Research

MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane.

J Clin Invest. 2016 Oct 4;:

Authors: Kurz AR, Pruenster M, Rohwedder I, Ramadass M, Schäfer K, Harrison U, Gouveia G, Nussbaum C, Immler R, Wiessner JR, Margraf A, Lim DS, Walzog B, Dietzel S, Moser M, Klein C, Vestweber D, Haas R, Catz SD, Sperandio M

Abstract
Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1-/-) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane. Mst1-/- neutrophils also failed to extravasate from gastric submucosal vessels in a murine model of Helicobacter pylori infection. Mechanistically, we observed defective translocation of VLA-3, VLA-6, and neutrophil elastase from intracellular vesicles to the surface of Mst1-/- neutrophils, indicating that MST1 is required for this crucial step in neutrophil transmigration. Furthermore, we found that MST1 associates with the Rab27 effector protein synaptotagmin-like protein 1 (JFC1, encoded by Sytl1 in mice), but not Munc13-4, thereby regulating the trafficking of Rab27-positive vesicles to the cellular membrane. Together, these findings highlight a role for MST1 in vesicle trafficking and extravasation in neutrophils, providing an additional mechanistic explanation for the severe immune defect observed in patients with MST1 deficiency.

PMID: 27701149 [PubMed – as supplied by publisher]

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Long term outcomes of 176 patients with X-linked hyper IgM syndrome treated with or without hematopoietic cell transplantation.

J Allergy Clin Immunol. 2016 Sep 30;:

Authors: de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla F, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Espanol T, Shcherbina A, Hanson C, Litzman J, Routes J, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, Gonzalez-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Grunebaum E, Dorsey M, Costa Carvalho BT, Condino-Neto A, Cunningham-Rundles C, Knutsen AP, Sleasman J, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, Roifman C

Abstract
BACKGROUND: X-linked hyper IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared to normal individuals. Hematopoietic cell transplant (HCT) has been considered a curative therapy, but the procedure has inherent complications, and may not be available for all patients.
OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM in order to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality, and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT.
METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and the Primary Immune Deficiency Treatment Consortium. Data was collected using a REDCap web application. Survival from time of diagnosis or transplant was estimated using the Kaplan-Meier method, compared using log-rank tests, and modeled using proportional hazards regression.
RESULTS: Twenty-eight clinical sites provided data on 189 patients diagnosed with XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven patients (38%) received HCT. The average follow-up time was 8.5 ± 7.2 years (range: 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (p=0.671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly < 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival [HR (95% CL): 4.9 (2.2, 10.8), p<0.001]. Among survivors, those treated with HCT had higher median Lansky and Karnofsky scores than those treated without HCT (p<0.001). Among patients receiving HCT, 27 (40%) developed graft versus host disease, and most deaths occurred within 1 year of transplant.
CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years 1964-2013. However, survivors treated with HCT experienced somewhat greater well-being and hazards associated with HCT decreased, reaching levels of significantly less risk, in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival Optimism remains guarded as additional evidence accumulates.

PMID: 27697500 [PubMed – as supplied by publisher]

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Primary Immunodeficiency Diseases in Oman: 10-Year Experience in a Tertiary Care Hospital.

J Clin Immunol. 2016 Oct 3;:

