Research

Corrigendum: Specific Antibody Deficiency: Controversies in Diagnosis and Management.

Front Immunol. 2018;9:450

Authors: Perez E, Bonilla FA, Orange JS, Ballow M

Abstract
[This corrects the article on p. 586 in vol. 8, PMID: 28588580.].

PMID: 29576764 [PubMed – in process]

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Airway cells from protracted bacterial bronchitis and bronchiectasis share similar gene expression profiles.

Pediatr Pulmonol. 2018 Mar 24;:

Authors: Chen AC, Pena OM, Nel HJ, Yerkovich ST, Chang AB, Baines KJ, Gibson PG, Petsky HL, Pizzutto SJ, Hodge S, Masters IB, Buntain HL, Upham JW

Abstract
AIM: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lower airways in both PBB and bronchiectasis and may cause persistent infections. However, there is a paucity of information available on the pathogenesis of PBB and the factors associated with persistent bacterial infection and progression to bronchiectasis. This study hypothesised that lung immune cells in recurrent PBB and bronchiectasis differentially express genes related to immune cell dysfunction compared to lung immune cells from control subjects.
METHOD: Cells isolated from bronchoalveolar lavage (adult-control and PBB BAL cells) were stimulated with nontypeable Haemophilus influenzae (NTHi), and expression of genes involved in various inflammatory pathways was assessed.
RESULT: NTHi induced production of large amounts of IL-1β, IL-6, and IL-8 in adult-control BAL cells, however BAL cells from PBB airways appeared refractory to NTHi stimulation. BAL cells from PBB and bronchiectasis showed differential expression of several genes relative to control cells, including CCL20, MARCO, CCL24, IL-10, PPAR-γ, CD200R, TREM2, RelB. Expression of genes involved in resolution of inflammation and anti-inflammation response, such as CD200R and IL-10, was associated with the number of pathogenic bacteria found in the airways.
CONCLUSION: In summary, we have shown that the expression of genes related to macrophage function and resolution of inflammation are similar in PBB and bronchiectasis. Lung immune cell dysfunction in PBB and bronchiectasis may contribute to poor bacterial clearance and prolonged resolution of inflammation.

PMID: 29575797 [PubMed – as supplied by publisher]

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Rheumatologic Complications in a Cohort of 227 Patients with Common variable immunodeficiency.

Scand J Immunol. 2018 Mar 24;:e12663

Authors: Azizi G, Kiaee F, Hedayat E, Yazdani R, Dolatshahi E, Alinia T, Sharifi L, Mohammadi H, Kavosi H, Jadidi-Niaragh F, Ziaee V, Abolhassani H, Aghamohammadi A

Abstract
INTRODUCTION: Common variable immunodeficiency (CVID) is the most prevalent symptomatic type of human primary immunodeficiency diseases (PID). Clinically, CVID is characterized by increased susceptibility to infections and a wide variety of autoimmune and rheumatologic disorders.
METHODS: All CVID patients registered in Iranian PID Registry (IPIDR) were enrolled in this retrospective cohort study. We investigated the frequency of rheumatologic diseases and its association with immunological and clinical phenotypes in CVID patients.
RESULTS: A total of 227 CVID patients were enrolled in this study. The prevalence of rheumatologic disorders was 10.1% with a higher frequency in women than men. Most common rheumatologic manifestations were juvenile idiopathic arthritis (JIA) and adult rheumatoid arthritis (RA) followed by juvenile spondyloarthritis (JSpA) and undifferentiated inflammatory arthritis (UIA). Septic arthritis in CVID patients with a history of RA and JIA were higher than patients without rheumatologic complication. CVID patients with a history of autoimmunity (both rheumatologic and non-rheumatologic autoimmunity) had lower regulatory T-cells counts in comparison to patients without autoimmune disorders. There was an association between defect in specific antibody responses and negative serologic test results in patients with rheumatologic manifestations.
CONCLUSION: JIA, RA, JSpA and UIA are the most frequent rheumatologic disorders in CVID patients. Due to antibody deficiency, serologic tests may be negative in these patients. Therefore, these conditions pose significant diagnostic and therapeutic challenges for immunologists and rheumatologists in charge of the care for these patients. This article is protected by copyright. All rights reserved.

PMID: 29574865 [PubMed – as supplied by publisher]

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Role of Hippo signaling in regulating immunity.

