Research

Primary Immune Deficiency Treatment Consortium (PIDTC) update.

J Allergy Clin Immunol. 2016 Apr 22;

Authors: Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Shearer WT, Burroughs LM, Torgerson TR, Decaluwe H, Haddad E, workshop participants

Abstract
The Primary Immune Deficiency Treatment Consortium (PIDTC) is a collaboration of 41 North American centers studying therapy for rare primary immune deficiency diseases (PIDs), including severe combined immune deficiency (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD). An additional 3 European centers have partnered with the PIDTC to study CGD. Natural history protocols of the PIDTC analyze outcomes of treatment for rare PIDs in multicenter longitudinal retrospective, prospective, and cross-sectional studies. Since 2009, participating centers have enrolled more than 800 subjects on PIDTC protocols for SCID, and enrollment in the studies on WAS and CGD is underway. Four pilot projects have been funded, and 12 junior investigators have received fellowship awards. Important publications of the consortium describe the outcomes of hematopoietic cell transplantation for SCID during 2000-2009, diagnostic criteria for SCID, and the pilot project of newborn screening for SCID in the Navajo Nation. The PIDTC Annual Scientific Workshops provide an opportunity to strengthen collaborations with junior investigators, patient advocacy groups, and international colleagues. Funded by the National Institute of Allergy and Infectious Diseases and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, the PIDTC has recently received renewal for another 5 years. Here we review accomplishments of the group, projects underway, highlights of recent workshops, and challenges for the future.

PMID: 27262745 [PubMed – as supplied by publisher]

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Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

J Med Genet. 2016 Jun 1;

Authors: Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F

Abstract
Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2-10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2 With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype.

PMID: 27250108 [PubMed – as supplied by publisher]

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Development of a Low-Cost Stem-Loop Real-Time Quantification PCR Technique for EBV miRNA Expression Analysis.

Mol Biotechnol. 2016 May 31;

Authors: Bergallo M, Merlino C, Montin D, Galliano I, Gambarino S, Mareschi K, Fagioli F, Montanari P, Martino S, Tovo PA

Abstract
MicroRNAs (miRNAs) are short, single stranded, non-coding RNA molecules. They are produced by many different species and are key regulators of several physiological processes. miRNAs are also encoded by the genomes of multiple virus families, such as herpesvirus family. In particular, miRNAs from Epstein Barr virus were found at high concentrations in different associated pathologies, such as Burkitt’s lymphoma, Hodgkin disease, and nasopharyngeal carcinoma. Thanks to their stability, these molecules could possibly serve as biomarkers for EBV-associated diseases. In this study, a stem-loop real-time PCR for miR-BART2-5p, miR-BART15, and miR-BART22 EBV miRNAs detection and quantification has been developed. Evaluation of these miRNAs in 31 serum samples (12 from patients affected by primary immunodeficiency, 9 from X-linked agammaglobulinemia and 10 from healthy subjects) has been carried out. The amplification performance showed a wide dynamic range (10(8)-10(2) copies/reaction) and sensibility equal to 10(2) copies/reaction for all the target tested. Serum samples analysis, on the other hand, showed a statistical significant higher level of miR-BART22 in primary immunodeficiency patients (P = 0.0001) compared to other groups and targets. The results confirmed the potential use of this assay as a tool for monitoring EBV-associated disease and for miRNAs expression profile analysis.

PMID: 27246439 [PubMed – as supplied by publisher]

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Granulomatous-Lymphocytic Interstitial Lung Disease as the First Manifestation of Common Variable Immunodeficiency.

Clin Respir J. 2016 May 31;

Authors: Tashtoush B, Memarpour R, Ramirez J, Bejarano P, Mehta J

Abstract
Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, which is characterized by reduced serum immunoglobulin levels and B-lymphocyte dysfunction. There are many clinical manifestations of this disease, the most common of which are recurrent respiratory tract infections. Among the most recently recognized autoimmune manifestation of CVID is a disease described as granulomatous-lymphocytic interstitial lung disease (GLILD), where CVID coexists with a small airway lymphoproliferative disorder, mimicking follicular bronchiolitis, or lymphocytic interstitial pneumonitis (LIP) on histology specimens. We herein describe the clinical and radiological features of GLILD in a 55-year-old woman where the diagnosis of CVID was actively pursued and eventually confirmed after her lung biopsy showed characteristic features of GLILD. The patient had dramatic response to treatment with IVIG and corticosteroids for 3 months followed by Mycophenolate mofetil for maintenance therapy. This article is protected by copyright. All rights reserved.

