Manish Butte

Sclerosing Cholangitis: Clinicopathologic Features, Imaging Spectrum, and Systemic Approach to Differential Diagnosis.

Korean J Radiol. 2016 Jan-Feb;17(1):25-38

Authors: Seo N, Kim SY, Lee SS, Byun JH, Kim JH, Kim HJ, Lee MG

Abstract
Sclerosing cholangitis is a spectrum of chronic progressive cholestatic liver disease characterized by inflammation, fibrosis, and stricture of the bile ducts, which can be classified as primary and secondary sclerosing cholangitis. Primary sclerosing cholangitis is a chronic progressive liver disease of unknown cause. On the other hand, secondary sclerosing cholangitis has identifiable causes that include immunoglobulin G4-related sclerosing disease, recurrent pyogenic cholangitis, ischemic cholangitis, acquired immunodeficiency syndrome-related cholangitis, and eosinophilic cholangitis. In this review, we suggest a systemic approach to the differential diagnosis of sclerosing cholangitis based on the clinical and laboratory findings, as well as the typical imaging features on computed tomography and magnetic resonance (MR) imaging with MR cholangiography. Familiarity with various etiologies of sclerosing cholangitis and awareness of their typical clinical and imaging findings are essential for an accurate diagnosis and appropriate management.

PMID: 26798213 [PubMed – in process]

Powered by WPeMatico

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]

Powered by WPeMatico

Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency.

Mol Immunol. 2016 Jan 12;71:1-9

Authors: Yazdani R, Fatholahi M, Ganjalikhani-Hakemi M, Abolhassani H, Azizi G, Hamid KM, Rezaei N, Aghamohammadi A

Abstract
Common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD) are the most common primary immunodeficiencies in human. Both diseases share clinical manifestation and molecular defects. Increased apoptosis may be one of the mechanisms involved in the pathogenesis of CVID and SIgAD. Elevated apoptosis in this disorder leads to defective long-term survival of B-cells, reduced antibody production, decreased lymphocyte proliferation and defective cytokine secretion. For the first time, we reviewed the role of apoptosis in CVID and SIgAD.

PMID: 26795881 [PubMed – as supplied by publisher]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico

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]

Powered by WPeMatico