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G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia.

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G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia.

J Pediatr Hematol Oncol. 2015 Nov;37(8):616-22

Authors: Kiykim A, Baris S, Karakoc-Aydiner E, Ozen AO, Ogulur I, Bozkurt S, Ataizi CC, Boztug K, Barlan IB

Abstract
Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency was recently defined as a new severe congenital neutropenia subgroup remarkable with congenital heart defects, urogenital malformations, endocrine abnormalities, and prominent superficial veins. Here, we report 3 patients with G6PC3 deficiency presenting with recurrent diarrhea, failure to thrive, and sinopulmonary infections leading to bronchiectasis. In patient I and II, a combined immune deficiency was suspected due to early-onset disease with lymphopenia, neutropenia, and thrombocytopenia, along with variable reductions in lymphocyte subpopulations and favorable response to intravenous γ-globulin therapy. Apart from neutropenia, all 3 patients had intermittent thrombocytopenia, anemia, and lymphopenia. All patients had failure to thrive and some of the classic syndromic features of G6PC3 deficiency, including cardiac abnormalities and visibility of superficial veins in all, endocrinologic problems in PI and PIII, and urogenital abnormalities in PII. Our experience suggests that a diagnosis of congenital neutropenia due to G6PC3 may not be as straightforward in such patients with combined lymphopenia and thrombocytopenia. A high index of suspicion and the other syndromic features of G6PC3 were clues to diagnosis. Screening of all combined immune deficiencies with neutropenia may help to uncover the whole spectra of G6PC3 deficiency.

PMID: 26479985 [PubMed – indexed for MEDLINE]

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Experience with Subgam, a Subcutaneously Administered Human Normal Immunoglobulin (ClinicalTrials.gov–NCT02247141).

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Experience with Subgam, a Subcutaneously Administered Human Normal Immunoglobulin (ClinicalTrials.gov–NCT02247141).

PLoS One. 2015;10(7):e0131565

Authors: Dash C, Gascoigne E, Gillanders K, Gooi H

Abstract
BACKGROUND AND OBJECTIVES: A multi-centre, non-comparative study examining the efficacy and safety of Subgam, a normal immunoglobulin (IgG) given weekly as a rapid subcutaneous infusion to patients with primary immune deficiency (PID), is reported. Also included is a summary of adverse drug reactions associated with the use of marketed Subgam in the UK.
MATERIALS AND METHODS: 50 patients with stable PID on IgG therapy were enrolled: Stage 1 included three infusions with prior IgG product followed by 6 months with Subgam, Stage 2 involved long-term Subgam therapy up to 4 years.
RESULTS: Stage 1, 85% of the subjects aged >12 years and 93% of the subjects aged <12 years achieved IgG levels ≥6 and ≥4 g/L, respectively at all observations. There were 3.62 infections/patient/year during Subgam treatment. The most common product-related events were infusion site reactions (50% of patients). Recent post-hoc pharmacokinetics analysis of the post-infusion serum total IgG concentration indicated that the mean dose-normalised incremental IgG AUCτ following intravenous dosing (120.5 g.day/L) was 1.64-fold that of the dose-normalised mean incremental IgG AUCτ following subcutaneous dosing (73.6 g.day/L), corresponding to an estimated IgG bioavailability for subcutaneous dosing of 61%. Only 34 post-licensing adverse reactions have been received in 30 patients over a period of 10 years; fourteen were classed as serious as defined by the ICH guidelines on good clinical practice. The most common post-licensing adverse reaction was infusion site reaction (7 reports). There were 7 reports of flu-like symptoms (pyrexia/shivering/rigors/feeling hot or cold), 2 other reports of combined flu-like symptoms and infusion site reactions, 5 reports of generalised skin reactions, and 3 reports of combined infusion site and skin reactions. There were also reports of anaphylaxis (2 reports) and 8 other adverse events (including headache). In conclusion, Subgam is effective and well tolerated in the treatment of PID.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02247141.

