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Lymphomatoid granulomatosis associated with azathioprine therapy in Crohn disease.

BMC Gastroenterol. 2014;14:127

Authors: Connors W, Griffiths C, Patel J, Belletrutti PJ

Abstract
BACKGROUND: Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disorder. It most often occurs in patients with immunodeficiency and the clinical course ranges from indolent behavior to that of an aggressive malignancy. Pulmonary, central nervous system and dermatological manifestations are most common. To our knowledge this is the first reported case of LYG related to azathioprine therapy in Crohn disease.
CASE PRESENTATION: A twenty-six year old Caucasian woman with colonic Crohn disease on maintenance azathioprine therapy presented with right upper quadrant pain and fever. Diagnostic imaging revealed extensive liver, pulmonary and cerebral lesions. A diagnosis of LYG was made based on the pattern of organ involvement and the immunohistochemical features on liver and lung biopsy.
CONCLUSIONS: Thiopurine therapy for inflammatory bowel disease is associated with an increased incidence of lymphoproliferative disorders. This report highlights the diagnostic challenges associated with LYG. As long-term thiopurine therapy remains central to the management of inflammatory bowel diseases it is essential that both patients and clinicians are aware of this potential adverse outcome.

PMID: 25022612 [PubMed – indexed for MEDLINE]

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Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients.

Haematologica. 2014 Jun;99(6):1101-6

Authors: Compagno N, Cinetto F, Semenzato G, Agostini C

Abstract
Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders.

PMID: 24682509 [PubMed – indexed for MEDLINE]

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NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation.

Front Pharmacol. 2015;6:51

Authors: Alhajjat AM, Lee AE, Strong BS, Shaaban AF

Abstract
The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.

PMID: 25852555 [PubMed]

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Compound Heterozygous Mutation of Rag1 Leading to Omenn Syndrome.

PLoS One. 2015;10(4):e0121489

Authors: Matthews AG, Briggs CE, Yamanaka K, Small TN, Mooster JL, Bonilla FA, Oettinger MA, Butte MJ

Abstract
Omenn syndrome is a primary immunodeficiency disorder, featuring susceptibility to infections and autoreactive T cells and resulting from defective genomic rearrangement of genes for the T cell and B cell receptors. The most frequent etiologies are hypomorphic mutations in “non-core” regions of the Rag1 or Rag2 genes, the protein products of which are critical members of the cellular apparatus for V(D)J recombination. In this report, we describe an infant with Omenn syndrome with a previously unreported termination mutation (p.R142*) in Rag1 on one allele and a partially characterized substitution mutation (p.V779M) in a “core” region of the other Rag1 allele. Using a cellular recombination assay, we found that while the p.R142* mutation completely abolished V(D)J recombination activity, the p.V779M mutation conferred a severe, but not total, loss of V(D)J recombination activity. The recombination defect of the V779 mutant was not due to overall misfolding of Rag1, however, as this mutant supported wild-type levels of V(D)J cleavage. These findings provide insight into the role of this poorly understood region of Rag1 and support the role of Rag1 in a post-cleavage stage of recombination.

PMID: 25849362 [PubMed – as supplied by publisher]

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PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.

J Allergy Clin Immunol. 2015 Apr 1;

Authors: Mathieu AL, Verronese E, Rice GI, Fouyssac F, Bertrand Y, Picard C, Chansel M, Walter JE, Notarangelo LD, Butte MJ, Nadeau KC, Csomos K, Chen DJ, Chen K, Delgado A, Rigal C, Bardin C, Schuetz C, Moshous D, Reumaux H, Plenat F, Phan A, Zabot MT, Balme B, Viel S, Bienvenu J, Cochat P, van der Burg M, Caux C, Kemp EH, Rouvet I, Malcus C, Méritet JF, Lim A, Crow YJ, Fabien N, Ménétrier-Caux C, De Villartay JP, Walzer T, Belot A

Abstract
BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.
OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.
METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.
RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.
CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

PMID: 25842288 [PubMed – as supplied by publisher]

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[Adenosine deaminase 1 deficiency, an inborn error of metabolism underlying a severe form of combined immunodeficiency].

