Research

Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

July 1, 2015 By Manish Butte

Application of Whole Genome and Rna Sequencing to Investigate the Genomic Landscape of Common Variable Immunodeficiency.

Clin Immunol. 2015 Jun 26;

Authors: van Schouwenburg PA, Davenport EE, Kienzler AK, Marwah I, Wright B, Lucas M, Malinauskas T, Martin HC, WGS500 Consortium, Lockstone HE, Cazier JB, Chapel HM, Knight JC, Patel SY

Abstract
Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are a highly variable disease and a genetic cause has been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. By using an extensive analysis strategy we found variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. Pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm a polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together out data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

PMID: 26122175 [PubMed – as supplied by publisher]

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

July 1, 2015 By Manish Butte

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology.

Front Pediatr. 2015;3:54

Authors: Lyons JJ, Milner JD, Rosenzweig SD

Abstract
Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.

PMID: 26125015 [PubMed]

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

July 1, 2015 By Manish Butte

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

Brain. 2015 Jun 29;

Authors: Shahni R, Cale CM, Anderson G, Osellame LD, Hambleton S, Jacques TS, Wedatilake Y, Taanman JW, Chan E, Qasim W, Plagnol V, Chalasani A, Duchen MR, Gilmour KC, Rahman S

Abstract
Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.

PMID: 26122121 [PubMed – as supplied by publisher]

CD21(-/low) B cells: A snapshot of a unique B-cell subset in health and disease.

June 30, 2015 By Manish Butte

CD21(-/low) B cells: A snapshot of a unique B-cell subset in health and disease.

Scand J Immunol. 2015 Jun 28;

Authors: Thorarinsdottir K, Camponeschi A, Gjertsson I, Mårtensson IL

Abstract
B cells represent one of the cellular components of the immune system that protects the individual from invading pathogens. In response to the invader, these cells differentiate into plasma cells and produce large amounts of antibodies that bind to and eliminate the pathogen. A hallmark of autoimmune diseases is the production of autoantibodies i.e. antibodies that recognize self. Those that are considered pathogenic can damage tissues and organs, either by direct binding or when deposited as immune complexes. For decades B cells have been considered to play a major role in autoimmune diseases by antibody production. However, as pathogenic autoantibodies appear to derive mainly from T-cell dependent responses, T cells have been the focus for many years. The successful treatment of patients with autoimmune diseases with either B-cell depletion therapy (rituximab) or inhibition of B-cell survival (belimumab), suggested that not only the autoantibodies but also other B-cell features are important. This has caused a surge of interest in B cells and their biology resulting in the identification of various subsets e.g. regulatory B cells, several memory B-cell subsets etc. Also in other conditions such as chronic viral infections and primary immunodeficiency several B-cell subsets with unique characteristics have been identified. In this review, we will discuss one of these subsets, a subset that is expanded in conditions characterized by chronic immune stimulation. This B-cell subset lacks, or expresses low, surface levels of the complement receptor 2 (CD21) and has therefore been termed CD21(-/low) B cells. This article is protected by copyright. All rights reserved.

PMID: 26119182 [PubMed – as supplied by publisher]

Stem cell transplantation for primary immunodeficiencies: the European experience.

June 30, 2015 By Manish Butte

Stem cell transplantation for primary immunodeficiencies: the European experience.

Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):516-20

Authors: Cavazzana M, Touzot F, Moshous D, Neven B, Blanche S, Fischer A

Abstract
PURPOSE OF REVIEW: Primary immunodeficiencies (PIDs) constitute a heterogeneous group of inherited disorders affecting the development and/or function of the immune system. This review focuses on the recent advances in hematopoietic stem cell transplantation (HSCT) for PIDs, as it remains the only potentially curative option for many of these diseases.
RECENT FINDINGS: We report on the most recent HSCT European results and suggest some opportunities for better treatment of certain PIDs. Progress on gene therapy is also discussed, as it emerges as an interesting option for PIDs management.
SUMMARY: Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies – such as gene therapy – emerge as an interesting option for some PIDs.

