Research

Patterns of Allergic Sensitization in High IgE Syndromes.

October 24, 2015 By Manish Butte

Patterns of Allergic Sensitization in High IgE Syndromes.

Curr Allergy Asthma Rep. 2015 Dec;15(12):70

Authors: Lawrence MG

Abstract
Dramatic elevations in the serum IgE level are seen both in polygenic allergic diseases such as atopic dermatitis and food allergy, and in a growing list of monogenic primary immune deficiencies (PIDs). Although the IgE produced in patients with PID has generally been considered to be driven by dysregulated IL-4 production and thus lack antigen specificity, in fact allergen-specific IgE can be detected by skin and serum testing in many of these patients. However, perhaps not surprisingly given the distinct immunologic pathways involved, the patterns of allergic disease and atopic sensitization vary widely between syndromes, leading to strikingly different clinical phenotypes.

PMID: 26492876 [PubMed – as supplied by publisher]

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

October 23, 2015 By Manish Butte

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

Nat Cell Biol. 2015 Aug;17(8):1074-87

Authors: Wheway G, Schmidts M, Mans DA, Szymanska K, Nguyen TM, Racher H, Phelps IG, Toedt G, Kennedy J, Wunderlich KA, Sorusch N, Abdelhamed ZA, Natarajan S, Herridge W, van Reeuwijk J, Horn N, Boldt K, Parry DA, Letteboer SJ, Roosing S, Adams M, Bell SM, Bond J, Higgins J, Morrison EE, Tomlinson DC, Slaats GG, van Dam TJ, Huang L, Kessler K, Giessl A, Logan CV, Boyle EA, Shendure J, Anazi S, Aldahmesh M, Al Hazzaa S, Hegele RA, Ober C, Frosk P, Mhanni AA, Chodirker BN, Chudley AE, Lamont R, Bernier FP, Beaulieu CL, Gordon P, Pon RT, Donahue C, Barkovich AJ, Wolf L, Toomes C, Thiel CT, Boycott KM, McKibbin M, Inglehearn CF, UK10K Consortium, University of Washington Center for Mendelian Genomics, Stewart F, Omran H, Huynen MA, Sergouniotis PI, Alkuraya FS, Parboosingh JS, Innes AM, Willoughby CE, Giles RH, Webster AR, Ueffing M, Blacque O, Gleeson JG, Wolfrum U, Beales PL, Gibson T, Doherty D, Mitchison HM, Roepman R, Johnson CA

Abstract
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

PMID: 26167768 [PubMed – indexed for MEDLINE]

A novel mutation in ORAI1 presenting with combined immunodeficiency and residual T-cell function.

October 23, 2015 By Manish Butte

A novel mutation in ORAI1 presenting with combined immunodeficiency and residual T-cell function.

J Allergy Clin Immunol. 2015 Aug;136(2):479-82.e1

Authors: Chou J, Badran YR, Yee CS, Bainter W, Ohsumi TK, Al-Hammadi S, Pai SY, Feske S, Geha RS

PMID: 26070885 [PubMed – indexed for MEDLINE]

Hypogammaglobulinemia in sub-Saharan Africa: a case report and review of the literature.

October 22, 2015 By Manish Butte

Hypogammaglobulinemia in sub-Saharan Africa: a case report and review of the literature.

Afr Health Sci. 2015 Mar;15(1):299-301

Authors: Hsu J, Opoka R, Lund TC

Abstract
UNLABELLED: Patients with hypogammaglobulinemia are susceptible to recurrent bacterial, viral, fungal, and parasitic infections. The most common clinical manifestation includes recurrent severe infections caused by encapsulated bacteria, in which antibody opsonization is the primary defense mechanism. To our knowledge, this is the first case report of hypogammaglobulinemia in a Ugandan child in Sub-Saharan Africa. The case emphasizes the importance of including hypogammaglobulinemia in the differential diagnosis for children presenting with a history of recurrent infections.
AIM: To raise the index of clinical suspicion of hypogammaglobulinemia in an African child and allow for prompt recognition and management of hypogammaglobulinemia.

PMID: 25834564 [PubMed – indexed for MEDLINE]

Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.

October 21, 2015 By Manish Butte

Evans Syndrome in Children: Long-Term Outcome in a Prospective French National Observational Cohort.

