Manish Butte

Iterative Excretion of Human Cosaviruses from Different Genotypes Associated with Combined Immunodeficiency Disorder.

Intervirology. 2019 Feb 06;:1-8

Authors: Lamari A, Triki H, Driss N, Touzi H, Meddeb Z, Ben Yahia A, Barbouche MR, Rezig D

Abstract
BACKGROUND: Human cosaviruses (HCoSVs) are newly discovered enteric viruses in the Picornaviridae family. They have been described in non-polio acute flaccid paralysis, diarrheal patients, and healthy individuals. They remain rarely documented in immunodeficient patients.
OBJECTIVES: This study reports iterative excretion of HCoSVs in a patient with major histocompatibility complex (MHC) class II combined immunodeficiency, a relatively common primary immunodeficiency in consanguineous settings.
METHODS: A total of 35 samples were collected from a patient followed for oral polio vaccine strains detection in stool samples during a 57-month period. Detection of HCoSVs in stools was performed by nested RT-PCR in the 5′ noncoding region. The genotype identification and screening for recombinant strains was performed by sequencing in the VP1 and 3D genomic regions followed by phylogenetic analysis.
RESULTS: The patient was infected with HCoSVs twice at a 3-year interval. The excreted viruses belonged to 2 different genotypes with 2 probable recombinant viruses. During HCoSV infections, the patient was also excreting Sabin-related polioviruses.
CONCLUSIONS: This study describes excretion kinetics and genetic characteristics of HCoSVs in a patient with combined immunodeficiency due to MHC class II expression defect. The patient did not have concomitant symptoms related to the HCoSV infection.

PMID: 30726837 [PubMed – as supplied by publisher]

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British Society for Immunology/United Kingdom Primary Immunodeficiency Network consensus statement on managing non-infectious complications of Common Variable Immunodeficiency Disorders.

Clin Exp Immunol. 2019 Feb 06;:

Authors: Bethune C, Egner W, Garcez T, Huissoon A, Jolles S, Karim Y, Jain R, Savic S, Kelley K, Grosse-Kreul D, Grigoriadou S

Abstract
Common variable immunodeficiency (CVID) represents a heterogeneous group of rare disorders. There is considerable morbidity and mortality as a result of non-infectious complications and this presents clinicians with management challenges. Clinical guidelines to support the management of CVID are urgently required. The UK Primary Immunodeficiency Network and the British Society for Immunology funded a joint project, to address this. A modified Delphi Survey was conducted for the assessment, diagnosis and treatment of the non-infectious blood, respiratory, gut and liver complications of CVID. A steering group of ten consultant immunologists and one nurse specialist developed and reviewed the survey statements and agreed the final recommendations. In total 22 recommendations and three areas for research were developed. This article is protected by copyright. All rights reserved.

PMID: 30724343 [PubMed – as supplied by publisher]

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CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID.

Front Immunol. 2018;9:3135

Authors: Kralickova P, Milota T, Litzman J, Malkusova I, Jilek D, Petanova J, Vydlakova J, Zimulova A, Fronkova E, Svaton M, Kanderova V, Bloomfield M, Parackova Z, Klocperk A, Haviger J, Kalina T, Sediva A

Abstract
Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.

PMID: 30723478 [PubMed – in process]

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A Novel Recessive Mutation of Interferon-γ Receptor 1 in a Patient with Mycobacterium tuberculosis in Bone Marrow Aspirate.

J Clin Immunol. 2019 Feb 05;:

Authors: Shabani M, Aleyasin S, Kashef S, Zoghi S, Deswarte C, Casanova JL, Bustamante J, Rezaei N

Abstract

PMID: 30719685 [PubMed – as supplied by publisher]

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Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

Front Pediatr. 2018;6:426

Authors: Staines Boone AT, Chinn IK, Alaez-Versón C, Yamazaki-Nakashimada MA, Carrillo-Sánchez K, García-Cruz MLH, Poli MC, González Serrano ME, Medina Torres EA, Muzquiz Zermeño D, Forbes LR, Espinosa-Rosales FJ, Espinosa-Padilla SE, Orange JS, Lugo Reyes SO

Abstract
DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

PMID: 30719430 [PubMed]

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TREC and KREC Levels as a Predictors of Lymphocyte Subpopulations Measured by Flow Cytometry.

