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Interleukin-2-Inducible T-Cell Kinase (ITK) Deficiency – Clinical and Molecular Aspects.

J Clin Immunol. 2014 Oct 24;

Authors: Ghosh S, Bienemann K, Boztug K, Borkhardt A

Abstract
In patients with underlying immunodeficiency, Epstein-Barr virus (EBV) may lead to severe immune dysregulation manifesting as fatal mononucleosis, lymphoma, lymphoproliferative disease (LPD), lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis (HLH) and dysgammaglobulinemia. Several newly discovered primary immunodeficiencies (STK4, CD27, MAGT1, CORO1A) have been described in recent years; our group and collaborators were able to reveal the pathogenicity of mutations in the Interleukin-2-inducible T-cell Kinase (ITK) in a cohort of nine patients with most patients presenting with massive EBV B-cell lymphoproliferation. This review summarizes the clinical and immunological findings in these patients. Moreover, we describe the functional consequences of the mutations and draw comparisons with the extensively investigated function of ITK in vitro and in the murine model.

PMID: 25339095 [PubMed – as supplied by publisher]

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When less is more: primary immunodeficiency with an autoinflammatory kick.

Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):491-500

Authors: Giannelou A, Zhou Q, Kastner DL

Abstract
PURPOSE OF REVIEW: Next-generation sequencing is revolutionizing the molecular taxonomy of human disease. Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity.
RECENT FINDINGS: Whole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes. First, a phenotypic spectrum, including livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome, is caused by loss-of-function mutations in cat eye syndrome chromosome region, candidate 1 (CECR1), encoding adenosine deaminase 2. Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells, and a regulator of macrophage differentiation and endothelial development. Disease-associated mutations impair anti-inflammatory M2 macrophage differentiation. Second, patients presenting with cold-induced urticaria, granulomatous rash, autoantibodies, and common variable immunodeficiency, or with blistering skin lesions, bronchiolitis, enterocolitis, ocular inflammation, and mild immunodeficiency harbor distinct mutations in phospholipase Cγ2, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase Cγ2 autoinhibitory domain, causing increased or constitutive signaling.
SUMMARY: These findings underscore the power of next-generation sequencing, demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation, and suggesting a possible role for cat eye syndrome chromosome region, candidate 1 and phospholipase Cγ2 in common diseases.

PMID: 25337682 [PubMed – as supplied by publisher]

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Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells.

J Exp Med. 2014 Aug 25;211(9):1759-77

Authors: Lancini C, van den Berk PC, Vissers JH, Gargiulo G, Song JY, Hulsman D, Serresi M, Tanger E, Blom M, Vens C, van Lohuizen M, Jacobs H, Citterio E

Abstract
Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3Δ/Δ), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3Δ/Δ HSCs. Beyond the hematopoietic system, Usp3Δ/Δ animals spontaneously developed tumors, and primary Usp3Δ/Δ cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress.

PMID: 25113974 [PubMed – indexed for MEDLINE]

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The Pulmonologist Approach to Diagnosis and Management of Patients With Primary Immunodeficiency Diseases.

Chest. 2014 Oct 1;146(4_MeetingAbstracts):486A

Authors: Orange J, Akhter J, Seeborg F, Boyle M, Scalchunes C, Hernandez-Trujillo V

