Research

Familial segregation of group B streptococcal infection in a consanguineous kindred.

Int J Infect Dis. 2016 Aug 25;

Authors: Licciardi F, Montin D, Versace A, Migliore G, Tzialla C, Fellay J, Borghesi A

Abstract
We describe two cases of neonatal group B streptococcal (GBS) infection occurring in one large consanguineous kindred suggesting that susceptibility to isolated GBS disease in this family may be an inborn error of immunity inherited as a Mendelian autosomal recessive trait.

PMID: 27569828 [PubMed – as supplied by publisher]

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A novel deletion mutation in IL2RG gene results in X-linked severe combined immunodeficiency with an atypical phenotype.

Immunogenetics. 2016 Aug 26;

Authors: Mou W, He J, Chen X, Zhang H, Ren X, Wu X, Ni X, Xu B, Gui J

Abstract
Severe combined immunodeficiency (SCID) is the most serious disorder among primary immunodeficiency diseases threatening children’s life. Atypical SCID variant, presenting with mild reduced T cells subsets, is often associated with infection susceptibility but poor clinical diagnosis. The atypical X-SCID patient in the present study showed a mild clinical presentation with a T(low)NK(+)B(+) immunophenotype. The patient has reduced T- cell subpopulations with a subdued thymic output measured by sjTRECs. Further analysis showed that T cells maintained a normal proliferation and a broad Vβ repertoire. NK cells, however, exhibited a skewed development toward immature CD3(-)CD16(+)CD56(-) cells. Genetic analysis revealed a novel deletion at nucleotide 52 in exon 1 of IL2RG gene. Sequence alignment predicted a truncated IL2RG protein missing signal peptide derived from a possible alternative reading frame. The novel mutation in IL2RG gene identified in our study may help the early diagnosis of atypical X-SCID.

PMID: 27566612 [PubMed – as supplied by publisher]

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[Use of intravenous immunoglobulin in pregnancy. Report of a patient with common variable immunodeficiency].

Rev Alerg Mex. 2016 Jul-Sep;63(3):311-315

Authors: Cambray-Gutiérrez JC, García-Ramírez UN, Del Rivero-Hernández LG, López-Pérez P, Chávez-García A

Abstract
BACKGROUND: Common variable immunodeficiency is the most commonly-diagnosed primary immunodeficiency in adults; it is characterized by recurrent sinopulmonary and gastrointestinal infections, and increased incidence of malignancy and autoimmune processes. Many patients begin to have clinical manifestations during reproductive age.
CASE REPORT: A 34-year-old woman with 12 weeks of gestation who was diagnosed with common variable immunodeficiency after recurrent episodes of rhinosinusitis, pharyngoamygdalitis, and pneumonia. 0.6 g/kg of IVIG was prescribed every 21 days during the second trimester; the patient only presented one episode of pharyngoamygdalitis, with adequate response to treatment with antibiotics. During the third trimester the dose was adjusted to every 14 days. The patient ended the pregnancy at term without complications, with a child without defects and with proper weight and size.
CONCLUSIONS: The administration of immunoglobulin is the main treatment to control common variable immunodeficiency. While the recommended starting dose is 400-800 mg/kg intravenously every 3 to 4 weeks, there is no consensus on the dose to be used in pregnant women. The recommendation is to perform serum level controls before infusion to determine and adjust it.

PMID: 27560919 [PubMed – as supplied by publisher]

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Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease.

Proc Natl Acad Sci U S A. 2016 Aug 24;

Authors: Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, Kuehn HS, Wang H, Yang D, Park YH, Ombrello AK, Blake M, Romeo T, Remmers EF, Chae JJ, Mullikin JC, Güzel F, Milner JD, Boehm M, Rosenzweig SD, Gadina M, Welch SB, Özen S, Topaloglu R, Abinun M, Kastner DL, Aksentijevich I

Abstract
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN (FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.

PMID: 27559085 [PubMed – as supplied by publisher]

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Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.

Blood. 2016 Aug 24;

Authors: Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Long Priel D, Riva D, Mendez L, Uzel G, Freeman AF, Olivier KN, Anderson VL, Currens R, Mackley V, Kang A, Al-Adeli M, Mace E, Orange JS, Kang E, Lockett SJ, Chen, Steinbach PJ, Hsu AP, Zarember KA, Malech HL, Gallin JI, Holland SM

Abstract
Cell motility, division, and structural integrity depend on dynamic remodeling of the cellular cytoskeleton, which is regulated in part by actin polymerization and depolymerization. In three families, we identified four children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death. All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal and neutrophil oxidative burst was increased both basally and upon stimulation. Neutrophil spreading on glass and cell polarization were also impaired. Neutrophil F-actin was elevated 4-fold, suggesting an abnormality in F-actin regulation. Two-dimensional differential in-gel electrophoresis identified abnormal actin-interacting protein 1 (Aip1), encoded by WDR1, in patient samples. Biallelic mutations in WDR1 affecting distinct anti-parallel β-strands of Aip1 were identified in all patients. It has been previously reported that Aip1 regulates cofilin-mediated actin depolymerization, which is required for normal neutrophil function. Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive. Allogeneic stem cell transplantation corrected the immunologic defect in one patient. Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency.