PMID: 26222441 [PubMed – indexed for MEDLINE]

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Mendelian Susceptibility to Mycobacterial Disease due to IL-12Rβ1 Deficiency in Three Iranian Children.

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Mendelian Susceptibility to Mycobacterial Disease due to IL-12Rβ1 Deficiency in Three Iranian Children.

Iran J Public Health. 2016 Feb;45(2):249-54

Authors: Sarrafzadeh SA, Mahloojirad M, Nourizadeh M, Casanova JL, Pourpak Z, Bustamante J, Moin M

Abstract
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare inheritance syndrome, characterized by a disseminated infection with mycobacterium in children following BCG vaccination at birth. Regarding the vaccination program in Iran, it may consider as a public health problem. The pathogenesis of MSMD is dependent on either insufficient production of IFN-gamma (γ) or inadequate response to it. Here, we want to introduce three cases including two siblings and one girl from two unrelated families with severe mycobacterial infections referred to Immunology, Asthma and Allergy Research Institute (IAARI), from 2013 to 2015; their MSMD was confirmed by both cytokine assessment and genetic analysis. Regarding the clinical features of the patients, cell proliferation against a mitogen and BCG antigen was ordered in a lymphocyte transformation test (LTT) setting. ELISA was performed for the measurement of IL-12p70 and IFN- γ in whole blood samples activated by BCG + recombinant human IFN-γ and BCG + recombinant human IL-12, respectively. In contrast to mitogen, the antigen-dependent proliferation activity of the patients’ leukocytes was significantly lower than that in normal range. We identified a homozygous mutation in IL12RB1 gene for two kindred who had a homozygous mutation affecting an essential splice site. For the third patient, a novel frameshift deletion in IL12RB1 gene was found. The genetic study results confirmed the impaired function of stimulated lymphocytes to release IFN-γ following stimulation with BCG+IL-12 while the response to rhIFN-γ for IL-12p70 production was relatively intact. Our findings show that cellular and molecular assessments are needed for precise identification of immunodeficiency disorders especially those without clear-cut diagnostic criteria.

PMID: 27114990 [PubMed]

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Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: an international survey of 274 patients from 167 kindreds.

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Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: an international survey of 274 patients from 167 kindreds.

Blood. 2016 Apr 25;

Authors: Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, Ouachée-Chardin M, Fouyssac F, Girisha KM, Etzioni A, Van Montfrans J, Camcioglu Y, Kerns LA, Belohradsky B, Blanche S, Bousfiha A, Rodriguez-Gallego C, Meyts I, Kisand K, Reichenbach J, Renner ED, Rosenzweig S, Grimbacher B, van de Veerdonk FL, Traidl-Hoffmann C, Picard C, Marodi L, Morio T, Kobayashi M, Lilic D, Milner JD, Holland S, Casanova JL, Puel A

Abstract
Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from five continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range: 1 – 71 years); 98% of them had CMC, with a median age at onset of one year (range: 0 – 24 years). Patients often displayed bacterial (74%) infections, mostly due to Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly due to Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or BCG vaccines, were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating IL-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

PMID: 27114460 [PubMed – as supplied by publisher]

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CNS vasculitis and stroke as a complication of DOCK8 deficiency: a case report.

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CNS vasculitis and stroke as a complication of DOCK8 deficiency: a case report.