Abstract
SESSION TITLE: Education and Teaching in Critical Care PostersSESSION TYPE: Original Investigation PosterPRESENTED ON: Wednesday, October 29, 2014 at 01:30 PM – 02:30 PMPURPOSE: As pulmonary symptoms are common in patients with primary immunodeficiency diseases (PID), pulmonologists are often the first referred specialists. In a recent Immune Deficiency Foundation (IDF) survey, patients reported ≥1 case of pneumonia (40%) and permanent lung damage before diagnosis (24%). We evaluated the practice of pulmonologists in regards to PID diagnosis and treatment.METHODS: The American Academy of Allergy, Asthma, and Immunology (AAAAI) Primary Immunodeficiency Committee and the IDF conducted an anonymous, incentivized mail survey of American Medical Association and American Osteopathic Association members specializing in pulmonology. Responses were compared to a historical survey of 71 sub-specialist immunologists (AAAAI members devoting >10% of their practice to PID management).RESULTS: Surveys were returned by 485 pulmonologists actively practicing in the United States; 39% reported a specialty of adult pulmonology and 52% reported they expect <3 new patients per year with PID. Forty-nine percent have diagnosed a patient with a PID. The most commonly followed diagnoses were common variable immunodeficiency (57%) and immunoglobulin G (IgG) subclass deficiency (51%), which were significantly more prevalent in sub-specialist immunologists practices (99% and 89%, respectively; p<.001). Pulmonologists most commonly ordered quantitative serum Igs (96%) and IgG subclasses (83%) for PID diagnosis; 48% requested vaccine antibody titers (no comparative sub-specialist immunologist data). Significant differences between pulmonologists and sub-specialist immunologists were evident in the utilization of intravenously-administered IgG therapy and prophylactic antibiotics across PIDdiagnoses and in live viral vaccine avoidance for patients with several diagnoses (p<.001). Significantly fewer pulmonologists (11% vs 79%, p<.001) were aware of published professional guidelines regarding management of PI.CONCLUSIONS: Pulmonologists can have an important role in management of patients with PID, especially given the incidence of pneumonia in these patients. The current study reveals several significant differences in how pulmonologists diagnose and treat patients with PID compared with sub-specialist immunologists.CLINICAL IMPLICATIONS: Increased educational and training initiatives aimed at pulmonologists may contribute to improved PID diagnosis and patient management and potentially minimize long-term pulmonary damage.DISCLOSURE: Jordan Orange: Grant monies (from industry related sources): CSL Behring, Grant monies (from industry related sources): Baxter, Consultant fee, speaker bureau, advisory committee, etc.: ASD, Consultant fee, speaker bureau, advisory committee, etc.: Griffols, Consultant fee, speaker bureau, advisory committee, etc.: Octapharma, Consultant fee, speaker bureau, advisory committee, etc.: IDT/Viracor, Consultant fee, speaker bureau, advisory committee, etc.: BPL, Consultant fee, speaker bureau, advisory committee, etc.: Atlantic Research, Consultant fee, speaker bureau, advisory committee, etc.: Up to date, Consultant fee, speaker bureau, advisory committee, etc.: Immune Deficiency Foundation Marcia Boyle: Employee: Immune Deficiency Foundation Chris Scalchunes: Employee: Immune Deficiency Foundation Vivian Hernandez-Trujillo: Consultant fee, speaker bureau, advisory committee, etc.: CSL Behring, Consultant fee, speaker bureau, advisory committee, etc.: IFIR , Consultant fee, speaker bureau, advisory committee, etc.: Baxter, Consultant fee, speaker bureau, advisory committee, etc.: Sanofi, Consultant fee, speaker bureau, advisory committee, etc.: Merck, Consultant fee, speaker bureau, advisory committee, etc.: Immune Deficiency Foundation The following authors have nothing to disclose: Javeed Akhter, Filiz SeeborgNo Product/Research Disclosure Information.

PMID: 25334519 [PubMed – as supplied by publisher]

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Mycobacterium avium Complex Presenting as Lung Mass With Eosinophilic Pneumonia.

