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Inflammatory bowel disease-like colitis pathology in a patient with common variable immune deficiency.

BMJ Case Rep. 2015;2015

Authors: Comunoglu N, Kara S, Kepil N

Abstract
Common variable immunodeficiency (CVID) can show variant histological patterns in the gastrointestinal system. We present a case of an 11-year-old boy who has been followed up with a diagnosis of CVID since he was 6 months old. He presented with abdominal pain and diarrhoea. Colonoscopic biopsy showed crypt destructive colitis, severe decrease and focal absence of plasma cells. Three months later he suffered from abdominal pain, vomiting and bloody diarrhoea. Macroscopic examination of small intestinal resection material revealed multiple perforation areas, ulcers. Histopathology showed mild-moderate active enteritis with aphthous ulcers, purulent peritonitis, decrease in plasma cells and loss of primary follicles in lymph nodes. Histopathological findings were consistent with inflammatory bowel disease (IBD)-like CVID. Although in 6-10% of patients with CVID an IBD-like presentation is observed, this highly aggressive form is rarely seen. We present this case because of its extraordinary presentation displaying perforating active enteropathy.

PMID: 25716035 [PubMed – in process]

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Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration.

Proc Natl Acad Sci U S A. 2015 Feb 23;

Authors: Krishnaswamy JK, Singh A, Gowthaman U, Wu R, Gorrepati P, Sales Nascimento M, Gallman A, Liu D, Rhebergen AM, Calabro S, Xu L, Ranney P, Srivastava A, Ranson M, Gorham JD, McCaw Z, Kleeberger SR, Heinz LX, Müller AC, Bennett KL, Superti-Furga G, Henao-Mejia J, Sutterwala FS, Williams A, Flavell RA, Eisenbarth SC

Abstract
Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.

PMID: 25713392 [PubMed – as supplied by publisher]

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Establishment and characterization of patient-derived tumor xenograft using gastroscopic biopsies in gastric cancer.

Sci Rep. 2015;5:8542

Authors: Zhu Y, Tian T, Li Z, Tang Z, Wang L, Wu J, Li Y, Dong B, Li Y, Li N, Zou J, Gao J, Shen L

Abstract
The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX models using gastroscopic biopsies, which are best for evaluating new drugs, are unreported. In our study, a total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo, and the mean latency period of xenografts was 65.86 ± 32.84 days (11-160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P = 0.000). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. In summary PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time, and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer.

PMID: 25712750 [PubMed – as supplied by publisher]

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Entinostat, a novel histone deacetylase inhibitor is active in B-cell lymphoma and enhances the anti-tumour activity of rituximab and chemotherapy agents.

Br J Haematol. 2015 Feb 23;

Authors: Frys S, Simons Z, Hu Q, Barth MJ, Gu JJ, Mavis C, Skitzki J, Song L, Czuczman MS, Hernandez-Ilizaliturri FJ

Abstract
Histone deacetylases (HDACs) inhibitors are active in T-cell lymphoma and are undergoing pre-clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half-life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B-cell lymphoma we studied its anti-tumour activity in several rituximab-sensitive or -resistant pre-clinical models. We demonstrated that entinostat is active in rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl-XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms-of-action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma-bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B-cell lymphoma.

PMID: 25712263 [PubMed – as supplied by publisher]

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Fusarium falciforme infection in a patient with chronic granulomatous disease: Unique long-term course of epidural abscess.

Pediatr Int. 2015 Feb;57(1):e4-6

Authors: Okura Y, Kawamura N, Okano M, Toita N, Takezaki S, Yamada M, Kobayashi I, Ariga T

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease characterized by recurrent life-threatening bacterial and fungal infections with granuloma formation. Species of the genus Fusarium are opportunistic environmental microorganisms that are rarely pathogenic in humans. We report here the first case of X-linked CGD complicated with epidural abscess caused by Fusarium falciforme infection. The abscesses extended along the dura mater for >7 years and finally resulted in fatal meningitis and cervical myelitis. Early intervention with hematopoietic stem cell transplantation should be considered, especially in patients with severe CGD, before the development of serious infectious complication.

PMID: 25711271 [PubMed – in process]

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Familial Hepatopulmonary Syndrome in Common Variable Immunodeficiency.

J Clin Immunol. 2015 Feb 24;

Authors: Holmes SN, Condliffe A, Griffiths W, Baxendale H, Kumararatne DS

Abstract
Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis.

