, three after transplantation) died.
CONCLUSIONS: Non-tuberculosis mycobacteria including mainly Mycobacterium bovis were observed with a higher rate compared to Mycobacterium tuberculosis in primary immunodeficiencies, especially in those affecting the interleukin 12/interferon gamma pathway. Early diagnosis of primary immunodeficiencies with neonatal screening program and preventing administration of the Bacille Calmette-Guerin vaccine in these patients is important.

PMID: 29062247 [PubMed]

HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression.

October 25, 2017 By Manish Butte

HBZ-mediated shift of JunD from growth suppressor to tumor promoter in leukemic cells by inhibition of ribosomal protein S25 expression.

Leukemia. 2017 Oct;31(10):2235-2243

Authors: Terol M, Gazon H, Lemasson I, Duc-Dodon M, Barbeau B, Césaire R, Mesnard JM, Péloponèse JM

Abstract
Human T-cell leukemia virus type 1 (HTLV-1) basic-leucine zipper (bZIP) factor (HBZ) is a key player in proliferation and transformation of HTLV-1-infected cells, thus contributing to adult T-cell leukemia (ATL) development. HBZ deregulates gene expression within the host cell by interacting with several cellular partners. Through its C-terminal ZIP domain, HBZ is able to contact and activate JunD, a transcription factor of the AP-1 family. JunD mRNA is intronless but can generate two protein isoforms by alternative translation initiation: JunD full-length and Δ JunD, an N-terminal truncated form unresponsive to the tumor suppressor menin. Using various cell lines and primary T-lymphocytes, we show that after serum deprivation HBZ induces the expression of Δ JunD isoform. We demonstrate that, unlike JunD, Δ JunD induces proliferation and transformation of cells. To decipher the mechanisms for Δ JunD production, we looked into the translational machinery and observed that HBZ induces nuclear retention of RPS25 mRNA and loss of RPS25 protein expression, a component of the small ribosomal subunit. Therefore, HBZ bypasses translational control of JunD uORF and favors the expression of Δ JunD. In conclusion, we provide strong evidences that HBZ induces Δ JunD expression through alteration of the cellular translational machinery and that the truncated isoform Δ JunD has a central role in the oncogenic process leading to ATL.

PMID: 28260789 [PubMed – indexed for MEDLINE]

Reversible Hypogammaglobulinemia in 2 Pediatric Patients With Primary Immunodeficiency.

October 24, 2017 By Manish Butte

Reversible Hypogammaglobulinemia in 2 Pediatric Patients With Primary Immunodeficiency.

J Investig Allergol Clin Immunol. 2017;27(5):320-321

Authors: Pasic S

PMID: 29057740 [PubMed – in process]

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.

October 24, 2017 By Manish Butte

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.

Expert Opin Orphan Drugs. 2017;5(10):813-825

Authors: Heusinkveld LE, Yim E, Yang A, Azani AB, Liu Q, Gao JL, McDermott DH, Murphy PM

Abstract
21 INTRODUCTION: WHIM syndrome is a rare combined primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4. It is the only Mendelian condition known to be caused by mutation of a chemokine or chemokine receptor. As such, it provides a scientific opportunity to understand chemokine-dependent immunoregulation in humans and a medical opportunity to develop mechanism-based treatment and cure strategies.
22 AREAS COVERED: This review covers the clinical features, genetics, immunopathogenesis and clinical management of WHIM syndrome. Clinical trials of targeted therapeutic agents and potential cure strategies are also included.
23 EXPERT OPINION: WHIM syndrome may be particularly amenable to mechanism-based therapeutics for three reasons: 1) CXCR4 has been validated as the molecular target in the disease by Mendelian genetics; 2) the biochemical abnormality is excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been developed. Plerixafor is FDA-approved for hematopoietic stem cell (HSC) mobilization and has shown preliminary safety and efficacy in phase I clinical trials in WHIM syndrome. Gene editing may represent a viable cure strategy, since chromothriptic deletion of the disease allele in HSCs resulted in clinical cure of a patient and because CXCR4 haploinsufficiency enhances engraftment of transplanted HSCs in mice.

PMID: 29057173 [PubMed]

DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile.

October 21, 2017 By Manish Butte

DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile.

Clin Immunol. 2017 Oct 16;:

Authors: Al-Herz W, Massaad MJ, Chou J, Notarangelo LD, Geha RS

Abstract
Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.

PMID: 29051008 [PubMed – as supplied by publisher]