Cell Mol Immunol. 2018 Mar 22;:

Authors: Hong L, Li X, Zhou D, Geng J, Chen L

Abstract
The Hippo signaling pathway has been established as a key regulator of organ size control, tumor suppression, and tissue regeneration in multiple organisms. Recently, emerging evidence has indicated that Hippo signaling might play an important role in regulating the immune system in both Drosophila and mammals. In particular, patients bearing a loss-of-function mutation of MST1 are reported to have an autosomal recessive primary immunodeficiency syndrome. MST1/2 kinases, the mammalian orthologs of Drosophila Hippo, may activate the non-canonical Hippo signaling pathway via MOB1A/B and/or NDR1/2 or cross-talk with other essential signaling pathways to regulate both innate and adaptive immunity. In this review, we present and discuss recent findings of cellular mechanisms/functions of Hippo signaling in the innate immunity in Drosophila and in mammals, T cell immunity, as well as the implications of Hippo signaling for tumor immunity.

PMID: 29568120 [PubMed – as supplied by publisher]

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Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency.

Front Immunol. 2018;9:445

Authors: Mace EM

Abstract
Human natural killer (NK) cells play a critical role in the control of viral infections and malignancy. Their importance in human health and disease is illustrated by severe viral infections in patients with primary immunodeficiencies that affect NK cell function and/or development. The recent identification of patients with phosphoinositide-3-kinase (PI3K)-signaling pathway mutations that can cause primary immunodeficiency provides valuable insight into the role that PI3K signaling plays in human NK cell maturation and lytic function. There is a rich literature that demonstrates a requirement for PI3K in multiple key aspects of NK cell biology, including development/maturation, homing, priming, and function. Here, I briefly review these previous studies and place them in context with recent findings from the study of primary immunodeficiency patients, particularly those with hyperactivating mutations in PI3Kδ signaling.

PMID: 29563913 [PubMed]

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Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case.

Front Immunol. 2018;9:420

Authors: Bradshaw G, Lualhati RR, Albury CL, Maksemous N, Roos-Araujo D, Smith RA, Benton MC, Eccles DA, Lea RA, Sutherland HG, Haupt LM, Griffiths LR

Abstract
Background: We investigated the molecular etiology of a young male proband with confirmed immunodeficiency of unknown cause, presenting with recurrent bacterial and Varicella zoster viral infections in childhood and persistent lymphopenia into early adulthood.
Aim: To identify causative functional genetic variants related to an undiagnosed primary immunodeficiency.
Method: Whole genome microarray copy number variant (CNV) analysis was performed on the proband followed by whole exome sequencing (WES) and trio analysis of the proband and family members. A >4 kbp deletion identified by repeated CNV analysis of exome sequencing data along with three damaging missense single nucleotide variants were validated by Sanger sequencing in all family members. Confirmation of the causative role of the candidate gene was performed by qPCR and Western Blot analyses on the proband, family members and a healthy control.
Results: CNV identified our previously reported interleukin 25 amplification in the proband; however, the variant was not validated to be a candidate gene for immunodeficiency. WES trio analysis, data filtering and in silico prediction identified a novel, damaging (SIFT: 0; Polyphen 1; Grantham score: 101) and disease-causing (MutationTaster) single base mutation in the X chromosome (c.511C > T p.Arg171Trp) MSN gene not identified in the UCSC Genome Browser database. The mutation was validated by Sanger sequencing, confirming the proband was hemizygous X-linked recessive (-/T) at this locus and inherited the affected T allele from his non-symptomatic carrier mother (C/T), with other family members (father, sister) confirmed to be wild type (C/C). Western Blot analysis demonstrated an absence of moesin protein in lymphocytes derived from the proband, compared with normal expression in lymphocytes derived from the healthy control, father and mother. qPCR identified significantly lower MSN mRNA transcript expression in the proband compared to an age- and sex-matched healthy control subject in whole blood (p = 0.02), and lymphocytes (p = 0.01). These results confirmed moesin deficiency in the proband, directly causative of his immunodeficient phenotype.
Conclusion: These findings confirm X-linked moesin-associated immunodeficiency in a proband previously undiagnosed up to 24 years of age. This study also highlights the utility of WES for the diagnosis of rare or novel forms of primary immunodeficiency disease.

PMID: 29556235 [PubMed]

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Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications.

Clin Immunol. 2018 Mar 13;:

Authors: De Rose DU, Giliani S, Notarangelo LD, Lougaris V, Lanfranchi A, Moratto D, Martire B, Specchia F, Tommasini A, Plebani A, Badolato R

Abstract
Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

PMID: 29548898 [PubMed – as supplied by publisher]

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Unveiling the Role of Ecto-5′-Nucleotidase/CD73 in Astrocyte Migration by Using Pharmacological Tools.