Arch Pediatr. 2015 Apr 1;

Authors: Giraud A, Lavocat MP, Cremillieux C, Patural H, Thouvenin S, David A, Perignon JL, Stephan JL

Abstract
Severe combined immune deficiencies (SCIDs) are a heterogeneous group of severe cellular immunodeficiencies. Early diagnosis is essential to allow adapted care before life-threatening systemic infections or complications associated with live vaccines. Adenosine deaminase 1 deficiency (ADA1) is an inborn error of metabolism leading to severe lymphopenia and characteristic bone lesions. Herein, we present the typical case of a child in whom ADA SCID was diagnosed at 2months of life, revealed by lung involvement and extreme lymphopenia. Immune restoration in terms of peripheral lymphocyte count with enzyme replacement therapy, namely pegylated bovine ADA, is satisfactory so far. The search for a compatible donor is underway. Correcting the genetic defect by gene transfer is also being considered. The phenotype of this very rare condition is described. A severe peripheral lymphopenia in a young child is a finding of utmost importance for the diagnosis of a primary cellular immunodeficiency.

PMID: 25842197 [PubMed – as supplied by publisher]

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Systematic neonatal screening for severe combined immunodeficiency and severe T-cell lymphopenia: Analysis of cost-effectiveness based on French real field data.

J Allergy Clin Immunol. 2015 Apr 1;

Authors: Clément MC, Mahlaoui N, Mignot C, Le Bihan C, Rabetrano H, Hoang L, Neven B, Moshous D, Cavazzana M, Blanche S, Fischer A, Audrain M, Durand-Zaleski I

Abstract
BACKGROUND: The inclusion of severe combined immunodeficiency (SCID) in a Europe-wide screening program is currently debated.
OBJECTIVE: In making a case for inclusion in the French newborn screening program, we explored the costs incurred and potentially saved by early management of SCID.
METHODS: For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, ≤3 vs >3 months, respectively).
RESULTS: The unit cost of the test varied between €4.69 and €6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were €195,776 (interquartile range, €165,884-€257,160) versus €86,179 (range, €59,014-€272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome.
CONCLUSION: Early detection of SCID could reduce the cost of treatment by €50,000-100,000 per case. Assuming a €5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective.

PMID: 25840725 [PubMed – as supplied by publisher]

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Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.

J Allergy Clin Immunol. 2015 Mar 31;

Authors: Mitsui-Sekinaka K, Imai K, Sato H, Tomizawa D, Kajiwara M, Nagasawa M, Morio T, Nonoyama S

Abstract
BACKGROUND: The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT).
OBJECTIVE: We sought to determine the clinical features and factors affecting outcomes in patients with XHIM.
METHODS: We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT.
RESULTS: The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P = .0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15).
CONCLUSION: On the basis of these results, we concluded that HSCT improved the outcomes of patients with XHIM and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years.

PMID: 25840720 [PubMed – as supplied by publisher]

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Identification of potential therapeutic target genes, key miRNAs and mechanisms in acute myeloid leukemia based on bioinformatics analysis.

Med Oncol. 2015 May;32(5):572

Authors: Zhao Y, Zhang X, Zhao Y, Kong D, Qin F, Sun J, Dong Y

Abstract
The study was aimed to explore the underlying mechanisms and identify the potential target genes and key miRNAs for acute myeloid leukemia (AML) treatment by bioinformatics analysis. The microarray data of GSE9476 were downloaded from Gene Expression Omnibus database. A total of 64 samples, including 26 AML and 38 normal samples, were used to identify differentially expressed genes (DEGs) between AML and normal samples. The functional enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by Cytoscape software. Besides, the target miRNAs for DEGs were identified. Totally, 323 DEGs were identified, including 87 up-regulated and 236 down-regulated genes. Not only up-regulated genes but also down-regulated genes were related to hematopoietic-related functions. Besides, down-regulated genes were also enriched in primary immunodeficiency pathway. Tumor necrosis factor (TNF), interleukin 7 receptor (IL7R), lymphocyte-specific protein tyrosine kinase (LCK), CD79a molecule and immunoglobulin-associated alpha (CD79A) were identified in these functions. TNF and LCK were hub nodes in PPI networks. miR-124 and miR-181 were important miRNAs in this study. The hematopoietic-related functions and primary immunodeficiency pathway may be associated with AML development. Genes, such as TNF, IL7R, LCK and CD79A, may be potential therapeutic target genes for AML, and miR-124 and miR-181 may be key miRNAs in AML development.

PMID: 25832863 [PubMed – as supplied by publisher]

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