Manish Butte

Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus.

Clin Transl Immunology. 2017 Oct;6(10):e159

Authors: Ameratunga R, Koopmans W, Woon ST, Leung E, Lehnert K, Slade CA, Tempany JC, Enders A, Steele R, Browett P, Hodgkin PD, Bryant VL

Abstract
Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies where monogenetic causes account for only a fraction of cases. On this evidence, CVID is potentially polygenic and epistatic although there are, as yet, no examples to support this hypothesis. We have identified a non-consanguineous family, who carry the C104R (c.310T>C) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in TNFRSF13B/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (T168fsX191) in the Transcription Factor 3 (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son. We demonstrate mutations of TNFRSF13B/TACI impair immunoglobulin isotype switching and antibody production predominantly via T-cell-independent signalling, while mutations of TCF3 impair both T-cell-dependent and -independent pathways of B-cell activation and differentiation. We conclude that epistatic interactions between mutations of the TNFRSF13B/TACI and TCF3 signalling networks lead to the severe CVID-like disorder and SLE in the proband.

PMID: 29114388 [PubMed]

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Human plasma C3 is essential for the development of memory B, but not T, lymphocytes.

J Allergy Clin Immunol. 2017 Nov 04;:

Authors: Jiménez-Reinoso A, Marin AV, Subias M, López-Lera A, Román-Ortiz E, Payne K, Ma CS, Arbore G, Kolev M, Freeley SJ, Kemper C, Tangye SG, Fernández-Malavé E, Rodríguez de Córdoba S, López-Trascasa M, Regueiro JR

Abstract
Primary or secondary plasma C3 deficiency due to mutations in C3 or in complement Factor I impairs memory B, but not T, cell differentiation, but does not preclude intracellular C3 fragment expression in lymphocytes.

PMID: 29113906 [PubMed – as supplied by publisher]

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Cancer Therapy-associated Lymphoproliferative Disorders: An Under-Recognized Type of Immunodeficiency-associated Lymphoproliferative Disorder.

Am J Surg Pathol. 2017 Nov 03;:

Authors: Pina-Oviedo S, Miranda RN, Medeiros LJ

Abstract
We describe the clinicopathologic features of 17 patients who had a hematologic malignancy of various types, were treated, and subsequently developed a lymphoproliferative disorder (LPD). There were 10 men and 7 women with a median age of 59 years (range, 36 to 83 y). The primary hematologic neoplasms included: 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, 3 plasma cell myeloma, 2 acute monoblastic leukemia, and 1 case each of mixed-phenotype acute leukemia, chronic myeloid leukemia, splenic marginal zone lymphoma, follicular lymphoma, mantle cell lymphoma, T-cell prolymphocytic leukemia, and peripheral T-cell lymphoma. All patients were treated with chemotherapy with or without therapeutic antibodies; 3 also underwent autologous stem cell transplantation. The mean interval from initiation of therapy for initial hematologic malignancy to onset of LPD was 66 months (range, 3 to 299 mo). Ten (59%) LPDs were extranodal and 7 (41%) involved nodal tissues. The histologic diagnoses included: 8 diffuse large B-cell lymphoma, 4 classical Hodgkin lymphoma, 3 polymorphic LPD, 1 lymphomatoid granulomatosis, and 1 Epstein-Barr virus (EBV) mucocutaneous ulcer. Fourteen cases were EBV. Following the onset of LPD, chemotherapy was administered to 10 (59%) patients. With a median follow-up of 100 months (range, 5 to 328 mo), 8 (47%) patients are alive and 9 (53%) died. One (6%) patient with lymphomatoid granulomatosis underwent spontaneous remission. On the basis of the clinicopathologic features and high prevalence of EBV infection in this cohort, we believe that these LPDs show similarities with other types of immunodeficiency-associated LPDs. We suggest that cancer therapy-associated LPD be included in future classification systems for immunodeficiency-associated LPDs.

PMID: 29112013 [PubMed – as supplied by publisher]

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A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations.

