Manish Butte

[Interpretation of primary immunodeficiency diseases classification (2017 in London) update].

Zhonghua Er Ke Za Zhi. 2018 Sep 02;56(9):648-650

Authors: Yang X, Zhao XD

PMID: 30180401 [PubMed – in process]

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Short telomere syndromes cause a primary T cell immunodeficiency.

J Clin Invest. 2018 Sep 04;:

Authors: Wagner CL, Hanumanthu VS, Talbot CC, Abraham RS, Hamm D, Gable DL, Kanakry CG, Applegate CD, Siliciano J, Jackson JB, Desiderio SV, Alder JK, Luznik L, Armanios M

Abstract
The mechanisms that drive T cell aging are not understood. We report children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell aging phenotypes seen in adults five decades older including depleted naïve T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting newborn screening may identify individuals with germline telomere maintenance defects. Telomerase null mice with short TL showed defects throughout T cell development including increased apoptosis of stimulated thymocytes, their intra-thymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells up-regulated DNA damage and intrinsic apoptosis pathways, while older adult T cells up-regulated extrinsic apoptosis pathways and PD-1 expression. T cells from mice with short TL also showed an active DNA damage response, in contrast to old wild-type mice, despite their shared propensity to apoptosis. Our data suggest there are telomere length-dependent and telomere length-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.

PMID: 30179220 [PubMed – as supplied by publisher]

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A Novel Homozygous JAK3 Mutation Leading to T-B+NK- SCID in Two Brazilian Patients.

Front Pediatr. 2018;6:230

Authors: Barreiros LA, Segundo GRS, Grumach AS, Torgerson TR, Ochs HD, Condino-Neto A

Abstract
We report a novel homozygous JAK3 mutation in two female Brazilian SCID infants from two unrelated kindreds. Patient 1 was referred at 2 months of age due to a family history of immunodeficiency and the appearance of a facial rash. The infant was screened for TRECs (T-cell receptor excision circles) and KRECs (kappa-deleting recombination excision circles) for the assessment of newly formed naïve T and B cells respectively, which showed undetectable TRECs and normal numbers of KRECs. Lymphocyte immunophenotyping by flow cytometry confirmed the screening results, revealing a T-B+NK- SCID. The patient underwent successful HSCT. Patient 2 was admitted to an intensive care unit at 8 months of age with severe pneumonia, BCGosis, and oral moniliasis; she also had a positive family history for SCID but newborn screening was not performed at birth. At 10 months of age she was diagnosed as a T-B+NK- SCID and underwent successful HSCT. JAK3 sequencing revealed the same homozygous missense mutation (c.2350G>A) in both patients. This mutation affects the last nucleotide of exon 17 and it is predicted to disrupt the donor splice site. cDNA sequencing revealed skipping of exon 17 missing in both patients, confirming the predicted effect on mRNA splicing. Skipping of exon 17 leads to an out of frame deletion of 151 nucleotides, frameshift and creation of a new stop codon 60 amino acids downstream of the mutation resulting in a truncated protein which is likely nonfunctional.

PMID: 30177960 [PubMed]

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The Rare Anaphylaxis-Associated FcγRIIa3 Exhibits Distinct Characteristics From the Canonical FcγRIIa1.

Front Immunol. 2018;9:1809

Authors: Anania JC, Trist HM, Palmer CS, Tan PS, Kouskousis BP, Chenoweth AM, Kent SJ, Mackay GA, Hoi A, Koelmeyer R, Slade C, Bryant VL, Hodgkin PD, Aui PM, van Zelm MC, Wines BD, Hogarth PM

Abstract
FcγRIIa is an activating FcγR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcγRIIa1. A unique splice variant, we designated FcγRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcγRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcγRIIa forms from macaque and human PBMCs were investigated for IgG-subclass specificity, biochemistry, membrane localization, and functional activity. Disease-associated SNPs were analyzed by sequencing genomic DNA from 224 individuals with immunodeficiency or autoimmune disease. FcγRIIa3 was identified in macaque and human PBMC. The FcγRIIa3 is distinguished from the canonical FcγRIIa1 by a unique 19-amino acid cytoplasmic insertion and these two FcγRIIa forms responded distinctly to antibody ligation. Whereas FcγRIIa1 was rapidly internalized, FcγRIIa3 was retained longer at the membrane, inducing greater calcium mobilization and cell degranulation. Four FCGR2A SNPs were identified including the previously reported intronic SNP associated with anaphylaxis, but in only 1 of 224 individuals. The unique cytoplasmic element of FcγRIIa3 delays internalization and is associated with enhanced cellular activation. The frequency of the immunodeficiency-associated SNP varies between disease populations but interestingly occurred at a lower frequency than previously reported. None-the-less enhanced FcγRIIa3 function may promote a proinflammatory environment and predispose to pathological inflammatory responses.

PMID: 30177930 [PubMed – in process]

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[Bronchiectasis severity in adult patients with common variable immunodeficiency].

Rev Alerg Mex. 2018 Jul-Sep;65(3):162-169

Authors: Vivas-Rosales IJ, Hernández-Ojeda M, O’Farrill-Romanillos PM, Herrera-Sánchez DA, Maciel-Fierro AE, Núñez-Enríquez JC

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is the most common primary symptomatic humoral immunodeficiency in adults. Antibody deficiency entails higher susceptibility to sinopulmonary infections and bronchiectasis formation, which is related to increased mortality. Scales have been established to assess the degree of severity of bronchiectasis in order to predict outcomes such as mortality, exacerbations and hospitalizations.
OBJECTIVE: To determine bronchiectasis severity in adult patients with common variable immunodeficiency using the Brief Symptom Inventory scale.
METHOD: Cross-sectional study in adult population diagnosed with common variable immunodeficiency and attended to at the Mexican Institute of Social Security National Medical Center Siglo XXI Specialty Hospital.
RESULTS: Bronchiectasis severity according to the Brief Symptom Inventory was mild in 60% of patients and moderate in 40%. Statistically significant differences were found for body mass index, number of affected lobes and type of bronchiectasis (p < 0.001).
CONCLUSIONS: Using bronchiectasis severity scales in patients with common variable immunodeficiency is indispensable for clinical and therapeutic decision making; however, determining the most appropriate instrument to assess bronchiectasis severity in this population is necessary.

