Research

PI3Kδ and primary immunodeficiencies.

Nat Rev Immunol. 2016 Sep 12;

Authors: Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K

Abstract
Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

PMID: 27616589 [PubMed – as supplied by publisher]

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[Case Report; Primary central nervous system lymphoma mimicking progressive multifocal leukoencephalopathy in a patient with acquired immune deficiency syndrome].

Nihon Naika Gakkai Zasshi. 2014 Oct 10;103(10):2578-80

Authors: Yamakawa T, Fujimoto K, Ebata K, Iwasaki J, Takahashi S, Shiratori S, Sugita J, Kondo T, Nishio M, Teshima T

PMID: 27514208 [PubMed – indexed for MEDLINE]

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[Specific antibody deficiency: Primary immunodeficiency associated to respiratory allergy].

Rev Chil Pediatr. 2016 Sep 7;

Authors: Fernández F, Campillay R, Palma V, Norambuena X, Quezada A

Abstract
INTRODUCTION: Specific antibody deficiency (SAD) with normal immunoglobulin and normal B cells is a primary immunodeficiency characterized by reduced ability to produce antibodies to specific antigens especially polysaccharides.
OBJECTIVE: To describe the characteristics of patients diagnosed with SAD emphasizing the association between primary immunodeficiency and allergic diseases.
PATIENTS AND METHOD: Descriptive study showing patients with SAD treated at a public hospital between August 2007 and July 2015. Other secondary or primary immunodeficiency was discarded. The diagnosis of SAD was based on recurrent infections and abnormal response to pneumococcal polysaccharide vaccine assessed by specific IgG to 10 pneumococcal serotypes.
RESULTS: Twelve patients were included, 4 males, mean age 6 years, recurrent pneumonia predominated (91.7%) as well as other respiratory and invasive infections. All patients with SAD had associated asthma, 11 had allergic rhinitis, and other allergies. Three patients did not respond to any of the 10 serotypes contained in pneumococcal polysaccharide vaccine, and those who responded were with low titers. Treatment with conjugate pneumococcal vaccine was favorable in 11/12 patients.
CONCLUSION: In children older than 2 years with recurrent respiratory infections or invasive S. pneumoniae infections with normal immunoglobulin we recommend to investigate SAD, especially if they have a concurrent allergic disease.

PMID: 27614984 [PubMed – as supplied by publisher]

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Cellular and molecular mechanisms of immune dysregulation and autoimmunity.

Cell Immunol. 2016 Aug 27;

Authors: Azizi G, Pouyani MR, Abolhassani H, Sharifi L, Dizaji MZ, Mohammadi J, Mirshafiey A, Aghamohammadi A

Abstract
Primary immunodeficiencies (PIDs) constitute a large group of rare disorders that affect the function of the immune system. A specific group of PIDs entitled “diseases of immune dysregulation” are developed due to mutation in the genes which have critical roles in the regulation of immune responses and immunological tolerance. This group of PID patients develop autoimmune and inflammatory disorders as a result of their impaired immunity, therefore they could be considered as a model for analyzing the link between immune dysregulation and autoimmunity. In this article, our aim is to describe the function of the mutated gene, the molecular and cellular mechanisms underlying the immune dysregulation and review the literature in regard with the reported autoimmune disorders in the main types of immunodysregulatory diseases including genetic defects of regulatory T cells, familial hemophagocytic lymphohistiocytosis syndromes, autoimmunity without lymphoproliferation, autoimmune lymphoproliferative syndrome, immune dysregulation with colitis, and type 1 interferonopathies.

PMID: 27614846 [PubMed – as supplied by publisher]

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Ataxia telangiectasia presenting as hyper IgM syndrome without neurologic signs.

Ann Allergy Asthma Immunol. 2016 Sep;117(3):221-6

Authors: Doshi A, Ryu J, Thornburg CD, Hershey D, Cherry R, Milligan K, Rosenzweig S, Leonard S

PMID: 27613453 [PubMed – in process]

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Chronic granulomatous disease as an SOS call for multicenter cooperative effort to prevent infections: A meta-analysis of the treatments.

