Manish Butte

Invasive Meningococcal Disease Unraveling a Novel Mutation in the C5 Gene in a Portuguese Family.

Pediatr Infect Dis J. 2018 Jul 31;:

Authors: Marujo F, Costa LC, Duarte R, Brito MJ, Cordeiro A, Neves C, Neves JF

Abstract
Although bacterial meningitis is a rare presentation of a congenital immunodeficiency, invasive meningococcal disease (IMD) is classicaly associated with complement deficiencies. We report a patient from a consanguineous kindred presenting with an IMD caused by serogroup B meningococcus that revealed an underlying C5 deficiency caused by a novel mutation in the C5 gene.

PMID: 30067596 [PubMed – as supplied by publisher]

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Comparison of the Percentage of Regulatory T cells and their p-STAT5 Expression in Allergic and Non-Allergic Common Variable Immunodeficiency Patients.

Immunol Invest. 2018 Jul 31;:1-12

Authors: Sadati ZA, Motedayyen H, Sherkat R, Ostadi V, Eskandari N

Abstract
BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by an immunologic deficiency in immunoglobulin production. Regulatory T cells (Tregs) play a key role in preventing the development allergic disorders. p-STAT5 is a known factor for the function and survival of Tregs. This study aimed to investigate the number of Tregs and their p-STAT5 expression in allergic and non-allergic CVID patients.
METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 10 healthy volunteers, 10 allergic patients, and 16 CVID patients (allergic and non-allergic) using Ficoll density centrifugation. The percentage of Tregs in PBMCs was analyzed by flow cytometry. Tregs were also isolated from participants using an immunomagnetic separation method and p-STAT5 expression was evaluated in Tregs using flow cytometry.
RESULTS: The results revealed that Treg percentage was significantly lower in the CVID patients than the control groups (healthy and allergic individuals) (p<0.001). There was a significant reduction in Treg percentage in allergic patients compared to healthy subjects (p<0.05). No significant difference in Treg percentage between allergic and non-allergic CVID patients was observed. The expression of p-STAT5 in Tregs was significantly lower in CVID patients than the control groups (p<0.001). In addition, the expression of p-STAT5 in Tregs of allergic patients was significantly decreased compared to healthy subjects (p<0.001). However, the deference of p-STAT5 level was not statistically significant between allergic and non-allergic CVID patients.
CONCLUSION: These findings suggest that p-STAT5 signaling defect and decreased Treg number may not participate in the development of allergy in CVID patients.

PMID: 30064289 [PubMed – as supplied by publisher]

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Autosomal Recessive Agammaglobulinemia – first case with a novel TCF3 mutation from Pakistan.

Clin Immunol. 2018 Jul 28;:

Authors: Qureshi S, Sheikh MDA, Qamar FN, Bainter W, Chou J, Geha RS

Abstract
Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5-11.

PMID: 30063982 [PubMed – as supplied by publisher]

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Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations.

Clin Immunol. 2018 Jul 28;:

Authors: Dieli-Crimi R, Martínez-Gallo M, Franco-Jarava C, Antolin M, Blasco L, Paramonov I, Semidey ME, Fernández AÁ, Molero X, Velásquez J, Martín-Nalda A, Pujol-Borrell R, Colobran R

Abstract
Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn’s disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β, TNFα). The patient’s 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient’s daughter provides a glimpse of the preclinical phase of the condition.

PMID: 30063981 [PubMed – as supplied by publisher]

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Double Trouble? CMC with a Mutation in both AIRE and STAT1.

J Clin Immunol. 2018 Jul 27;:

Authors: Al Dhanhani H, Al Shehri T, Lilic D, Buddles M, Kisand K, Maccari ME, Leahy TR

PMID: 30054782 [PubMed – as supplied by publisher]

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Clinical and molecular features of X-linked hyper IgM syndrome – An experience from North India.

Clin Immunol. 2018 Jul 24;:

Authors: Rawat A, Mathew B, Pandiarajan V, Jindal A, Sharma M, Suri D, Gupta A, Goel S, Karim A, Saikia B, Minz RW, Imai K, Nonoyama S, Ohara O, Giliani SC, Notarangelo LD, Chan KW, Lau YL, Singh S

Abstract
X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500 G > A, p.G167E and c.156 G > C, p.K52 N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.

PMID: 30053428 [PubMed – as supplied by publisher]

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Spermatogonial quantity in human prepubertal testicular tissue collected for fertility preservation prior to potentially sterilizing therapy.