PMID: 30176202 [PubMed – in process]

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Nasopharyngeal Carriage Prevalence, Serotype Distribution and Antimicrobial Resistance of Streptococcus Pneumoniae Among Children with Chronic Diseases.

Jpn J Infect Dis. 2018 Aug 31;:

Authors: Pekuz S, Soysal A, Akkoc G, Atıcı S, Yakut N, Gelmez GA, Kadayifci EK, Güneser D, Demir SO, Söyletir G, Bakır M

Abstract
The aim of this study is to evaluate the nasopharyngeal (NP) carriage prevalence, serotype distribution and antimicrobial resistance of Streptococcus pneumoniae (SP) in children with chronic diseases that predispose them to invasive pneumococcal disease (IPD) in comparison with healthy children.A cross sectional prevalence study was performed between February 2015 and February 2016 in Istanbul, Turkey. We enrolled 1024 children with chronic diseases and 394 healthy children aged 0-18 years.Overall prevalence of SPNP carriage was 9.8%. The prevalence of SPNP carriage among the healthy children was 8.4%, and among the children with chronic diseases, it was 10.3%.The prevalences of carriage were 17.5%, 13.5%, 10.5%, 9.3%, 8.6%, 8.6%, 8%, 6.7% and 4%, respectively, in each of the following risk groups: primary immunodeficiency, asthma, chronic renal failure, congenital heart diseases, chronic lung disease, leukemia, nephrotic syndrome, solid organ tumors and type 1 diabetes mellitus In the multivariate analysis, history of otitis media within the last year, history of pneumonia within the last year, and number of siblings age under 8 years more than one, were found to be independent risk factors for SPNP carriage in whole study population..

PMID: 30175734 [PubMed – as supplied by publisher]

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Chronic norovirus infection in primary immune deficiency disorders: an international case series.

Diagn Microbiol Infect Dis. 2018 Aug 12;:

Authors: Rolfes MC, Sriaroon P, Dávila Saldaña BJ, Dvorak CC, Chapdelaine H, Ferdman RM, Chen K, Jolles S, Patel NC, Kim YJ, Tarrant TK, Martelius T, Seppanen M, Joshi AY

Abstract
OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking.
METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society’s CIS-PIDD Listserv e-mail group.
RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/μL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy.
CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.

PMID: 30174143 [PubMed – as supplied by publisher]

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Advances Series, Advances and Highlights In Primary Immunodeficiencies 2017.

J Allergy Clin Immunol. 2018 Aug 28;:

Authors: Chinen J, Cowan MJ

Abstract
This manuscript reviews selected topics in primary immunodeficiency diseases (PIDD) published in 2017. These include: 1. The role of follicular T cells in the differentiation of B cells and development of optimal antibody responses. 2. Impaired NFkB1 signaling in the pathogenesis of common variable immunodeficiency (CVID) revealing an association between impaired B cell maturation and development of inflammatory conditions. 3. Autoimmune and inflammatory manifestations in PIDDs in T and B cell deficiencies, as well as in neutrophil disorders. 4. Newly described gene defects causing PIDD including: exostosin-like 3 (EXTL3), TNF-α-induced protein 3 (TNFAIP3, A20), ARPC1B (actin-related protein 2/3 complex-subunit 1B), v-Rel avian reticuloendotheliosis viral oncogene homolog A (RELA), hypoxia upregulated 1 (HYOU1), BTB Domain And CNC Homolog 2 (BACH2), CD70 and CD55. 5. The use of rapamycin and a PI3K inhibitor, leniolisib, to reduce autoimmunity and regulate B cell function in the activated phosphoinositide 3-kinase δ syndrome (APDS). 6. Improved outcomes in hematopoietic stem cell transplantation (HSCT) for severe combined immunodeficiency (SCID) in the last decade with an overall two-year survival of 90%, in part due to early diagnosis by the implementation of universal newborn screening. 7. The demonstration of efficacy of lentiviral vector mediated gene therapy for ADA-SCID. 8. The promise of gene editing for PIDD using CRISPR/Cas9 and Zinc Finger Nuclease technology for SCID and chronic granulomatous disease (CGD). 9. The efficacy of thymus transplantation in Europe, although associated with an unexpected high incidence of autoimmunity. Thus, remarkable progress in the understanding and management of PIDDs reflects the current interest in this area and continues to improve the care of immunodeficient patients.

PMID: 30170128 [PubMed – as supplied by publisher]

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Risk factors for H. influenzae and pneumococcal respiratory tract colonization in CVID.

J Allergy Clin Immunol. 2018 Aug 28;:

Authors: Pulvirenti F, Camilli R, Giufrè M, Milito C, Pimentel de Araujo F, Mancini F, Cardines R, Ciervo A, Pantosti A, Cerquetti M, Quinti I

Abstract
In patients affected by severe primary antibody deficiencies, H. influenzae and S. pneumoniae airways colonization is a risk factor for upper tract respiratory infections. Recent antibiotic usage influences the emergence of antibiotic-resistant bacteria.

PMID: 30170126 [PubMed – as supplied by publisher]

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