Front Pharmacol. 2018;9:153

Authors: Adzic M, Nedeljkovic N

Abstract
CD73 is a bifunctional glycosylphosphatidylinositol (GPI)-anchored membrane protein which functions as ecto-5′-nucleotidase and a membrane receptor for extracellular matrix protein (ECM). A large body of evidence demonstrates a critical involvement of altered purine metabolism and particularly, increased expression of CD73 in a number of human disorders, including cancer and immunodeficiency. Massive up-regulation of CD73 was also found in reactive astrocytes in several experimental models of human neuropathologies. In all the pathological contexts studied so far, the increased expression of CD73 has been associated with the altered ability of cells to adhere and/or migrate. Thus, we hypothesized that increased expression of CD73 in reactive astrocytes has a role in the process of astrocyte adhesion and migration. In the present study, the involvement of CD73 in astrocyte migration was investigated in the scratch wound assay (SW), using primary astrocyte culture prepared from neonatal rat cortex. The cultures were treated with one of the following pharmacological inhibitors which preferentially target individual functions of CD73: (a) α,β-methylene ADP (APCP), which inhibits the catalytic activity of CD73 (b) polyclonal anti-CD73 antibodies, which bind to the internal epitope of CD73 molecule and mask their surface exposure and (c) small interfering CD73-RNA (siCD73), which silences the expression of CD73 gene. It was concluded that approaches that reduce surface expression of CD73 increase migration velocity and promote wound closure in the scratch wound assay, while inhibition of the enzyme activity by APCP induces redistribution of CD73 molecules at the cell surface, thus indirectly affecting cell adhesion and migration. Application of anti-CD73 antibodies induces a decrease in CD73 activity and membrane expression, through CD73 molecules shedding and their release to the culture media. In addition, all applied pharmacological inhibitors differentially affect other aspects of astrocyte function in vitro, including reduced cell proliferation, altered expression of adenosine receptors and increased expression of ERK1/2. Altogether these data imply that CD73 participates in cell adhesion/migration and transmits extracellular signals through interactions with ECM.

PMID: 29545748 [PubMed]

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KREC levels remain low or undetectable throughout life in patients with X-linked agammaglobulinemia.

Pediatr Allergy Immunol. 2018 Mar 15;:

Authors: King J, Borte S, Brodszki N, von Döbeln U, Smith CIE, Hammarströma L

Abstract
KREC (kappa-deleting recombining excision circles) quantification has been used in newborn screening programs to identify infants with X-linked agammaglobulinemia (XLA) and other B cell associated forms of primary immunodeficiency disease (PID). We evaluated KREC quantification in patients with XLA at various time points throughout life in order to determine the utility of this assay beyond the newborn period. We found that levels remain consistently low or absent throughout life, thus demonstrating that KREC quantification enables identification of patients with XLA and is a useful diagnostic tool in the newborn period, childhood and adulthood. This article is protected by copyright. All rights reserved.

PMID: 29543351 [PubMed – as supplied by publisher]

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Implanted ports in adults with primary immunodeficiency.

J Vasc Access. 2018 Mar 01;:1129729818757966

Authors: Barton JC, Barton JC, Bertoli LF

Abstract
BACKGROUND: We sought to learn more about the utility and safety of implanted ports for monthly immunoglobulin G infusions in adults with primary immune deficiency.
METHODS: We reviewed charts of adults who were referred to a single practice during the interval 2006-2016 for evaluation and management of frequent or severe upper and lower respiratory tract and other infections, subnormal total immunoglobulin G or immunoglobulin G subclasses, and suboptimal responses to polyvalent pneumococcal polysaccharide vaccinations; were diagnosed to have primary immune deficiency; and were advised to undergo immunoglobulin G therapy.
RESULTS: Of 606 patients, 20 (19 women, 1 man; 16 immunoglobulin G subclass deficiency, 4 common variable immunodeficiency; 3.3%) needed implanted ports because they had inadequate upper extremity superficial venous access. Median age at diagnosis was 48 years (range: 32-65 years). In total, 17 of the 20 patients preferred monthly in-office intravenous immunoglobulin G treatment to weekly at-home subcutaneous immunoglobulin G. The other three patients could not be treated with subcutaneous immunoglobulin G (unfavorable self-treatment experiences and insurance limitations). Median duration of treatment via implanted ports was 73 months (range: 10-153 months). In the man, the first implanted port was replaced after 26 months due to catheter fracture of unknown cause. His second port has been used for 112 months. We observed no other port-related failure, infections, thrombosis, or other adverse events.
CONCLUSION: The utility and safety of implanted ports in adults with primary immune deficiency for whom subcutaneous immunoglobulin G therapy is not desired or feasible are probably similar to those of ports in patients without primary immune deficiency.

PMID: 29542377 [PubMed – as supplied by publisher]

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