Authors: Al-Tamemi S, Naseem SU, Al-Siyabi N, El-Nour I, Al-Rawas A, Dennison D

Abstract
PURPOSE: Primary immunodeficiency (PID) diseases are rare, complex medical disorders that often are overlooked in clinical settings. There are emerging reports of PID from Middle Eastern populations. This study describes the features of PID patients in a tertiary care setting in Oman and compares them with regional and worldwide reports.
METHOD: Sultan Qaboos University Hospital (SQUH) is an academic tertiary care-level hospital for specialized healthcare, including PID patients. At the time of diagnosis, patients’ sociodemographics, clinical features, laboratory investigations, and management were entered in electronic form. This study included patients seen between August 2005 and July 2015.
RESULTS: One hundred forty patients were registered with a minimum estimated population prevalence of 7.0/100,000. The male/female ratio was 1.6:1, the median age of onset of symptoms was 8 months, and diagnosis was 21 months with a delay of 13 months. Family history was positive in 44 %, consanguinity was present in 76 %, death of a previous sibling was present in 36 %, and there was an overall mortality in 18 %, with an 85 % probability of survival 10 years following diagnosis. The most common type of immunodeficiency was phagocytic disorders (35.0 %), followed by predominantly antibody disorders (20.7 %), combined immunodeficiency (17.8 %), other well-defined PID syndromes (15.0 %), immune dysregulation syndromes (3.5 %), complement deficiencies (3.5 %), and unclassified immunodeficiency (4.2 %). The commonest presenting infection was pneumonia (47.1 %).
CONCLUSION: PID is not a rare condition in Oman. The prevalence is in concordance with reports from the region but higher than in Western populations. The findings of the current study would help to improve the awareness and management of, and policy making for PID.

PMID: 27699572 [PubMed – as supplied by publisher]

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Physical health conditions and quality of life in adults with primary immune deficiency diagnosed during childhood: a CEREDIH study.

J Allergy Clin Immunol. 2016 Sep 30;:

Authors: Barlogis V, Mahlaoui N, Auquier P, Pellier I, Fouyssac F, Vercasson C, Allouche M, De Azevedo CB, Suarez F, Moshous D, Neven B, Pasquet M, Jeziorski E, Aladjidi N, Schleinitz N, Thomas C, Gandemer V, Mazingue F, Lutz P, Hermine O, Picard C, Blanche S, Michel G, Fischer A

Abstract
BACKGROUND: Most children with primary immune deficiency (PID) now reach adulthood. However, few studies have evaluated their health status and health related quality of life (HRQoL).
OBJECTIVE: To investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the F-CILC (French Childhood Immune deficiency Long-term Cohort). The data collected was used to assess the physical health condition of patients who reached adulthood and the impact on their quality of life.
METHODS: Patients were asked to complete health status questionnaires. A severity score (grade1 [“mild”] to grade 4 [“life-threatening”]) was assigned to each health condition. The HRQoL of patients was compared to age- and sex-matched French normal values using the SF36 HRQoL questionnaire.
RESULTS: Among 329 participants, the mean age at evaluation was 27.6 years with a 21-year mean follow-up after diagnosis, 43% reported at least one grade 4 health condition and 86% reported at least one grade 3 (severe) or 4 health condition. Twenty-five patients (7.6%) had been treated for cancer. Compared with the French norms, adults with PID scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains.
CONCLUSION: Adults with PID diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population.

PMID: 27697497 [PubMed – as supplied by publisher]

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Microbicidal activity measured by flow cytometry: optimization and standardization for detection of primary and functional deficiencies.

J Immunol Methods. 2016 Sep 29;:

Authors: Jeraiby M, Sidi Yahya K, Depince-Berger, Lambert C

Abstract
Microbicidal activity is related to the production of reactive oxygen species (ROS) that can be measured by Flow-Cytometry using Rhodamine 123 (R123). Few assays have been proposed to measure ROS production, usually on heparinized samples but none of them is standardized. Here we propose to improve the test by selecting polymorphonuclears (PMN) and monocytes, labelled and activated in one step to keep the test short, and to standardize the process even between different systems (i.e. Navios™ and FACSCanto™) using Fluorescence Intensity Target Setting (“FITS”). We applied this test on 15 patients without inflammation, 19 patients from an intensive care unit (ICU) and 11 healthy volunteers.
RESULTS: provided calcium restitution, we show that the test can be performed on EDTA that is a better sample preservative. The results were highly correlated between instruments (r(2)=0,898). PMN CD16 (and not CD14) expression was altered under stimulation with E. coli (MdFI =239.3±93.5) or PMA (139.7±76.8) as compared to resting sample (307.6±145.1). RH123 was strongly and homogeneously induced by PMA (14.2±6.6) and more heterogeneously by E coli (MdFI 21.9±23.4) as compared to unstimulated PNN (0.9±1.3, p<0.0001). The test useful for genetic disorders but is also for secondary deficiencies as observed in ICU (E coli RH123 MFI=10.5±11.1 patients vs 30.1±26.5 in healthy donors). In ICU, CD16 expression was already altered on unstimulated samples (MdFI =197.4±131.2 vs 418, 2±81.3 in healthy donors; p≤0.0001). Bacterial stimulation was dependent of the complement that partly explains deficiency to bacterial stimulus in ICU patients.