BMC Neurol. 2016;16(1):54

Authors: AlKhater SA

Abstract
BACKGROUND: Primary immunodeficiency disorders associated with autoimmunity are poorly understood. Central nervous system (CNS) vasculitis can complicate the courses of such entities, but it is underappreciated. Deletion of the dedicator of cytokinesis 8 (DOCK8) gene is considered to be the autosomal recessive form of hyperimmunoglobulin E syndrome which is a rare type of primary immunodeficiency disease characterized by elevated levels of IgE antibody, eczema, and recurrent staphylococcal infections. DOCK8 deletion is associated with fatal CNS vasculitis. However, descriptions of such cases and their outcomes are scarce in the literature.
CASE PRESENTATION: This report describes a young female with a DOCK8 gene deletion presenting acutely with squint, fatigue and visual hallucinations. The patient was diagnosed as having neuritis of the third oculomotor nerve and encephalitis, which were thought to be related to her underlying immune deficiency, however, she subsequently was diagnosed with CNS vasculitis based on brain magnetic imaging and magnetic resonance angiography findings. We provide here a comprehensive description of the patient’s clinical outcome and outline an effective treatment approach that may be useful for similar patients and includes the use of steroids and mycophenolate mofetil (MMF). The treatment was well tolerated and enabled the patient to recover most of her neurological deficits. However, despite the initial improvement, she later developed stroke.
CONCLUSIONS: To the best of our knowledge, this is the first report in the literature of a case of primary immunodeficiency complicated by CNS vasculitis demonstrating a successful outcome. Our observations indicate that the combination of MMF and steroids is an effective treatment for CNS vasculitis associated with DOCK8 deficiency. However, lack of awareness of the neurological comorbidities associated with primary immunodeficiencies and the delay in diagnosis likely contributed to the development of acute cerebral infarction. Early treatment and aggressive control of the disease’s initial inflammation is essential for preventing catastrophic stroke.

PMID: 27113444 [PubMed – in process]

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Idiopathic pancreatitis in a patient with a STAT3 mutation.

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Idiopathic pancreatitis in a patient with a STAT3 mutation.

Allergy Rhinol (Providence). 2016 Jan;7(1):42-4

Authors: Michaud C, Peppers B, Frith J, Tcheurekdjian H, Hostoffer R

Abstract
BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin infections with abscesses, recurrent pneumonias with pneumatoceles, and immunoglobulin E levels of >10 times the upper limit of normal.
CASE: The patient described herein had a classic case of signal transducer and activator of transcription 3 (STAT3) deficiency associated with HIES diagnosed several years before this particular presentation. He demonstrated extraimmune manifestations of the disease as well, including characteristic facies and a history of skeletal fractures. In addition, the patient had several distinct episodes of idiopathic pancreatitis for which a full gastrointestinal workup had been performed. STAT3 mutation was confirmed by genotyping at the time of diagnosis of HIES.
CONCLUSIONS: STAT3, a mammalian protein that regulates cell growth, survival, and differentiation, has been linked to human pancreatic carcinogenesis as well as the above-mentioned immune deficiency. Mouse studies demonstrated that genetic ablation of STAT3 exacerbates the course of acute pancreatitis, whereas normal pancreatic STAT3 seems to have a protective effect against necrotizing pancreatitis. An association between STAT3 mutations and pancreatitis has not yet been revealed in humans. Here we describe a case of acute pancreatitis that presented in a patient with STAT3 mutation.

PMID: 27103560 [PubMed]

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Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

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Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

Immunol Cell Biol. 2016 Apr 22;

Authors: Moens L, Kane A, Tangye SG

Abstract
Immunological memory is characterized by the rapid re-activation of memory B cells that produce large quantities of high affinity antigen-specific Abs. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these diverse responses of naïve and memory B cells is incompletely resolved. Here, we investigated the nature of BCR signaling in human splenic naïve, IgM(+) memory and isotype switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and SYK) and propagation (BLNK, PLCγ2) signaling components in these different B cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared to naïve cells. While no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) ER stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show intrinsic signaling features of B-cell subsets contribute both to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B cell responses, and provides a framework to modulate these responses in the setting of vaccination and immunopathologies such as immunodeficiency and autoimmunity.Immunology and Cell Biology accepted article preview online, 22 April 2016. doi:10.1038/icb.2016.41.

PMID: 27101923 [PubMed – as supplied by publisher]

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