Hum Reprod. 2018 Jul 25;:

Authors: Stukenborg JB, Alves-Lopes JP, Kurek M, Albalushi H, Reda A, Keros V, Töhönen V, Bjarnason R, Romerius P, Sundin M, Norén Nyström U, Langenskiöld C, Vogt H, Henningsohn L, Mitchell RT, Söder O, Petersen C, Jahnukainen K

Abstract
STUDY QUESTION: Does chemotherapy exposure (with or without alkylating agents) or primary diagnosis affect spermatogonial quantity in human prepubertal testicular tissue?
SUMMARY ANSWER: Spermatogonial quantity is significantly reduced in testes of prepubertal boys treated with alkylating agent therapies or with hydroxyurea for sickle cell disease.
WHAT IS KNOWN ALREADY: Cryopreservation of spermatogonial stem cells, followed by transplantation into the testis after treatment, is a proposed clinical option for fertility restoration in children. The key clinical consideration behind this approach is a sufficient quantity of healthy cryopreserved spermatogonia. However, since most boys with malignancies start therapy with agents that are not potentially sterilizing, they will have already received some chemotherapy before testicular tissue cryopreservation is considered.
STUDY DESIGN, SIZE, DURATION: We examined histological sections of prepubertal testicular tissue to elucidate whether chemotherapy exposure or primary diagnosis affects spermatogonial quantity. Quantity of spermatogonia per transverse tubular cross-section (S/T) was assessed in relation to treatment characteristics and normative reference values in histological sections of paraffin embedded testicular tissue samples collected from 32 consecutive boy patients (aged 6.3 ± 3.8 [mean ± SD] years) between 2014 and 2017, as part of the NORDFERTIL study, and in 14 control samples (from boys aged 5.6 ± 5.0 [mean ± SD] years) from an internal biobank.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Prepubertal boys in Sweden, Finland and Iceland who were facing treatments associated with a very high risk of infertility, were offered the experimental procedure of testicular cryopreservation. Exclusion criteria were testicular volumes >10 ml and high bleeding or infection risk. There were 18 patients with a diagnosis of malignancy and 14 patients a non-malignant diagnosis. While 20 patients had the testicular biopsy performed 1-45 days after chemotherapy, 12 patients had not received any chemotherapy. In addition, 14 testicular tissue samples of patients with no reported testicular pathology, obtained from the internal biobank of the Department of Pathology at Karolinska University Hospital, were included as control samples in addition to reference values obtained from a recently published meta-analysis. The quantity of spermatogonia was assessed by both morphological and immunohistochemical analysis.
MAIN RESULTS AND THE ROLE OF CHANCE: The main finding was a significant reduction in spermatogonial cell counts in boys treated with alkylating agents or with hydroxyurea for sickle cell disease. The mean S/T values in boys exposed to alkylating agents (0.2 ± 0.3, n = 6) or in boys with sickle cell disease and exposed to hydroxyurea (0.3 ± 0.6, n = 6) were significantly lower (P = 0.003 and P = 0.008, respectively) than in a group exposed to non-alkylating agents or in biobank control samples (1.7 ± 1.0, n = 8 and 4.1 ± 4.6, n = 14, respectively). The mean S/T values of the testicular tissue samples included in the biobank control group and the patient group exposed to non-alkylating agents were within recently published normative reference values.
LIMITATIONS, REASONS FOR CAUTION: Normal testicular tissue samples included in this study were obtained from the internal biobank of Karolinska University Hospital. Samples were considered normal and included in the study if no testicular pathology was reported in the analysed samples. However, detailed information regarding previous medical treatments and testicular volumes of patients included in this biobank were not available.
WIDER IMPLICATIONS OF THE FINDINGS: This study summarizes, for the first time, spermatogonial quantity in a prepubertal patient cohort just before and after potentially sterilizing treatments. Boys facing cancer and cytotoxic therapies are regarded as the major group who will benefit from novel fertility preservation techniques. There are no previous reports correlating spermatogonial quantity to cumulative exposure to alkylating agents and anthracyclines (non-alkylating agents) and no information about the timing of cytotoxic exposures among this particular patient cohort. For prepubertal boys in whom fertility preservation is indicated, testicular tissue should be obtained before initiation of chemotherapy with alkylating agents, whilst for those with sickle cell disease and treated with hydroxyurea, this approach to fertility preservation may not be feasible.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from The Swedish Childhood Cancer Foundation (PR2016-0124; TJ2016-0093; PR2015-0073, TJ2015-0046) (J.-B.S. and K.J.), the Jane and Dan Olssons Foundation (2016-33) (J.-B.S.), the Finnish Cancer Society (K.J.), the Foundation for Paediatric Research (J.-B.S.), Kronprinsessan Lovisas Förening För Barnasjukvård/ Stiftelsen Axel Tielmans Minnesfond, Samariten Foundation (J.-B.S.), the Väre Foundation for Paediatric Cancer Research (K.J.) and the Swedish Research Council (2012-6352) (O.S.). R.T.M. was supported by a Wellcome Trust Fellowship (09822). J.P.A.-L. and M.K. were supported by the ITN Marie Curie program ‘Growsperm’ (EU-FP7-PEOPLE-2013-ITN 603568). The authors declare no conflicts of interest.
TRIAL REGISTRATION NUMBER: N/A.