Front Pediatr. 2015;3:79

Authors: Aladjidi N, Fernandes H, Leblanc T, Vareliette A, Rieux-Laucat F, Bertrand Y, Chambost H, Pasquet M, Mazingue F, Guitton C, Pellier I, Roqueplan-Bellmann F, Armari-Alla C, Thomas C, Marie-Cardine A, Lejars O, Fouyssac F, Bayart S, Lutz P, Piguet C, Jeziorski E, Rohrlich P, Lemoine P, Bodet D, Paillard C, Couillault G, Millot F, Fischer A, Pérel Y, Leverger G

Abstract
Evans syndrome (ES) is a rare autoimmune disorder whose long-term outcome is not well known. In France, a collaborative pediatric network set up via the National Rare Disease Plan now provides comprehensive clinical data in children with this disease. Patients aged less than 18 years at the initial presentation of autoimmune cytopenia have been prospectively included into a national observational cohort since 2004. The definition of ES was restricted to the simultaneous or sequential association of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). Cases were deemed secondary if associated with a primitive immunodeficiency or systemic lupus erythematosus. In December 2014, we analyzed the data pertaining to 156 children from 26 centers with ES whose diagnosis was made between 1981 and 2014. Median age (range) at the onset of cytopenia was 5.4 years (0.2-17.2). In 85 sequential cases, the time lapse between the first episodes of AIHA and ITP was 2.4 years (0.1-16.3). The follow-up period as from ES diagnosis was 6.5 years (0.1-28.8). ES was secondary, revealing another underlying disease, in 10% of cases; various associated immune manifestations (mainly lymphoproliferation, other autoimmune diseases, and hypogammaglobulinemia) were observed in 60% of cases; and ES remained primary in 30% of cases. Five-year ITP and AIHA relapse-free survival were 25 and 61%, respectively. Overall, 69% of children required one or more second-line immune treatments, and 15 patients (10%) died at the age of 14.3 years (1.7-28.1). To our knowledge, this is the first consistent long-term clinical description of this rare syndrome. It underscores the high rate of associated immune manifestations and the burden of long-term complications and treatment toxicity. Future challenges include (1) the identification of the underlying genetic defects inducing immune dysregulation and (2) the need to better characterize patient subgroups and second-line treatment strategies.

PMID: 26484337 [PubMed]

The autoimmune conundrum in common variable immunodeficiency disorders.

October 21, 2015 By Manish Butte

The autoimmune conundrum in common variable immunodeficiency disorders.

Curr Opin Allergy Clin Immunol. 2015 Oct 17;

Authors: van de Ven AA, Warnatz K

Abstract
PURPOSE OF REVIEW: Autoimmune and inflammatory manifestations are the biggest clinical challenge in the care of patients with common variable immunodeficiency (CVID). The increasing pathogenic knowledge and potential therapeutic implications require a new evaluation of the status quo.
RECENT FINDINGS: The conundrum of the simultaneous manifestation of primary immunodeficiency and autoimmune disease (AID) is increasingly elucidated by newly discovered genetic defects. Thus, cytotoxic T lymphocyte-associated antigen 4 or caspase-9 deficiency presenting with CVID-like phenotypes reiterate concepts of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and autoimmune lymphoproliferative syndrome. Activating signaling defects downstream of antigen or cytokine receptors are often associated with loss-of-tolerance in the affected patients. Increasingly, forms of combined immunodeficiency are discovered among CVID-like patients. Although different autoimmune manifestations often coincide in the same patient their immunopathology varies. Treatment of AID in CVID remains a challenge, but based on a better definition of the immunopathology first attempts of targeted treatment have been made.
SUMMARY: The increasing comprehension of immunological concepts promoting AID in CVID will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially in light of the fact that some patients might require hematopoietic stem cell transplantation because of their underlying immunodeficiency.

PMID: 26485099 [PubMed – as supplied by publisher]

Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutations in the phosphoglucomutase 3 (PGM3) gene.

October 21, 2015 By Manish Butte

Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutations in the phosphoglucomutase 3 (PGM3) gene.

Clin Immunol. 2015 Oct 16;

Authors: Lundin KE, Hamasy A, Backe PH, Moens LN, Falk-Sörqvist E, Elgstøen KB, Mørkrid L, Bjørås M, Granert C, Norlin AC, Nilsson M, Christensson B, Stenmark S, Smith CI

PMID: 26482871 [PubMed – as supplied by publisher]

Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.

October 21, 2015 By Manish Butte

Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.

J Clin Immunol. 2015 Oct 19;

Authors: Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar HB

Abstract
We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

PMID: 26482257 [PubMed – as supplied by publisher]

Frequency and Severity of Pulmonary Hemorrhage in Patients Undergoing Percutaneous CT-guided Transthoracic Lung Biopsy: Single-Institution Experience of 1175 Cases.

October 20, 2015 By Manish Butte

Frequency and Severity of Pulmonary Hemorrhage in Patients Undergoing Percutaneous CT-guided Transthoracic Lung Biopsy: Single-Institution Experience of 1175 Cases.