PMID: 25708586 [PubMed – as supplied by publisher]

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Gene therapy for primary immunodeficiencies.

Clin Genet. 2015 Feb 24;

Authors: Fischer A, Hacein-Bey Abina S, Touzot F, Cavazzana M

Abstract
Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long-lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of Severe Combined Immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious.It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years.

PMID: 25708106 [PubMed – as supplied by publisher]

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Related Articles

Usefulness of neutrophil-to-lymphocyte ratio in risk stratification of patients with advanced heart failure.

Am J Cardiol. 2015 Jan 1;115(1):57-61

Authors: Benites-Zapata VA, Hernandez AV, Nagarajan V, Cauthen CA, Starling RC, Tang WH

Abstract
Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in patients with acute heart failure (HF) and neoplastic diseases. We investigated the association between NLR and mortality or cardiac transplantation in a retrospective cohort of 527 patients presented to the Cleveland Clinic for evaluation of advanced HF therapy options from 2007 to 2010. Patients were divided according to low, intermediate, and high tertiles of NLR and were followed longitudinally for time to all-cause mortality or heart transplantation (primary outcome). The median NLR was 3.9 (interquartile range 2.5 to 6.5). In univariate analysis, intermediate and highest tertiles of NLR had a higher risk than the lowest tertile for the primary outcome and all-causes mortality. Compared with the lowest tertile, there was no difference in the risk of heart transplantation for intermediate and high tertiles. In multivariate analysis, compared with the lowest tertile, the intermediate and high NLR tertiles remained significantly associated with the primary outcome (hazard ratio [HR] = 1.61, 95% confidence interval [CI] 1.10 to 2.37 and HR = 1.55, 95% CI 1.02 to 2.36, respectively) and all-cause mortality (HR = 1.83, 95% CI 1.07 to 3.14 and HR = 2.16, 95% CI 1.21 to 3.83, respectively). In conclusion, elevated NLR is associated with increased mortality or heart transplantation risk in patients with advanced HF.

PMID: 25456873 [PubMed – indexed for MEDLINE]

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Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

Immunol Rev. 2015 Mar;264(1):103-20

Authors: Boisson-Dupuis S, Bustamante J, El-Baghdadi J, Camcioglu Y, Parvaneh N, El Azbaoui S, Agader A, Hassani A, El Hafidi N, Mrani NA, Jouhadi Z, Ailal F, Najib J, Reisli I, Zamani A, Yosunkaya S, Gulle-Girit S, Yildiran A, Cipe FE, Torun SH, Metin A, Atikan BY, Hatipoglu N, Aydogmus C, Kilic SS, Dogu F, Karaca N, Aksu G, Kutukculer N, Keser-Emiroglu M, Somer A, Tanir G, Aytekin C, Adimi P, Mahdaviani SA, Mamishi S, Bousfiha A, Sanal O, Mansouri D, Casanova JL, Abel L

Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

PMID: 25703555 [PubMed – in process]

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Intravenous immunoglobulin in critically ill adults: When and what is the evidence?

J Crit Care. 2015 Feb 7;

Authors: Wang J, McQuilten ZK, Wood EM, Aubron C

Abstract
Intravenous immunoglobulin (IVIg) use is growing dramatically internationally due to the increasing numbers of acute and chronic conditions that may benefit from IVIg. Patients with conditions that may benefit from IVIg might require intensive care unit (ICU) admission, supporting the need to review IVIg use in the critical care setting. The most common clinical indications for IVIg in adults that may require ICU admission and are commonly supported under clinical practice guidelines are Guillain-Barré syndrome, myasthenia gravis and Lambert-Eaton myasthenic syndrome, inflammatory myopathies, and primary or secondary immunodeficiency diseases complicated by severe bacterial sepsis. Other emerging indications include necrotizing fasciitis, toxic epidermal necrolysis/Stevens-Johnson syndrome, and toxic shock syndrome. The evidence for IVIg use in sepsis and septic shock remains controversial and insufficient to recommend its routine use. Intravenous immunoglobulin is expensive and also carries risks of adverse effects, including common and benign infusion-related reactions, as well as relatively rare and more serious problems, such as thromboembolic events, renal failure, and aseptic meningitis. In this article, we review the literature on conditions requiring ICU admission and IVIg, and we classify them as supported, emerging, or unsupported indications based on the available evidence and guidelines for clinical use of IVIg.

PMID: 25702845 [PubMed – as supplied by publisher]

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