J Clin Invest. 2017 Nov 06;:

Authors: Hoyos-Bachiloglu R, Chou J, Sodroski CN, Beano A, Bainter W, Angelova M, Al Idrissi E, Habazi MK, Alghamdi HA, Almanjomi F, Al Shehri M, Elsidig N, Alaa Eldin M, Knipe DM, AlZahrani M, Geha RS

Abstract
Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium tuberculosis, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.

PMID: 29106381 [PubMed – as supplied by publisher]

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Modulation of the Interleukin-21 Pathway with Interleukin-4 Distinguishes Common Variable Immunodeficiency Patients with More Non-infectious Clinical Complications.

J Clin Immunol. 2017 Nov 04;:

Authors: Desjardins M, Béland M, Dembele M, Lejtenyi D, Drolet JP, Lemire M, Tsoukas C, Ben-Shoshan M, Noya FJD, Alizadehfar R, McCusker CT, Mazer BD

Abstract
PURPOSE: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and clinical manifestations such as infections, autoimmunity, and malignancy. We sought to determine if responsiveness to interleukin-21 (IL-21), a key cytokine for B cell differentiation, correlates with distinct clinical phenotypes in CVID.
METHODS: CVID subjects were recruited through the Canadian Primary Immunodeficiency Evaluative Survey registry. Peripheral blood mononuclear cells were cultured with anti-CD40 ± interferon-gamma, interleukin-4 (IL-4), IL-21, and/or IL-4+IL-21. B cell subpopulations and IgG production were determined at baseline and day 7 by flow cytometry and ELISA. Clinical complications were compared using contingency tables.
RESULTS: CVID subjects exhibited decreased CD27(+) B cells and IgG production after 7 days of stimulation with anti-CD40+IL-21 (p < 0.05). In a subset of subjects [CVID responders (R)], the addition of IL-4 led to significant increases in CD27(+) B cells and IgG (p < 0.05). In CVID non-responders (NR), CD27(+) B cells and IgG remained lower despite the addition of IL-4. CVID NR experienced significantly more non-infectious clinical complications of CVID than R [OR 8.8, 95% confidence interval (CI) 1.6 to 48.13]. Previous studies reported that CVID subjects with ≤ 2% class-switched memory B cells were more at risk of these complications, but no significant association was found among this cohort of subjects [OR 3.5, CI 0.9 to 13.3]. In fact, 34.6% of CVID NR had > 2% class-switched memory B cells at baseline.
CONCLUSIONS: The IL-4 and IL-21 in vitro assays distinguish two groups of CVID subjects and can be used with baseline B cell subpopulation phenotyping to better identify patients experiencing more vs. fewer clinical non-infectious complications and potentially to modulate therapy.

PMID: 29103189 [PubMed – as supplied by publisher]

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Prostaglandin E2 Increases Lentiviral Vector Transduction Efficiency of Adult Human Hematopoietic Stem and Progenitor Cells.

Mol Ther. 2017 Oct 05;:

Authors: Heffner GC, Bonner M, Christiansen L, Pierciey FJ, Campbell D, Smurnyy Y, Zhang W, Hamel A, Shaw S, Lewis G, Goss KA, Garijo O, Torbett BE, Horton H, Finer MH, Gregory PD, Veres G

Abstract
Gene therapy currently in development for hemoglobinopathies utilizes ex vivo lentiviral transduction of CD34(+) hematopoietic stem and progenitor cells (HSPCs). A small-molecule screen identified prostaglandin E2 (PGE2) as a positive mediator of lentiviral transduction of CD34(+) cells. Supplementation with PGE2 increased lentiviral vector (LVV) transduction of CD34(+) cells approximately 2-fold compared to control transduction methods with no effect on cell viability. Transduction efficiency was consistently increased in primary CD34(+) cells from multiple normal human donors and from patients with β-thalassemia or sickle cell disease. Notably, PGE2 increased transduction of repopulating human HSPCs in an immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 gamma receptor null [NSG]) xenotransplantation mouse model without evidence of in vivo toxicity, lineage bias, or a de novo bias of lentiviral integration sites. These data suggest that PGE2 improves lentiviral transduction and increases vector copy number, therefore resulting in increased transgene expression. As a result, PGE2 may be useful in clinical gene therapy applications using lentivirally modified HSPCs.

