Research

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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Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings.

J Clin Immunol. 2015 Mar 27;

Authors: Niemela J, Kuehn HS, Kelly C, Zhang M, Davies J, Melendez J, Dreiling J, Kleiner D, Calvo K, Oliveira JB, Rosenzweig SD

Abstract
Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients.

PMID: 25814141 [PubMed – as supplied by publisher]

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Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency.

Dig Dis Sci. 2015 Mar 28;

Authors: Lougaris V, Ravelli A, Villanacci V, Salemme M, Soresina A, Fuoti M, Lanzarotto F, Lanzini A, Plebani A, Bassotti G

Abstract
BACKGROUND: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients.
AIM: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients.
METHODS: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view.
RESULTS: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age.
CONCLUSIONS: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients.

PMID: 25821101 [PubMed – as supplied by publisher]

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[Interstitial lung diseases and granulomatoses associated common variable immunodeficiency.]

Vnitr Lek. 2015;61(2):119-124

Authors: Doubková M, Moulis M, Skřičková J

Abstract
Common variable immunodeficiency disorder belongs to the most common primary human immunodeficiencies and it is characterized by primary defective immunoglobulin production. Hypogammaglobulinemia manifests in every age, usually in adult people. There is no gender predisposition. The prevalence is 1 : 25 000-1 : 50 000. The ethiopathogenesis of the majority of CVIDs is unknown. The main clinical respiratory symptoms include recurrent respiratory infects, especially bacterial etiology, sinusitis, bronchitis, pneumonia, leading to bronchiectasis and lung fibrosis. Interstitial lung fibrosis and granulomatosis often manifest at diagnosis of CVID and they are negative prognostic factors of the disease.Key words: common variable immunodeficiency – granulomatosis – interstitial lung fibrosis.

PMID: 25813254 [PubMed – as supplied by publisher]

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Related Articles

Keratinocyte antiviral response to Poly(dA:dT) stimulation and papillomavirus infection in a canine model of X-linked severe combined immunodeficiency.

PLoS One. 2014;9(7):e102033

Authors: Luff JA, Yuan H, Kennedy D, Schlegel R, Felsburg P, Moore PF

Abstract
X-linked severe combined immunodeficiency (XSCID) is caused by a genetic mutation within the common gamma chain (γc), an essential component of the cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT) to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV) infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT) and canine papillomavirus-2 (CPV-2) upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG) on poly(dA:dT) stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT) as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients.

PMID: 25025687 [PubMed – indexed for MEDLINE]

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