Ann Allergy Asthma Immunol. 2016 Sep;117(3):285-9

Authors: Loffredo L, Perri L, Zicari A, Del Ben M, Angelico F, Violi F

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease. Patients with CGD experience recurrent life-threatening infections. Lack of large interventional trials generated several doubts for the treatment of infections in CGD.
OBJECTIVE: To evaluate the effect of interferon gamma, antifungal drugs, and antibiotics in patients with CGD undergoing prophylaxis of infections.
METHODS: A meta-analysis of the interventional trials was performed. The studies were identified by searching MEDLINE, ISI Web of Science, SCOPUS, and Cochrane database. The last search was run on January 2016. Reference lists of all studies included in the present systematic review were screened for potential additional eligible studies.
RESULTS: Two studies with 163 patients with CGD were included in the interferon gamma analysis. Severe infections occurred in 17 of 73 patients (23%) treated with interferon gamma and in 49 of 90 patients (54%) not undergoing treatment with interferon gamma. Compared with control, severe infections were significantly reduced in patients treated with interferon gamma (relative risk, 0.46; 95% confidence interval, 0.29-0.73; P = .001). Interferon gamma treatment was associated with an absolute risk reduction of 31% and a number needed to treat of 3. Furthermore, compared with control, interferon gamma treatment reduced pulmonary infections (relative risk, 0.43; 95% confidence interval, 0.19-0.96; P = .04). Two studies with 172 patients with CGD were included in the antifungal drug analysis. Infections occurred in 4 of 69 patients (6%) treated with antifungals and in 17 of 103 patients (16%) not receiving treatment with antifungals. Compared with control, Aspergillus infections were not significantly reduced in patients treated with antifungals. No randomized prospective clinical trials of antibacterial prophylaxis in patients with CGD have been performed.
CONCLUSION: Despite the fact that interferon gamma prophylaxis seems to have a positive effect on severe infections, small sample sizes preclude definite conclusions. Further trials with interferon gamma and/or antifungal and antibiotics are necessary to optimize the treatment of CGD.

PMID: 27613462 [PubMed – in process]

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Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies.

J Allergy Clin Immunol. 2016 Aug 31;

Authors: Perelygina L, Plotkin S, Russo P, Hautala T, Bonilla F, Ochs HD, Joshi A, Routes J, Patel K, Wehr C, Icenogle J, Sullivan KE

PMID: 27613149 [PubMed – as supplied by publisher]

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Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a phase 2/3 study in Europe in patients with primary immunodeficiencies.

Clin Exp Immunol. 2016 Sep 10;

Authors: Borte M, Kriván G, Derfalvi B, Maródi L, Harrer T, Jolles S, Bourgeois C, Engl W, Leibl H, McCoy B, Gelmont D, Yel L

Abstract
A highly-concentrated (20%) immunoglobulin G (IgG) preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2 to 67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0.022/patient-year, p<0.0001); the rate of all infections was 4.38/patient-year. Median trough IgG concentrations were ≥8g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0.101 event/infusion. The incidence of local related AEs was 0.069 event/infusion (0.036 event/infusion, when excluding a 13 year-old patient who reported 79/162 total related local AEs). The incidence of related systemic AEs was 0.032 event/infusion. Most related AEs were mild, none severe. For 64.6% of patients and in 94.8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0.95 (range: 0.3-4.1) h using mostly 1 to 2 administration sites (median = 2 sites [range: 1-5]). Almost all infusions (99.8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment. This article is protected by copyright. All rights reserved.

PMID: 27613250 [PubMed – as supplied by publisher]

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Draft Genome Sequence of Leptospira interrogans Serovar Bataviae Strain LepIMR 22 Isolated from a Rodent in Johor, Malaysia.

Genome Announc. 2016;4(5)

Authors: Amran F, Mohd Khalid MK, Mohamad S, Mat Ripen A, Ahmad N, Goris MG, Muhammad AH, Noor Halim NA

Abstract
Leptospira interrogans serovar Bataviae was recently identified as one of the persistent Leptospira serovars in Malaysia. Here, we report the draft genome sequence of the L. interrogans serovar Bataviae strain LepIMR 22 isolated from kidney of a rodent in Johor, Malaysia.

PMID: 27609924 [PubMed]

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Vesicourethral reflux-induced renal failure in a patient with ICF syndrome due to a novel DNMT3B mutation.

Am J Med Genet A. 2016 Sep 8;

Authors: Kutluğ S, Ogur G, Yilmaz A, Thijssen PE, Abur U, Yildiran A

Abstract
ICF syndrome is a primary immunodeficiency disease characterized by hypo- or agammaglobulinemia, centromeric instability mainly on chromosomes 1, 9, and 16 and facial anomalies. ICF syndrome presents with frequent respiratory tract infections in infancy. A 20-month-old female patient was referred to our clinic due to frequent lower respiratory tract infections. ICF syndrome was considered because of comorbidity of hypogammaglobulinemia, facial anomalies, and neuromotor growth retardation. Metaphase chromosome analysis revealed centromeric instability on chromosomes 1, 9, and 16 and through Sanger a previously unreported homozygous missense mutation (c.1805T>C; [p.V602A]) was identified in the DNMT3B, confirming ICF1. The patient was found to have a breakdown in renal function 1 year later; the urinary system was examined and bilateral vesicoureteral reflux was found, warranting the need for dialysis in time. This report expands the mutation spectrum of ICF1 and is the first to describe bilateral vesicoureteral reflux accompanying ICF syndrome. © 2016 Wiley Periodicals, Inc.

PMID: 27604394 [PubMed – as supplied by publisher]

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