Chest. 2014 Oct 1;146(4_MeetingAbstracts):175A

Authors: Doumit J, Ters P, Harting J

Abstract
SESSION TITLE: Infectious Disease Student/Resident Case Report Posters IISESSION TYPE: Medical Student/Resident Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM – 02:30 PMINTRODUCTION: Nontuberculous mycobacteria pulmonary infections are often due to Mycobacterium Avium Complex (MAC) [1]. Few cases reported MAC causing lung mass. Radiographically, the form of MAC without known underlying lung disease could be associated with lung nodules [2]. We present a patient with chronic cough whose workup for lung masses revealed MAC.CASE PRESENTATION: A previously healthy 57-year-old female with no immunodeficiency presented with a 4-month history of progressive dyspnea, chest pain, and cough with productive clear sputum. She manifested chills and night sweats without any weight changes. Imaging included a chest x-ray that revealed right and lower lobe infiltrative opacities. A CT angiography of the chest (Fig 1) was consistent with a right lung infiltrates that revealed a 9 x 6.5 cm mass along the right upper lobe and a 2.6 x 7.4 cm mass in the right lower lobe. Eosinophilia was up to 2.38 K/uL. Her Quantiferon TB test and AFB were negative. Gram stain, bacterial, and fungal cultures were negative. She received Azithromycin and Piperacillin/Tazobactam for community-acquired and post-obstructive pneumonia respectively. Bronchoscopy showed mucosal erythema and edema without endobronchial mass. Transbronchial biopsies revealed no granulomas or malignant cells. A CT-guided biopsy of the right upper lobe lesion showed fibrin deposition, macrophages/CD68 positive, S-100 negative, CD1a negative and many eosinophilic infiltrations with no evidence of eosinophilic granuloma. These findings were suggestive of eosinophilic pneumonia (Fig 2). The patient was started on prednisone to treat the eosinophilic pneumonia. Eight weeks following her bronchoscopy, her cultures were positive for MAC. Ethambutol, Rifampin and Clarithromycin were initiated.DISCUSSION: MAC rarely presents as a lung mass [3] and has never been associated with eosinophilic pneumonia. The diagnosis of MAC was essential to change the course of treatment from eosinophilic pneumonia to MAC infection associated with eosinophilic pneumonia. Following therapy, a repeated CT of the chest showed interval improvement. Medical and/or surgical resection could effectively treat the lung masses caused by MAC [3].CONCLUSIONS: Physicians and pulmonologists should consider MAC in the differential diagnosis of lung mass despite primary negative workup and unusual radiologic and pathologic findings. MAC pulmonary infection can be misdiagnosed with lung cancer. Eosinophilic pneumonia, however, has never been associated with MAC.Reference #1: Johnson MM, Odell JA. Nontuberculous mycobacterial pulmonary infections. J Thorac Dis. 2014 Mar; 6(3):210-220.Reference #2: Reich JM, Johnson RE. Mycobacterium Avium Complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest. 1992 Jun; 101(6):1605-9.Reference #3: Matsuoka T, et all. MAC infection needed differential diagnosis of the recurrence after surgery for double lung cancer; report of a case. Kyobu Geka. 2007 Dec; 60(13):1200-3.DISCLOSURE: The following authors have nothing to disclose: Jimmy Doumit, Patrick Ters, Janel HartingNo Product/Research Disclosure Information.

PMID: 25334177 [PubMed – as supplied by publisher]

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Diffuse large B cell lymphoma in wiskott-Aldrich syndrome: a case report and review of literature.

Indian J Hematol Blood Transfus. 2014 Sep;30(Suppl 1):309-13

Authors: Senapati J, Devasia AJ, David S, Manipadam MT, Nair S, Jayandharan GR, George B

Abstract
Wiskott-Aldrich syndrome (WAS) is an X linked rare primary immunodeficiency syndrome with an increased propensity for infection, autoimmunity and malignancy. Here we report a male child, who was diagnosed with WAS at 1 year of age following evaluation for symptomatic thrombocytopenia and eczematous skin lesions. He presented later with lymphadenopathy, which was consistent with diffuse large B cell lymphoma on histopathology. He received 6 cycles of R-CHOP chemotherapy for the same and is presently in remission after 6 months. We review the major publications of lymphoma in WAS and discuss the pathological findings, treatment and prognosis of lymphoma in WAS.

PMID: 25332606 [PubMed]

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Ten-Year Follow-Up of a DOCK8-Deficient Child With Features of Systemic Lupus Erythematosus.

