Research

Clinical Recommendations for Oral Management of Patients with Primary Antibody Deficiencies.

Expert Rev Clin Immunol. 2016 Jan 21;

Authors: Yousefi H, Aghamohammadi A, Rezaei N

PMID: 26796048 [PubMed – as supplied by publisher]

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Primary immunodeficiency in the neonate: Early diagnosis and management.

Semin Fetal Neonatal Med. 2016 Jan 8;

Authors: Walkovich K, Connelly JA

Abstract
Many primary immunodeficiencies (PIDs) manifest in the neonatal period but can be challenging to diagnose and manage optimally. In part, the difficulty stems from the natural immaturity of the neonatal immune system that may mask immune deficits and/or complicate interpretation of clinical findings and laboratory assays. The great diversity of PIDs – from innate immune system defects to those that impact the humoral and/or cellular components of the adaptive immune system – and the rapid rate at which new PIDs are being discovered makes it challenging for practioners to stay current. Moreover, recent appreciation for immune deficiencies that lead to autoinflammation and autoimmunity have broadened the spectrum of neonatal PID, adding additional complexity to an already intricate field. This article serves to highlight the deficiencies in the neonatal immune system, while providing a review of the more common PIDs that present in the neonate and guidelines for diagnosis and supportive care.

PMID: 26776073 [PubMed – as supplied by publisher]

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Actin polymerisation after FCγR stimulation of human fibroblasts is BCL10 independent.

Clin Immunol. 2016 Jan 13;

Authors: Garcia-Gomez S, Alvarez Doforno R, Martinez-Barricarte R, Torres JM, Ferreira Cerdan A, Davila M, Hernández-Jiménez E, Toledano V, Cubillos-Zapata C, Vallejo-Cremades MT, López-Collazo E, Sánchez-Ramón S, Casanova JL, de Diego RP

Abstract
B-cell lymphoma 10 (BCL10) is not essential for actin polymerisation after FcγR stimulation in human fibroblasts.

PMID: 26774590 [PubMed – as supplied by publisher]

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The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency.

J Allergy Clin Immunol. 2016 Jan;137(1):223-30

Authors: Gámez-Díaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, Morio T, Worth AJ, Blessing J, Van de Veerdonk F, Feuchtinger T, Kanariou M, Schmitt-Graeff A, Jung S, Seneviratne S, Burns S, Belohradsky BH, Rezaei N, Bakhtiar S, Speckmann C, Jordan M, Grimbacher B

Abstract
BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression.
OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients.
METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency.
RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents.
CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.

PMID: 26768763 [PubMed – in process]

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Munc18-2 is required for Syntaxin 11 Localization on the Plasma Membrane in Cytotoxic T-Lymphocytes.

Traffic. 2015 Dec;16(12):1330-1341

Authors: Dieckmann NM, Hackmann Y, Aricò M, Griffiths GM

Abstract
Cytotoxic T-lymphocytes (CTL) kill their targets by cytolytic granule secretion at the immunological synapse. The Sec/Munc protein, Munc18-2, and its binding partner Syntaxin 11 (STX11) are both required for granule secretion, with mutations in either leading to the primary immunodeficiency, Familial Haemophagocytic Lymphohistiocytosis (FHL4 and 5). Understanding how Munc18-2 and STX11 function in CTL has been hampered by not knowing the endogenous localization of these proteins. Using a novel FHL5 Munc18-2 mutation that results in loss of protein, cytotoxicity and degranulation together with CTL from an FHL4 patient lacking STX11, enabled us to localize endogenous STX11 and Munc18-2 in CTL. Munc18-2 localized predominantly to cytolytic granules with low levels associated with the plasma membrane where STX11 localized. Importantly, while Munc18-2 localization is unaffected by the absence of STX11 in FHL4 CTL, STX11 is lost from the plasma membrane in FHL5 CTL lacking Munc18-2. These findings support a role for Munc18-2 in chaperoning STX11 to the plasma membrane where the final fusion events involved in secretion occur.

PMID: 26771955 [PubMed – as supplied by publisher]

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The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.

J Allergy Clin Immunol. 2016 Jan;137(1):3-17

Authors: Grimbacher B, Warnatz K, Yong PF, Korganow AS, Peter HH

Abstract
Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity.

PMID: 26768758 [PubMed – in process]

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cnvScan: a CNV screening and annotation tool to improve the clinical utility of computational CNV prediction from exome sequencing data.