PMID: 30052981 [PubMed – as supplied by publisher]

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Altered Humoral Immune Responses and IgG Subtypes in NOX2-Deficient Mice and Patients: A Key Role for NOX2 in Antigen-Presenting Cells.

Front Immunol. 2018;9:1555

Authors: Cachat J, Deffert C, Alessandrini M, Roux-Lombard P, Le Gouellec A, Stasia MJ, Hugues S, Krause KH

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting from loss of function mutations in the reactive oxygen species generating phagocyte NADPH oxidase (NOX2). CGD patients are prone to infection, but also have an increased susceptibility to autoimmune diseases. The aim of this study was to investigate the role of NOX2 in the regulation of specific immunity. In both CGD patients and NOX2-deficient mice, we observed an alteration in the basal proportions of IgG subtypes. Upon immunization with curdlan-a dectin 1 agonist-NOX2-deficient mice showed increased production of IgG2c compared to controls, and restimulation of lymph node-derived cells led to increased production of IFNγ, but not IL-5, indicative hallmark of an enhanced Th1 response. T cell activation was increased in NOX2-deficient mice and a similar trend was observed in vitro when T cells were co-cultured with NOX2-deficient bone marrow-derived cells. In contrast, no difference in T cell activation was observed when NOX2-deficient T cells were co-cultured with wild-type BMDC. Following stimulation of NOX2-deficient dendritic cells (DCs), no difference in costimulatory molecules was observed, while there was an increase in the release of Th1-driving cytokines. In summary, both CGD patients and CGD mice have an altered IgG subtype distribution, which is associated with an increased IFNγ production. Thus, NOX2 within DCs appears to be an important regulator at the interface of innate and specific immunity, especially after activation of the dectin 1 pathway, limiting immune activation and the development of autoimmunity.

PMID: 30050527 [PubMed]

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Loss of runx1 function results in B cell immunodeficiency but not T cell in adult zebrafish.

Open Biol. 2018 Jul;8(7):

Authors: Chi Y, Huang Z, Chen Q, Xiong X, Chen K, Xu J, Zhang Y, Zhang W

Abstract
Transcription factor RUNX1 holds an integral role in multiple-lineage haematopoiesis and is implicated as a cofactor in V(D)J rearrangements during lymphocyte development. Runx1 deficiencies resulted in immaturity and reduction of lymphocytes in mice. In this study, we found that runx1W84X/W84X mutation led to the reduction and disordering of B cells, as well as the failure of V(D)J rearrangements in B cells but not T cells, resulting in antibody-inadequate-mediated immunodeficiency in adult zebrafish. By contrast, T cell development was not affected. The decreased number of B cells mainly results from excessive apoptosis in immature B cells. Disrupted B cell development results in runx1W84X/W84X mutants displaying a similar phenotype to common variable immunodeficiency-a primary immunodeficiency disease primarily characterized by frequent susceptibility to infection and deficient immune response, with marked reduction of antibody production of IgG, IgA and/or IgM. Our studies demonstrated an evolutionarily conserved function of runx1 in maturation and differentiation of B cells in adult zebrafish, which will serve as a valuable model for the study of immune deficiency diseases and their treatments.

PMID: 30045885 [PubMed – in process]

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Hyper IgE in the Allergy Clinic- when is it Primary Immunodeficiency?

Allergy. 2018 Jul 25;:

Authors: Ponsford MJ, Klocperk A, Pulvirenti F, Dalm VASH, Milota T, Cinetto F, Chovancova Z, Rial MJ, Sediva A, Litzman J, Agostini C, van Hagen M, Quinti I, Jolles S

Abstract
The 2017 International Union of Immunological Societies (IUIS) classification recognises 3 Hyper-IgE Syndromes (HIES), including the prototypic Job’s syndrome (autosomal dominant STAT3-loss of function) and autosomal recessive PGM3 and SPINK5 syndromes. Early diagnosis of PID can direct life-saving or transformational interventions, however remains challenging owing to the rarity of these conditions. This can result in diagnostic delay and worsen prognosis. Within increasing access to ‘clinical-exome’ testing, clinicians need to be aware of the implication and rationale for genetic testing, including the benefits and limitations of current therapies. Extreme elevation of serum IgE have been associated with a growing number of PID syndromes including the novel CARD11 and ZNF341 deficiencies. Variable elevations in IgE are associated with defects in innate, humoral, cellular, and combined immunodeficiency syndromes. Barrier compromise can closely phenocopy these conditions. The aim of this article is to update readers on recent developments at this important interface between allergy and immunodeficiency, highlighting key clinical scenarios which should draw attention to possible immunodeficiency associated with extreme elevation of IgE, and outline initial laboratory assessment and management. This article is protected by copyright. All rights reserved.

PMID: 30043993 [PubMed – as supplied by publisher]

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