Radiology. 2015 Oct 19;:150381

Authors: Tai R, Dunne RM, Trotman-Dickenson B, Jacobson FL, Madan R, Kumamaru KK, Hunsaker AR

Abstract
Purpose To evaluate the frequency and severity of pulmonary hemorrhage after transthoracic needle lung biopsy (TTLB) and assess possible factors associated with pulmonary hemorrhage. Materials and Methods This retrospective study was approved by the institutional review board. The requirement to obtain informed consent was waived. Records from 1113 patients who underwent 1175 TTLBs between January 2008 and April 2013 were retrospectively reviewed. Primary outcomes were pulmonary hemorrhage, documented hemoptysis, and bleeding complications necessitating intervention. Pulmonary hemorrhage was graded as follows: 0, none; 1, less than or equal to 2 cm around the needle; 2, more than 2 cm and sublobar; 3, at least lobar; and 4, hemothorax. Patient, technique, and lesion-related variables were evaluated as predictors of pulmonary hemorrhage. Patient-related variables included main pulmonary artery diameter (mPAD) at computed tomography (CT), pulmonary artery pressures at echocardiography and right-sided heart catheterization, medications, chronic lung disease, bleeding diathesis, and immunodeficiency. Technique- and lesion-related variables included needle gauge, number of passes, pleura-needle angle, lesion size and morphologic characteristics, and distance to pleura. Univariate analysis was performed with χ(2), Fisher exact, and Student t tests. Results Pulmonary hemorrhage occurred in 483 of the 1175 TTLBs (41.1%); hemoptysis was documented in 21 of the 1175 TTLBs (1.8%). Higher-grade hemorrhage (grade 2 or higher) occurred in 201 of the 1175 TTLBs (17.1%); five of the 1175 TTLBs (0.4%) necessitated hemorrhage-related admission. Higher-grade hemorrhage was more likely to occur with female sex (P = .001), older age (P = .003), emphysema (P = .004), coaxial technique (P = .025), nonsubpleural location (P < .001), lesion size of 3 cm or smaller (P < .001), and subsolid lesions (P = .028). Enlarged mPAD at CT (≥2.95 cm) was not significantly associated with higher-grade hemorrhage (P = .430). Conclusion Pulmonary hemorrhage after TTLB is common but rarely requires intervention. An enlarged mPAD at CT may not be a risk factor for higher-grade hemorrhage. (©) RSNA, 2015 Online supplemental material is available for this article.

PMID: 26479161 [PubMed – as supplied by publisher]

CD19 controls Toll-like receptor 9 responses in human B cells.

October 20, 2015 By Manish Butte

CD19 controls Toll-like receptor 9 responses in human B cells.

J Allergy Clin Immunol. 2015 Oct 15;

Authors: Morbach H, Schickel JN, Cunningham-Rundles C, Conley ME, Reisli I, Franco JL, Meffre E

Abstract
BACKGROUND: CD19 is a B cell-specific molecule that serves as a major costimulatory molecule for amplifying B-cell receptor (BCR) responses. Biallelic CD19 gene mutations cause common variable immunodeficiency in human subjects. BCR- and Toll-like receptor (TLR) 9-induced B-cell responses are impaired in most patients with common variable immunodeficiency.
OBJECTIVE: We sought to analyze whether CD19 is required for TLR9 function in human B cells.
METHODS: Expression of surface activation markers was assessed after anti-IgM or CpG stimulation by using flow cytometry on B cells from patients with 1 or 2 defective CD19 alleles, which decrease or abrogate CD19 expression, respectively. The phosphorylation or interaction of signaling molecules was analyzed by using phospho flow cytometry, immunoblotting, or co-immunoprecipitation in CD19-deficient or control B cells and in a B-cell line in which CD19 has been knocked down with lentivirus-transduced short hairpin RNA.
RESULTS: B cells from subjects with 1 or 2 defective CD19 alleles showed defective upregulation in vitro of CD86, transmembrane activator and CAML interactor (TACI), and CD23 activation markers after TLR9 stimulation. TLR9 ligands normally induce phosphorylation of CD19 through myeloid differentiation primary response gene-88 (MYD88)/proline-rich tyrosine kinase 2 (PYK2)/LYN complexes, which allows recruitment of phosphoinositide 3-kinase (PI3K) and phosphorylation of Bruton tyrosine kinase (BTK) and AKT in human B cells with a different kinetic than that of BCRs. In addition, inhibition of PI3K, AKT, or BTK, as well as BTK deficiency, also resulted in TLR9 activation defects in B cells similar to those in patients with CD19 deficiency.
CONCLUSION: CD19 is required for TLR9-induced B-cell activation. Hence CD19/PI3K/AKT/BTK is an essential axis integrating BCRs and TLR9 signaling in human B cells.

PMID: 26478008 [PubMed – as supplied by publisher]