BMC Genomics. 2016;17(1):51

Authors: Samarakoon PS, Sorte HS, Stray-Pedersen A, Rødningen OK, Rognes T, Lyle R

Abstract
BACKGROUND: With advances in next generation sequencing technology and analysis methods, single nucleotide variants (SNVs) and indels can be detected with high sensitivity and specificity in exome sequencing data. Recent studies have demonstrated the ability to detect disease-causing copy number variants (CNVs) in exome sequencing data. However, exonic CNV prediction programs have shown high false positive CNV counts, which is the major limiting factor for the applicability of these programs in clinical studies.
RESULTS: We have developed a tool (cnvScan) to improve the clinical utility of computational CNV prediction in exome data. cnvScan can accept input from any CNV prediction program. cnvScan consists of two steps: CNV screening and CNV annotation. CNV screening evaluates CNV prediction using quality scores and refines this using an in-house CNV database, which greatly reduces the false positive rate. The annotation step provides functionally and clinically relevant information using multiple source datasets. We assessed the performance of cnvScan on CNV predictions from five different prediction programs using 64 exomes from Primary Immunodeficiency (PIDD) patients, and identified PIDD-causing CNVs in three individuals from two different families.
CONCLUSIONS: In summary, cnvScan reduces the time and effort required to detect disease-causing CNVs by reducing the false positive count and providing annotation. This improves the clinical utility of CNV detection in exome data.

PMID: 26764020 [PubMed – in process]

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Molecular and Immunological Characterization of DNA ligase IV deficiency.

Clin Immunol. 2016 Jan 4;

Authors: Jiang J, Tang W, An Y, Tang M, Wu J, Qin T, Zhao X

Abstract
DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by the LIG4 mutation. To date, fewer than 30 cases of patients have been reported worldwide. No reversion mutations have been previously identified in LIG4. This study enrolled seven Chinese patients with LIG4 deficiency who presented with combined immunodeficiency, microcephaly, and growth retardation. One patient (P1) acquired non-Hodgkin lymphoma. Four patients had impaired T cell proliferation function and skewed T cell receptor diversity. Five novel mutations in LIG4 and a potential hotspot mutation (c.833G>T; p.R278L) in the Chinese population were identified. TA cloning analysis of T cells, NK cells, granulocytes, and oral mucosa cells in P6 revealed wild-type clones and clones that contained both maternally and paternally inherited mutations, indicating possible somatic reversion which need further investigation since no functional or protein assays were possible for all the patients died and no cell lines were available.

PMID: 26762768 [PubMed – as supplied by publisher]

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IL-12 receptor 1β deficiency with features of autoimmunity and photosensitivity.

Autoimmunity. 2016 Jan 13;:1-4

Authors: Ling G, Ling E, Broides A, Poran Feldman H, Levy J, Garty BZ, Nahum A

Abstract
Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor β1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.

PMID: 26761636 [PubMed – as supplied by publisher]

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Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings.

Radiographics. 2016 Jan-Feb;36(1):53-70

Authors: Sirajuddin A, Raparia K, Lewis VA, Franks TJ, Dhand S, Galvin JR, White CS

Abstract
The pulmonary lymphoid system is complex and is composed of two compartments: the pulmonary lymphatics and the bronchus-associated lymphoid tissue (BALT). Additional important cells that function in the pulmonary lymphoid system include dendritic cells, Langherhans cells, macrophages, and plasma cells. An appreciation of the normal lymphoid anatomy of the lung as well as its immunology is helpful in understanding the radiologic and pathologic findings of the primary pulmonary lymphoid lesions. Primary lymphoid lesions of the lung arise from the BALT and are uncommon. However, they are increasingly recognized within the growing number of posttransplant patients as well as other patients who are receiving immunosuppressive therapies. Primary lymphoid lesions encompass a wide range of benign and malignant lesions. Benign lymphoid lesions of the lung include reactive lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia, and nodular lymphoid hyperplasia. Malignant lymphoid lesions of the lung include low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), other non-Hodgkin lymphomas, and Hodgkin lymphoma. Last, a miscellaneous group of primary lymphoid lesions includes lymphomatoid granulomatosis, posttransplant lymphoproliferative disorders, acquired immunodeficiency syndrome (AIDS)-related lymphoma, and intravascular lymphoma/lymphomatosis. These lesions are best evaluated with multidetector chest computed tomography. The radiologic findings of the primary lymphoid lesions are often nonspecific and are best interpreted in correlation with clinical data and pathologic findings. The purpose of this article is to review pulmonary lymphoid anatomy as well as the most common primary pulmonary lymphoid disorders. (©)RSNA, 2016.

PMID: 26761531 [PubMed – as supplied by publisher]

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