PMID: 25304229 [PubMed – indexed for MEDLINE]

[FREQUENCY OF IMMUNOGLOBULIN E DEFICIENCY AMONG PATIENTS WITH IMMUNODEPENDENT DISORDERS].

June 30, 2015 By Manish Butte

[FREQUENCY OF IMMUNOGLOBULIN E DEFICIENCY AMONG PATIENTS WITH IMMUNODEPENDENT DISORDERS].

Lik Sprava. 2014 Jul-Aug;(7-8):3-9

Authors:

Abstract
Isolated IgE deficiency is one of the most common primary immunodeficiency, which is still underestimated cause of health disorders of modern man. Recent genetic studies report that the cause of the IgE deficiency is immune dysregulation caused by polymorphisms of the gene, which is responsible for the synthesis of activation-induced cytidinedeaminase (AICDA). The Institute of Immunology and Allergology at Bogomolets NMU during the years 2012-2014 were examined 5298 patients with a range of different diseases, which could be suspected violations of immunity. All patients were conducted comprehensive immunological study, and 4476 of them were examined for content of total serum IgE. The criterion for the selection of patients for follow-up began serum IgE < 10 kIU/l. Serum immunoglobulin E was determined by ELISA. Serum IgE < 10 IU/ml was detected in 342 patients (7%). Average reduction in the study group made up (5.30 ± 1.31) IU/ml. Partial deficiency (5-10 kIU/l) was detected in 212 patients (4%), while the total–130 (3%). For follow-up, we are clinically selected group of patients with deficiency of IgE (n = 60) and control group (n = 30). All patients were distributed as per clinical syndromes, and the frequency of their manifestations: sinopulmonary syndrome (63%), gastrointestinal syndrome (13%), autoimmune manifestations (10%), allergic reactions (7%) and chronic fatigue syndrome (7%). The levels of serum IgG, IgA, IgM in the study group were within the age norm (IgG = 1160.00 mg/dl ± 2.88 mg/dl, IgA = 138 g/l ± 37 mg/dl, IgM = 114 mg/dl ± 30 mg/dl). However, only a small proportion of patients was observed decrease in other classes of immunoglobulins in 8 patients with IgG < 700 mg/dL in 16 patients with IgA < 90 mg/dl and 6 patients with decreased serum IgM < 90 mg/dl. These patients were examined the levels of serum IgG subclasses and sIgA levels in saliva. Significant violations by cellular immunity in determining lymphocyte subpopulations by flow cytometry using monoclonal antibodies also were found. Phagocytic indices were also no significant abnormalities. An important aspect of clinical deficiency of immunoglobulin E is its association with diseases of bacterial origin (H. influenza, M. catarrhalis, Str. pneumoniae), indicating a protective role of these antibodies in the mucosa of the respiratory tract. Thus, isolated IgE deficiency is associated with sustained decrease in serum concentrations of immunoglobulin E (< 10 kIU/l) in patients with normal immune status of other indicators that require dispensary and treatment. The results of their study indicate a high incidence of the IgE-deficiency among the population and its high incidence among the humoral defects.

PMID: 26118074 [PubMed – in process]

Dual-Tropic CXCR6/CCR5 Simian Immunodeficiency Virus Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in SIV Natural versus Pathogenic Hosts.

June 26, 2015 By Manish Butte

Dual-Tropic CXCR6/CCR5 Simian Immunodeficiency Virus Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in SIV Natural versus Pathogenic Hosts.

J Virol. 2015 Jun 24;

Authors: Elliott ST, Wetzel KS, Francella N, Bryan S, Romero DC, Riddick NE, Shaheen F, Vanderford T, Derdeyn CA, Silvestri G, Paiardini M, Collman RG

Abstract
Natural host sooty mangabeys (SM) infected with SIV exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4+ T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which has been linked to low expression of the canonical SIV entry receptor CCR5 on CD4+ T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by in SM in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIVsmm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIVinfection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4+ T cell subset targeting compared with non-natural hosts, enabling SIV to maintain high level replication without leading to widespread CD4(+) T cell loss.
IMPORTANCE: Natural hosts of SIV such as sooty mangabeys sustain high viral load but do not develop disease, while non-natural hosts like rhesus macaques develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5 suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that, in sooty mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may re-direct the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of non-essential cells and limit infection of critical cells in natural hosts, and thus contribute to benign outcome of infection.

