Research

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

February 26, 2015 By Manish Butte

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]

Gene therapy for primary immunodeficiencies.

February 25, 2015 By Manish Butte

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]

Familial Hepatopulmonary Syndrome in Common Variable Immunodeficiency.

February 25, 2015 By Manish Butte

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]

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

February 25, 2015 By Manish Butte

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]

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

February 24, 2015 By Manish Butte

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]

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood.

February 24, 2015 By Manish Butte

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]

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.

February 24, 2015 By Manish Butte

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.

J Allergy Clin Immunol. 2015 Feb 19;

Authors: Lanternier F, Mahdaviani SA, Barbati E, Chaussade H, Koumar Y, Levy R, Denis B, Brunel AS, Martin S, Loop M, Peeters J, de Selys A, Vanclaire J, Vermylen C, Nassogne MC, Chatzis O, Liu L, Migaud M, Pedergnana V, Desoubeaux G, Jouvion G, Chretien F, Darazam IA, Schäffer AA, Netea MG, De Bruycker JJ, Bernard L, Reynes J, Amazrine N, Abel L, Van der Linden D, Harrison T, Picard C, Lortholary O, Mansouri D, Casanova JL, Puel A

Abstract
BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained.
OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only.
METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients.
RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients’ monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis).
CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

PMID: 25702837 [PubMed – as supplied by publisher]

[Hyper IgE syndrome: three case reports].

February 24, 2015 By Manish Butte

[Hyper IgE syndrome: three case reports].

Rev Chil Pediatr. 2014 Jun;85(3):328-36

Authors: Tagle C MT, Melys G A, Castillo M A, Norambuena R X, Quezada L A

Abstract
INTRODUCTION: Autosomal dominant Hyper IgE syndrome (HIES-AD) is a primary immunodeficiency associated with connective tissue, skeletal, vascular and brain disorders. The pathogenesis of immune deficiency lies in an alteration of Th17 cells which explains the special susceptibility of these patients to S. aureus and Candida infections.
OBJECTIVE: To describe three children diagnosed with hyper IgE syndrome and conduct a study on the subject, with special focus on the dominant form of the disease.
CASE REPORTS: 3 children with HIES-AD (2 males and one female) with eczema since birth, skin, ear, lung, and lymph node infections, and serum IgE levels over 2,000 IU/ml and eosinophilia values, treated with antibiotics and topically, and 7 year follow-up.
CONCLUSIONS: It is a rare condition that requires a high index of suspicion and early management of infections. One of its main diagnoses is atopic syndrome with recurrent infections but both conditions differ in context, response and resolution against infections and lack of other phenotypic characteristics.

PMID: 25697250 [PubMed – in process]

Detection of impaired IgG antibody formation facilitates the decision on early immunoglobulin replacement in hypogammaglobulinemic patients.

February 24, 2015 By Manish Butte

Detection of impaired IgG antibody formation facilitates the decision on early immunoglobulin replacement in hypogammaglobulinemic patients.

Front Immunol. 2015;6:32

Authors: Wolf HM, Thon V, Litzman J, Eibl MM

Abstract
Hypogammaglobulinemia (serum IgG lower than 2 SD below the age-matched mean) and clinical symptoms such as increased susceptibility to infection, autoimmune manifestations, granulomatous disease, and unexplained polyclonal lymphoproliferation are considered to be diagnostic hallmarks in patients with common variable immunodeficiency (CVID), the most frequent clinically severe primary immunodeficiency syndrome. In the present study, we investigated patients with hypogammaglobulinemia and no clinical or immunological signs of defective cell-mediated immunity and differentiated two groups on the basis of their IgG antibody formation capacity against a variety of different antigens (bacterial toxins, polysaccharide antigens, viral antigens). Patients with hypogammaglobulinemia and intact antibody production (HIAP) displayed no or only mild susceptibility to infections, while CVID patients showed marked susceptibility to bacterial infections that normalized following initiation of IVIG or subcutaneous immunoglobulin replacement therapy. There was a substantial overlap in IgG serum levels between the asymptomatic HIAP group and the CVID patients examined before immunoglobulin treatment. HIAP patients showed normal levels of switched B-memory cells (CD19(+)CD27(+)IgD(-)), while both decreased and normal levels of switched B-memory cells could be found in CVID patients. IgG antibody response to a primary antigen, tick-borne encephalitis virus (TBEV), was defective in CVID patients, thus confirming their substantial defect in IgG antibody production. Defective IgG antibody production against multiple antigens could also be demonstrated in an adult patient with recurrent infections but normal IgG levels. To facilitate early treatment before recurrent infections may lead to organ damage, the antibody formation capacity should be examined in hypogammaglobulinemic patients and the decision to treat should be based on the finding of impaired IgG antibody production.

PMID: 25699049 [PubMed]

Unexpected reactions of the anti-IgA antibody particle gel immunoassay.

February 24, 2015 By Manish Butte

Unexpected reactions of the anti-IgA antibody particle gel immunoassay.

Transfus Med. 2014 Feb;24(1):55-7

Authors: Strobel E, von Meyer A

Abstract
BACKGROUND: The cause of allergic transfusion reactions remains often unknown, but in rare cases anti-immunoglobulin A (IgA) antibodies in patients with IgA-deficiency can be found. We report on the use of the DiaMed particle gel immunoassay (PaGIA) for detection of anti-IgA antibodies in patients with allergic transfusion reactions.
METHODS: The examination of the suspected adverse reactions included an anti-IgA antibody test (ID-PaGIA Anti-IgA antibody test; DiaMed GmbH, Cressier , Switzerland) and measurement of IgA concentration in the patient’s plasma. In the case of a discrepancy IgA subclasses were examined and neutralization of the anti-IgA antibodies by pure IgA was performed.
RESULTS: Of 142 patients tested for IgA concentration and anti-IgA antibodies, 8 gave positive results for the anti-IgA antibody test. In seven of these cases (4.9% of the patients tested) IgA levels were found to be normal, and in four of five so tested, the positive result could not be neutralized with purified IgA. Only one patient had confirmed IgA deficiency with anti-IgA antibodies that were neutralized by addition of purified IgA.
CONCLUSION: Cause and clinical relevance of a positive reaction of the anti-IgA antibody test in patients with normal total IgA and normal IgA subclasses remains unknown. Because of the high false positive rate we do not recommend this test as a screening test for anti-IgA antibodies when evaluating allergic transfusion reactions, but instead recommend measurement of total IgA in patient’s plasma or serum as a primary screen for IgA deficiency with antibodies as a cause of allergic transfusion reaction.

PMID: 24325384 [PubMed – indexed for MEDLINE]