PMID: 27243233 [PubMed – as supplied by publisher]

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Effect of stem cell source on long-term chimerism and event-free survival in children with primary immunodeficiency disorders after fludarabine and melphalan conditioning regimen.

J Allergy Clin Immunol. 2016 Apr 20;

Authors: Rao K, Adams S, Qasim W, Allwood Z, Worth A, Silva J, Lucchini G, Chiesa R, Veys P, Amrolia P

Abstract
BACKGROUND: Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism.
OBJECTIVES: We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source.
METHODS: One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7).
RESULTS: Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (<10% donor), especially in the myeloid lineage. Event-free survival in this group was significantly lower compared with that in the rest of the group (25% vs 70%, P < .001). With the use of PBSCs, more than 90% of patients achieved complete donor chimerism or high-level mixed chimerism (>50% donor chimerism) in all lineages.
CONCLUSIONS: On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism.

PMID: 27241891 [PubMed – as supplied by publisher]

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New clinical phenotypes of fungal infections in special hosts.

Clin Microbiol Infect. 2016 May 26;

Authors: Pilmis B, Puel A, Lortholary O, Lanternier F

Abstract
Invasive fungal infections incidence increases over time with the raise of at risk populations, in particular patients with acquired immunodeficiencies due to immunosuppressive therapies such as anti-tumor necrosis factor alpha (TNF-α) treatment, cirrhosis or burns. Some primary immunodeficiencies (PID) can also predispose selectively to invasive fungal diseases. Conversely, some atypical fungal diseases can reveal new PID. Deep dermatophytosis, Candida central nervous system or gastrointestinal disease, or disseminated phaeohyphomycosis revealed CARD9 deficiency. Most patients with inherited chronic mucocutaneous candidiasis were found to carry STAT1 gain-of-function mutations. The spectrum of fungal susceptibility and clinical presentation varies according to the PID. Among acquired immunodeficiencies, immunosuppressive treatments such as TNF-α blocker therapy, which has revolutionized autoimmune disorder treatment, may be complicated with endemic mycosis, aspergillosis, pneumocystosis or cryptococcosis. Burned patients with damaged skin barrier protection are susceptible to severe Candida and filamentous fungal (such as Aspergillus spp, Mucorales) infections. Moreover, patient with cirrhosis are at increased risk of fungal infections. Therefore, physicians should think of a potential underlying acquired or inherited immunodeficiency in a patient developing an atypical fungal infection, or of a potential fungal disease in the context of an atypical presentation in specific hosts.

PMID: 27237547 [PubMed – as supplied by publisher]

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20% subcutaneous immunoglobulin dosed biweekly for primary immunodeficiency.

Ann Allergy Asthma Immunol. 2016 May 25;

Authors: Wasserman RL, Stein MR, Younger ME, Fatteh S, Haddad E

PMID: 27236217 [PubMed – as supplied by publisher]

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Multicenter Study for the Evaluation of the Antibody Response against Salmonella Typhi Vi Vaccination (EMPATHY) for the Diagnosis of Anti-Polysaccharide Antibody Production Deficiency in Patients with Primary Immunodeficiency.

Clin Immunol. 2016 May 25;

Authors: Sánchez-Ramón S, de Gracia J, García Alonso AM, Rodríguez Molina JJ, Melero J, de Andrés A, García Ruiz de Morales JM, Ferreira A, Ocejo G, Cid JJ, García Martínez JM, Lasheras T, Vargas ML, Gil J, García Rodríguez MC, Castañer JL, González Granado LI, Allende L, Soler-Palacín P, Herraiz L, Lopez Hoyos M, Bellón JM, Silva G, Gurbindo DM, Carbone J, Rodríguez-Sáinz C, Matamoros N, Parker AR, Fernández-Cruz E, EMPATHY group

PMID: 27236002 [PubMed – as supplied by publisher]

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