PMID: 27693641 [PubMed – as supplied by publisher]

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[Primary immunodeficiencies in seriously ill children: Report of 3 clinical cases].

Rev Chil Pediatr. 2016 Sep 27;:

Authors: Yañez L, Lama P, Rivacoba C, Zamorano J, Marinovic MA

Abstract
Primary immunodeficiency diseases (PID) are congenital disorders secondary to an impaired immune response. Infections, autoimmune disorders, atopy, and lymphoproliferative syndromes are commonly associated with this disorder.
OBJECTIVE: To present and discuss 3 infants diagnosed with PID.
CLINICAL CASES: The cases are presented of three patients with PID diagnosed during their first admission to a Paediatric Intensive Critical Care Unit. The first patient, a 4-month-old infant affected by a severe pneumonia, and was diagnosed as a Severe Combined Immunodeficiency Disease. The second patient was an 8-month-old infant with Candida lusitaniae mesenteric adenitis, and diagnosed with a Chronic Granulomatous Disease. The last patient, a 6-month-old infant presented with ecthyma gangrenosum and X-linked agammaglobulinaemia.
CONCLUSION: PID should be suspected when an infectious disease does not responde to the appropriate therapy within the expected period. An update of each disease is presented.

PMID: 27692490 [PubMed – as supplied by publisher]

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Treatment with Hizentra in patients with primary and secondary immunodeficiencies: a real-life, non-interventional trial.

BMC Immunol. 2016;17(1):34

Authors: Viallard JF, Agape P, Barlogis V, Cozon G, Faure C, Fouyssac F, Gaud C, Gourin MP, Hamidou M, Hoarau C, Husseini F, Ojeda-Uribe M, Pavic M, Pellier I, Perlat A, Schleinitz N, Slama B

Abstract
BACKGROUND: Although Hizentra is indicated for immunoglobulin replacement therapy in patients with primary and secondary immunodeficiencies, phase III trials have focused on patients with primary immunodeficiencies. In this 9-month, real-life, prospective, non-interventional, longitudinal, multicenter study of patients with primary and secondary immunodeficiencies in France, treatment modalities (primary endpoint), efficacy, safety, tolerability, quality of life, and treatment satisfaction were evaluated using descriptive statistics.
RESULTS: Starting in January 2012, 117 patients were enrolled (99 adults, 18 children). Secondary immunodeficiencies were present in 48.7 % of patients. At follow-up, injections were administered every 7 days in 92.2 % of patients. Nine patients (7.8 %) were taking Hizentra every 10-14 days. The median dose of Hizentra administered was 0.1 g/kg/injection. Fifty-six patients were administered doses <0.1 g/kg/injection and 13 patients were administered doses >0.2 g/kg/injection. Mean trough IgG titers were 9.0 ± 3.3 g/L (median 8.3 g/L). The mean yearly rate of infection was 1.2 ± 1.9. Mean scores on the Short Form-36 physical and mental component summaries were 46.3 ± 10.0 and 46.6 ± 9.3, respectively. Scores on the Treatment Satisfaction Questionnaire for Medication ranged from 69.9 ± 19.9 to 88.3 ± 21.2 depending on the domain. Treatment with Hizentra was well tolerated. No single drug-related systemic reaction occurred in more than one patient and few local reactions were reported (n = 5).
CONCLUSIONS: Under real-life conditions and in a cohort that included patients with primary and secondary immunodeficiencies, treatment with Hizentra was effective and well tolerated and patients were generally satisfied with the treatment.