PMID: 29102562 [PubMed – as supplied by publisher]

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Update on Vaccine-Derived Polioviruses – Worldwide, January 2016-June 2017.

MMWR Morb Mortal Wkly Rep. 2017 Nov 03;66(43):1185-1191

Authors: Jorba J, Diop OM, Iber J, Henderson E, Sutter RW, Wassilak SGF, Burns CC

Abstract
In 1988, the World Health Assembly launched the Global Polio Eradication Initiative (GPEI) (1). Among the three wild poliovirus (WPV) serotypes, only type 1 (WPV1) has been detected since 2012. Since 2014, detection of WPV1 has been limited to three countries, with 37 cases in 2016 and 11 cases in 2017 as of September 27. The >99.99% decline worldwide in polio cases since the launch of the GPEI is attributable to the extensive use of the live, attenuated oral poliovirus vaccine (OPV) in mass vaccination campaigns and comprehensive national routine immunization programs. Despite its well-established safety record, OPV use can be associated with rare emergence of genetically divergent vaccine-derived polioviruses (VDPVs) whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (2). VDPVs can also emerge among persons with primary immunodeficiencies (PIDs). Immunodeficiency-associated VDPVs (iVDPVs) can replicate for years in some persons with PIDs. In addition, circulating vaccine-derived polioviruses (cVDPVs) can emerge very rarely among immunologically normal vaccine recipients and their contacts in areas with inadequate OPV coverage and can cause outbreaks of paralytic polio. This report updates previous summaries regarding VDPVs (3). During January 2016-June 2017, new cVDPV outbreaks were identified, including two in the Democratic Republic of the Congo (DRC) (eight cases), and another in Syria (35 cases), whereas the circulation of cVDPV type 2 (cVDPV2) in Nigeria resulted in cVDPV2 detection linked to a previous emergence. The last confirmed case from the 2015-2016 cVDPV type 1 (cVDPV1) outbreak in Laos occurred in January 2016. Fourteen newly identified persons in 10 countries were found to excrete iVDPVs, and three previously reported patients in the United Kingdom and Iran (3) were still excreting type 2 iVDPV (iVDPV2) during the reporting period. Ambiguous VDPVs (aVDPVs), isolates that cannot be classified definitively, were found among immunocompetent persons and environmental samples in 10 countries. Cessation of all OPV use after certification of polio eradication will eliminate the risk for new VDPV infections.

PMID: 29095803 [PubMed – in process]

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[Pulmonary infection by Arthrographis kalrae in patient with chronic granulomatous disease].

Arch Argent Pediatr. 2017 Dec 01;115(6):e458-e461

Authors: Campoverde Espinoza CJ, Carballo CM, Orlando MN, Hevia AI, Gómez Raccio AC, Di Giovanni D, Bezrodnik L, Vázquez Orlando MS, Cazes CI, López EL

Abstract
BACKGROUND: Arthrographis kalrae is a hyaline fungus that grows forming arthroconidia. It is an opportunistic pathogen that causes infections in immunocompromised as in immunocompetent people and has been rarely isolated from human clinical samples.
CASE REPORT: We describe the case of a male child with primary immunodeficiency who initially presented unilateral pneumonia and progressed to bilateral involvement despite antibiotic, antifungal treatment. A. kalrae was diagnosed by pulmonary biopsy. He received posaconazole with resolution of disease.
CONCLUSIONS: This is the first case of A. kalrae pulmonary infection in a pediatric patient with chronic granulomatous disease in Argentina.

PMID: 29087135 [PubMed – in process]

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