PMID: 26109719 [PubMed – as supplied by publisher]

Immunoglobulin class-switch recombination deficiencies.

June 24, 2015 By Manish Butte

Immunoglobulin class-switch recombination deficiencies.

Arthritis Res Ther. 2012;14(4):218

Authors: Durandy A, Kracker S

Abstract
Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

PMID: 22894609 [PubMed – indexed for MEDLINE]

Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population: A prospective study.

June 23, 2015 By Manish Butte

Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population: A prospective study.

Respirology. 2015 Jun 19;

Authors: Qi Q, Wang W, Li T, Zhang Y, Li Y

Abstract
BACKGROUND AND OBJECTIVE: Bronchiectasis is a chronic respiratory disease with diverse causes that may differ in clinical features and thus treatment options. However, few large-scale studies on the aetiology of bronchiectasis are currently available. This study aims to determine aetiology and clinical features of bronchiectasis in a Chinese Han population.
METHODS: This prospective study enrolled adult patients diagnosed with bronchiectasis as confirmed by high-resolution computed tomography at five general hospitals in Shandong from January 2010 to August 2014. Causes of bronchiectasis were sought by analysis of clinical history and auxiliary examinations (including serum immunoglobulin determination, saccharin test, Aspergillus skin prick test, autoantibody detection and electronic bronchoscopy).
RESULTS: A total of 476 adult patients with bronchiectasis were included, and all patients were of Chinese Han ethnicity. Idiopathic (66.0%) was the most common cause, followed by post-tuberculosis (16.0%). Other uncommon causes included post-infective (3.8%), immunodeficiency (3.8%), allergic bronchopulmonary aspergillosis (4.0%), rheumatic diseases (4.4%) and primary ciliary dyskinesia (0.9%). Patients with post-tuberculosis bronchiectasis had a higher frequency of upper lobe involvement (P < 0.05). Cylindrical bronchiectasis was the most common type of all causes, with varicose bronchiectasis occurring more frequently in post-tuberculosis bronchiectasis and allergic bronchopulmonary aspergillosis (P < 0.05). However, patients with different causes did not differ in lung function and sputum isolation rate of Pseudomonas aeruginosa (P > 0.05).
CONCLUSIONS: In a Chinese Han population in Shandong, idiopathic bronchiectasis is the most common form of bronchiectasis followed by post-tuberculosis bronchiectasis. Patients with different causes differ in distribution and pattern of bronchiectasis on computed tomography.

PMID: 26096854 [PubMed – as supplied by publisher]

Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.

June 23, 2015 By Manish Butte

Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.

Int J Immunogenet. 2015 Jun 19;

Authors: Sathkumara HD, De Silva NR, Handunnetti S, De Silva AD

Abstract
Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency, which represents a heterogeneous group of hypogammaglobulinemias of largely unknown molecular defects. The hallmark of the disease is the elevated susceptibility to recurrent infections of respiratory and gastrointestinal tract, mainly due to encapsulated bacteria while a significant proportion of patients with CVID develop autoimmune and lymphoproliferative complications. The primary cause of CVID is still not known. However, a number of distinct genetic defects including in inducible co-stimulator (ICOS), B-cell-activating factor receptor (BAFFR) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been identified in a minority of patients with CVID. Mutations in tumour necrosis factor receptor superfamily (TNFRSF) member, TACI, are more frequently found to be associated to the disease in about 10% of patients with CVID, but may require additional immunologic defects for complete expression of the phenotype, as unaffected heterozygotes have also been described. Clinically, patients with TACI mutations could present with the complete spectrum of complications seen in CVID. Recent animal studies have provided substantial information on TACI signalling, yet it still offers an outstanding opportunity for further exploration of the aetiology, as a large part of it remains poorly understood. In this review, we aim at giving an insight into the genetics underlying the CVID and particularly at outlining the role of TACI and its relative contribution to the development of CVID-like phenotypes in human.

PMID: 26096648 [PubMed – as supplied by publisher]