Pediatrics. 2014 Oct 20;

Authors: Jouhadi Z, Khadir K, Ailal F, Bouayad K, Nadifi S, Engelhardt KR, Grimbacher B

Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency is an innate error of adaptive immunity characterized by recurrent infections with viruses, bacteria, and fungi, typically high serum levels of immunoglobulin E, eosinophilia, and a progressive deterioration of T- and B-cell-mediated immunity. DOCK8 mutations are the second most common cause of hyper-immunoglobulin E syndromes (HIES). We report a case of DOCK8 deficiency associated with systemic lupus erythematosus (SLE). Association of SLE with HIES is very rare; to our knowledge, this is the sixth such case reported in the literature. A 10-year-old girl of consanguineous parents was followed in our clinic because of HIES since early childhood. She developed SLE with purpuric and necrotic skin lesions, diffuse arthritis, and glomerulonephritis. These autoimmune features were corroborated by the presence of antinuclear, anti-DNA, and antiphospholipid antibodies. The combination of HIES and autoimmunity makes treatment difficult, because the use of immunosuppressive drugs needed for SLE may worsen existing symptoms caused by the immunodeficiency. Our observation is the first case of association of SLE with HIES in the literature where the primary immune disease is genetically documented and labeled as DOCK8 deficiency.

PMID: 25332498 [PubMed – as supplied by publisher]

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Ex vivo assessment of cellular immune function – applications in patient care and clinical studies.

Tissue Antigens. 2014 Nov;84(5):439-449

Authors: Lindemann M

Abstract
Cellular ex vivo assays have a broad range of applications in patient care and clinical studies, especially when they are standardized and highly sensitive. As compared to analyses by molecular genetics such as the single nucleotide polymorphism (SNP) testing, they are usually more global. These assays partly mimic the in vivo situation, relying on a complex interaction of various immune cells. For example, they can be used to determine modulation of alloresponses by treatment or underlying disease, diagnose and quantify primary and secondary cellular immunodeficiency, follow-up vaccination responses, measure adoptive transfer of virus-specific immunity via hematopoietic stem cell or liver transplantation, assess allergy, antimicrobial immunity and also rare effector/memory cells directed against tumor antigens. This review will first shortly describe various cellular in vitro methods and then present applications, summarizing some own studies performed within the last 18 years.

PMID: 25329632 [PubMed – as supplied by publisher]

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[Bacillus Calmette-Guérin (BCG) disease and interleukin 12 receptor β1 deficiency: Clinical experience of two familial and one sporadic case].

Rev Chilena Infectol. 2014 Aug;31(4):444-51

Authors: Strickler A, Pérez A, Risco M, Gallo S

Abstract
BCG disease has been reported in primary and secondary immunodeficiency and as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Investigation of this syndrome has led to the identifications of a series of genetic, inherited defects in the IL-12/IFN-γ axis. MSMD-causing mutations have been found in seven autosomal and two X-linked genes. In these patients, local or disseminated vaccine BCG infections are common. We report a clinical series including two infants with left axillary adenitis ipsilateral to the site of neonatal BCG immunization; one of them member of a family with two previously reported cases and a single sporadic case. All of them were diagnosed sequentially in Puerto Montt, Chile. The aim of this report is to notify the first Chilean disseminated BCG patients without previous immunodeficiency, in whom it was possible to identify an underlying immunodeficiency, although specific tests for IL-12/IFN-γ axis was no performed in our country. Clinical suspicion and international collaboration permitted to confirm IL12-Rβ1 deficiency in 2 of 3 familial cases and a sporadic case.

PMID: 25327198 [PubMed – in process]

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A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Biol Blood Marrow Transplant. 2014 Mar;20(3):326-36

Authors: Parikh SH, Mendizabal A, Benjamin CL, Komanduri KV, Antony J, Petrovic A, Hale G, Driscoll TA, Martin PL, Page KM, Flickinger K, Moffet J, Niedzwiecki D, Kurtzberg J, Szabolcs P

Abstract
Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

PMID: 24296492 [PubMed – indexed for MEDLINE]

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