Research

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells.

Cell Rep. 2017 Feb 28;18(9):2189-2202

Authors: Smulski CR, Kury P, Seidel LM, Staiger HS, Edinger AK, Willen L, Seidl M, Hess H, Salzer U, Rolink AG, Rizzi M, Schneider P, Eibel H

Abstract
B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner.

PMID: 28249164 [PubMed – in process]

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[Papillon-Lefèvre syndrome: A new case].

Arch Pediatr. 2017 Feb 24;:

Authors: Martinho S, Levade T, Fergelot P, Stephan JL

Abstract
Papillon-Lefèvre syndrome (PLS) is a rare primary immunodeficiency, which combines severe periodontal disease with edentulism and palmoplantar keratosis (PPK). PLS is inherited as an autosomal recessive trait and is due to mutations in the cathepsin C gene. The biological properties of the neutrophils (PN) are altered, leading to a gingival dysbiosis and bacterial overgrowth, with intense inflammation of the periodontium. We report the observation of a 4-year-old girl who presented to the clinic with gingivitis, partial edentulism, and PPK, whose diagnosis, raised after a long delay, was suggested by null cathepsin C activity and confirmed by the presence of heterozygous mutations in exon 4: c.628C>T, pArg210* and in exon 7: c.1286G>A, p.Trp429*. A multidisciplinary approach transformed the functional and esthetic prognosis and psychological behavior of this child. This classical observation describes this poorly known phenotype.

PMID: 28242153 [PubMed – as supplied by publisher]

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First Case of CD40LG Deficiency in Ecuador, Diagnosed after Whole Exome Sequencing in a Patient with Severe Cutaneous Histoplasmosis.

Front Pediatr. 2017;5:17

Authors: Pedroza LA, Guerrero N, Stray-Pedersen A, Tafur C, Macias R, Muñoz G, Akdemir ZC, Jhangiani SN, Watkin LB, Chinn IK, Lupski JR, Orange JS

Abstract
Severe infections with Histoplasma capsulatum are commonly observed in patient with secondary immunodeficiency disorders. We report a two and a half years old boy previously healthy with disseminated cutaneous histoplasmosis. Using whole exome sequencing, we found an indel mutation at the CD40LG gene, suggesting a diagnosis of hyper-IgM (HIGM) syndrome, even in the absence of the usual features for the disease. Interestingly, the patient lives in a region endemic for histoplasmosis. The unusual infections in our case suggest that in children with severe histoplasmosis and resident in endemic areas, HIGM syndrome should be considered as a diagnosis.

PMID: 28239602 [PubMed – in process]

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The Role of Genomics in Common Variable Immunodeficiency Disorders.

Clin Exp Immunol. 2017 Feb 25;:

Authors: Kienzler AK, Hargreaves CE, Patel SY

Abstract
The advent of next generation sequencing (NGS) and ‘omic’ technologies has revolutionised the field of genetics and its implementation in healthcare has the potential to realise precision medicine. Primary immunodeficiencies (PID) are a group of rare diseases which have benefitted from NGS, with a massive increase in causative genes identified in the past few years. Common Variable Immunodeficiency Disorders (CVID) are a heterogeneous form of PID and the most common form of antibody failure in children and adults. While a monogenic cause of disease has been identified in a small subset of CVID patients, a genome wide association study and whole genome sequencing have found a polygenic cause is likely in the majority. Other NGS technologies such as RNA sequencing and epigenetic studies have further contributed to our understanding of the contribution of altered gene expression in CVID pathogenesis. We believe that to further unravel the complexities of CVID, a multi-omic approach, combining DNA sequencing with gene expression, methylation, proteomic and metabolomics data, will be essential to identify novel disease-associated pathways and therapeutic targets. This article is protected by copyright. All rights reserved.

PMID: 28236292 [PubMed – as supplied by publisher]

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Primary immunodeficiency diseases in Northern Iran.

Allergol Immunopathol (Madr). 2017 Feb 22;:

Authors: Mohammadzadeh I, Moazzami B, Ghaffari J, Aghamohammadi A, Rezaei N

Abstract
INTRODUCTION: Primary immunodeficiency diseases (PID) are a heterogeneous group of inherited disorders, characterised by recurrent severe infections, autoimmunity and lymphoproliferation. Despite impressive progress in identification of novel PID, there is an unfortunate lack of awareness among physicians in identification of patients with PID, especially in non-capital cities of countries worldwide.
RESULT: This study was performed in a single-centre paediatric hospital in Northern Iran during a 21-year period (1994-2015). Ninety-four patients were included in this study. The majority of cases had antibody deficiencies (37.23%), followed by well-defined syndromes with immunodeficiency in 16 (17.02%), phagocytic disorders in 15 patients (15.95%), complement deficiencies in 15 patients (15.95%), immunodeficiencies affecting cellular and humoral immunity in nine patients (9.57%), disease of immune dysregulation in three (3.19%), and defects in intrinsic and innate immunity in one (1.06%).
CONCLUSION: It seems that there are major variations in frequency of different types of PID in different regions of a country. Therefore, reporting local data could provide better ideas to improve the local health care system strategists and quality of care of PID patients.

PMID: 28237128 [PubMed – as supplied by publisher]

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Gastrointestinal Manifestations in X-linked Agammaglobulinemia.

J Clin Immunol. 2017 Feb 24;:

Authors: Barmettler S, Otani IM, Minhas J, Abraham RS, Chang Y, Dorsey MJ, Ballas ZK, Bonilla FA, Ochs HD, Walter JE

Abstract
PURPOSE: X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored.
METHODS: We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies.
RESULTS: In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental.
CONCLUSIONS: Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.

PMID: 28236219 [PubMed – as supplied by publisher]

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Case Studies.

J Clin Immunol. 2017 Feb;37(2):188-189

Authors: Shapiro RS, Wasserman RL, Bonagura V, Gupta S

PMID: 28236086 [PubMed – in process]

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Supplement: Frontiers in Immunoglobulin Therapy of Primary Immunodeficiency Disease.

J Clin Immunol. 2017 Feb;37(2):187

Authors: Shapiro RS

PMID: 28236085 [PubMed – in process]

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Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity.

Cell. 2017 Feb 23;168(5):789-800.e10

Authors: Israel L, Wang Y, Bulek K, Della Mina E, Zhang Z, Pedergnana V, Chrabieh M, Lemmens NA, Sancho-Shimizu V, Descatoire M, Lasseau T, Israelsson E, Lorenzo L, Yun L, Belkadi A, Moran A, Weisman LE, Vandenesch F, Batteux F, Weller S, Levin M, Herberg J, Abhyankar A, Prando C, Itan Y, van Wamel WJ, Picard C, Abel L, Chaussabel D, Li X, Beutler B, Arkwright PD, Casanova JL, Puel A

Abstract
The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

PMID: 28235196 [PubMed – in process]

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