Front Physiol. 2018;9:1877

Authors: Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Gordleeva S, Molchanov R, Asmanov A, Peshko D, Zinovieva N, Zimin S, Lazarev V, Salpagarova A, Filipenko M, Kozlov I, Prodeus A, Korsunskiy A, Hsu P, Munblit D

Abstract
Primary immunodeficiency diseases (PID) is a heterogeneous group of disorders caused by genetic defects of the immune system, which manifests clinically as recurrent infections, autoimmune diseases, or malignancies. Early detection of other PID remains a challenge, particularly in older children due to milder and less specific symptoms, a low level of clinician PID awareness and poor provision of hospital laboratories with appropriate devices. T-cell recombination excision circles (TREC) and kappa-deleting element recombination circle (KREC) in a dried blood spot and in peripheral blood using real-time polymerase chain reaction (PCR) are used as a tool for severe combined immune deficiency but not in PID. They represent an attractive and cheap target for a more extensive use in clinical practice. This study aimed to assess TREC/KREC correspondence with lymphocyte subpopulations, measured by flow cytometry and evaluate correlations between TREC/KREC, lymphocyte subpopulations and immunoglobulins. We carried out analysis of data from children assessed by clinical immunologists at Speransky Children’s Hospital, Moscow, Russia with suspected immunodeficiencies between May 2013 and August 2016. Peripheral blood samples were sent for TREC/KREC, flow cytometry (CD3, CD4, CD8, and CD19), IgA, IgM, and IgG analysis. A total of 839 samples were analyzed for using TREC assay and flow cytometry and 931 KREC/flow cytometry. TREC demonstrated an AUC of 0.73 (95% CI 0.70-0.76) for CD3, 0.74 (95% CI 0.71-0.77) for CD4 and 0.67 (95% CI 0.63-0.70) for CD8, respectively, while KREC demonstrated an AUC of 0.72 (95% CI 0.69-0.76) for CD19. Moderate correlation was found between the levels of TREC and CD4 (r = 0.55, p < 0.01) and KREC with CD19 (r = 0.56, p < 0.01). In this study, promising prediction models were tested. We found that TREC and KREC are able to moderately detect abnormal levels of individual lymphocyte subpopulations. Future research should assess associations between TREC/KREC and other lymphocyte subpopulations and approach TREC/KREC use in PID diagnosis.

PMID: 30719006 [PubMed]

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An essential role for the Zn2+ transporter ZIP7 in B cell development.

Nat Immunol. 2019 Feb 04;:

Authors: Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, Engelhardt KR, Xu X, Chen R, Alvarez L, Berlinguer-Palmini R, Bull KR, Cawthorne E, Cribbs AP, Crockford TL, Dang TS, Fearn A, Fenech EJ, de Jong SJ, Lagerholm BC, Ma CS, Sims D, van den Berg B, Xu Y, Cant AJ, Kleiner G, Leahy TR, de la Morena MT, Puck JM, Shapiro RS, van der Burg M, Chapman JR, Christianson JC, Davies B, McGrath JA, Przyborski S, Santibanez Koref M, Tangye SG, Werner A, Rutter GA, Padilla-Parra S, Casanova JL, Cornall RJ, Conley ME, Hambleton S

Abstract
Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

PMID: 30718914 [PubMed – as supplied by publisher]

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Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

J Clin Immunol. 2019 Feb 04;:

Authors: Sarrafzadeh SA, Nourizadeh M, Mahloojirad M, Fazlollahi MR, Shokouhi Shoormasti R, Badalzadeh M, Deswarte C, Casanova JL, Pourpak Z, Bustamante J, Moin M

Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients).
METHODS: We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients.
RESULTS: Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations.
CONCLUSIONS: We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.

PMID: 30715640 [PubMed – as supplied by publisher]

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G2-lymphocyte Chromosomal Radiosensitivity in Patients with LPS Responsive Beige-Like Anchor Protein (LRBA) Deficiency.

Int J Radiat Biol. 2019 Feb 04;:1-24

Authors: Mozdarani H, Kiaee F, Fekrvand S, Azizi G, Yazdani R, Zaki-Dizaji M, Mozdarani S, Mozdarani S, Nosrati H, Abolhassani H, Aghamohammadi A

Abstract
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disease characterized by a CVID-like phenotype, particularly severe autoimmunity and inflammatory bowel disease. This study was undertaken to evaluate radiation sensitivity in 11 LRBA-deficient patients. Therefore, stimulated lymphocytes of the studied subjects were exposed to a low dose γ-radiation (100cGy) in the G2 phase of the cell cycle and chromosomal aberrations were scored. Lymphocytes of age-sex matched healthy individuals used in the same way as controls. Based on the G2-assay, six (54.5%) of the patients had higher radiosensitivity score comparing to the healthy control group, forming the radiosensitive LRBA-deficient patients. This chromosomal radiosensitivity showed that these patients are predisposed to autoimmunity and/or malignancy, and should be protected from unnecessary diagnostic and therapeutic procedures using ionizing radiation and exposure to other DNA damaging agents.

PMID: 30714845 [PubMed – as supplied by publisher]

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