PMID: 27687879 [PubMed – as supplied by publisher]

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B-lymphoblastic leukemia in a patient with chronic lymphocytic leukemia: Sequential development of biclonal B-cell neoplasms over a 23-year period in a single individual.

Pathol Res Pract. 2016 Sep 22;

Authors: Wu B, Ingersoll K, Rehder C, Wang E

Abstract
Chronic lymphocytic leukemia (CLL) is an indolent mature B-cell neoplasm. During a prolonged disease course, a secondary B-cell neoplasm may arise in some patients, the most common example being the clonal evolution of CLL to diffuse large B-cell lymphoma, which is referred to as Richter transformation. Secondary de novo mature B-cell neoplasms arising in a patient with pre-existing CLL have been described; however, B-lymphoblastic leukemia (B-ALL) developing in untreated CLL is rare, and its clonal relationship to the primary neoplasm has been an interesting issue. Herein, we report an unusual case of the sequential development of CLL and B-ALL over a 23-year period in a 64-year-old male. Examination of the peripheral blood smear and bone marrow biopsy demonstrated dual neoplastic populations: small mature lymphocytes consistent with those seen in CLL and a population of blasts that were confirmed to be B-ALL by immunophenotyping. The biclonality of these two B-cell neoplasms was supported by cytogenetic studies. While an intrinsic immunodeficiency in patients with CLL may predispose them to the development of other malignancies, the pathogenesis of this unusual phenomenon remains to be further investigated.

PMID: 27688087 [PubMed – as supplied by publisher]

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Atypical Manifestation of LPS-Responsive Beige-Like Anchor Deficiency Syndrome as an Autoimmune Endocrine Disorder without Enteropathy and Immunodeficiency.

Front Pediatr. 2016;4:98

Authors: Bakhtiar S, Ruemmele F, Charbit-Henrion F, Lévy E, Rieux-Laucat F, Cerf-Bensussan N, Bader P, Paetow U

Abstract
Monogenic primary immunodeficiency syndromes can affect one or more endocrine organs by autoimmunity during childhood. Clinical manifestations include type 1 diabetes mellitus, hypothyroidism, adrenal insufficiency, and vitiligo. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency was described in 2012 as a novel primary immunodeficiency, predominantly causing immune dysregulation and early onset enteropathy. We describe the heterogeneous clinical course of LRBA deficiency in two siblings, mimicking an autoimmune polyendocrine disorder in one of them in presence of the same underlying genetic mutation. The third child of consanguineous Egyptian parents (Patient 1) presented at 6 months of age with intractable enteropathy and failure to thrive. Later on, he developed symptoms of adrenal insufficiency, autoimmune hemolytic anemia, thrombocytopenia, and infectious complications due to immunosuppressive treatment. The severe enteropathy was non-responsive to the standard treatment and led to death at the age of 22 years. His younger sister (Patient 2) presented at the age of 12 to the endocrinology department with decompensated hypothyroidism, perioral vitiligo, delayed pubertal development, and growth failure without enteropathy and immunodeficiency. Using whole exome sequencing, we identified a homozygous frameshift mutation (c.6862delT, p.Y2288MfsX29) in the LRBA gene in both siblings. To our knowledge, our patient (Patient 2) is the first case of LRBA deficiency described with predominant endocrine phenotype without immunodeficiency and enteropathy. LRBA deficiency should be considered as underlying disease in pediatric patients presenting with autoimmune endocrine symptoms. The same genetic mutation can manifest with a broad phenotypic spectrum without genotype-phenotype correlation. The awareness for disease symptoms among non-immunologists might be a key to early diagnosis. Further functional studies in LRBA deficiency are necessary to provide detailed information on the origin of autoimmunity in order to develop reliable predictive biomarkers for affected patients.

PMID: 27683652 [PubMed]

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