PMID: 27557945 [PubMed – as supplied by publisher]

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Primary T-cell immunodeficiency with functional revertant somatic mosaicism in CD247.

J Allergy Clin Immunol. 2016 Aug 20;

Authors: Marin AV, Jiménez-Reinoso A, Briones AC, Muñoz-Ruiz M, Aydogmus C, Pasick LJ, Couso J, Mazariegos MS, Alvarez-Prado AF, Blázquez-Moreno A, Cipe FE, Haskologlu S, Dogu F, Morín M, Moreno-Pelayo MA, García-Sánchez F, Gil-Herrera J, Fernández-Malavé E, Reyburn HT, Ramiro AR, Ikinciogullari A, Recio MJ, Regueiro JR, Garcillán B

PMID: 27555457 [PubMed – as supplied by publisher]

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Immunoglobulin replacement therapy reduces chronic rhinosinusitis in patients with antibody deficiency.

Int Forum Allergy Rhinol. 2016 Aug 23;

Authors: Walsh JE, Gurrola JG, Graham SM, Mott SL, Ballas ZK

Abstract
BACKGROUND: Patients with primary antibody deficiencies have an increased frequency of sinonasal and pulmonary infections. Immunoglobulin (Ig) replacement is a standard therapy for common variable immunodeficiency (CVID) and other antibody deficiency diseases. Although there is convincing evidence that Ig replacement reduces pulmonary infections, there is little evidence that it reduces sinus infections or abates chronic rhinosinusitis (CRS). This study aims to identify the impact of Ig replacement on CRS in antibody deficiencies.
METHODS: A single-center, retrospective chart review of adult patients from 1995 to 2015 was performed. Inclusion criteria were diagnosis of CVID or specific antibody deficiency (SAD), history of CRS requiring medical and/or surgical management within the year prior to presentation, treatment with Ig replacement therapy, and follow-up interval of at least 1 year after initiating Ig replacement. Patients with secondary immune deficiencies were excluded. Thirty-one patients met criteria. Data collected included pretreatment and posttreatment Lund-Mackay scores, and frequency of sinusitis and pulmonary infections requiring rescue antibiotics. Statistical analysis was performed using Wilcoxon signed-rank tests.
RESULTS: A significant decline in the Lund-Mackay score was evidenced from pretreatment to posttreatment (p < 0.01). Treatment also resulted in significantly lower rates of sinusitis (p < 0.01) and pulmonary infections (p < 0.01). Additionally, 56% of patients who were on prophylactic antibiotics prior to Ig replacement were able to discontinue their use.
CONCLUSION: We present objective evidence showing that Ig replacement therapy has a positive impact on the frequency of sinusitis and confirm its positive impact on pulmonary infections in adult patients with CVID and SAD.

PMID: 27552393 [PubMed – as supplied by publisher]

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Immunoglobulin G Subclass Deficiencies in Adult Patients with Chronic Airway Diseases.

J Korean Med Sci. 2016 Oct;31(10):1560-5

Authors: Kim JH, Park S, Hwang YI, Jang SH, Jung KS, Sim YS, Kim CH, Kim C, Kim DG

Abstract
Immunoglobulin G subclass deficiency (IgGSCD) is a relatively common primary immunodeficiency disease (PI) in adults. The biological significance of IgGSCD in patients with chronic airway diseases is controversial. We conducted a retrospective study to characterize the clinical features of IgGSCD in this population. This study examined the medical charts from 59 adult patients with IgGSCD who had bronchial asthma or chronic obstructive pulmonary disease (COPD) from January 2007 to December 2012. Subjects were classified according to the 10 warning signs developed by the Jeffrey Modell Foundation (JMF) and divided into two patient groups: group I (n = 17) met ≥ two JMF criteria, whereas group II (n = 42) met none. IgG3 deficiency was the most common subclass deficiency (88.1%), followed by IgG4 (15.3%). The most common infectious complication was pneumonia, followed by recurrent bronchitis, and rhinosinusitis. The numbers of infections, hospitalizations, and exacerbations of asthma or COPD per year were significantly higher in group I than in group II (P < 0.001, P = 0.012, and P < 0.001, respectively). The follow-up mean forced expiratory volume (FEV1) level in group I was significantly lower than it was at baseline despite treatment of asthma or COPD (P = 0.036). In conclusion, IgGSCD is an important PI in the subset of patients with chronic airway diseases who had recurrent upper and lower respiratory infections as they presented with exacerbation-prone phenotypes, decline in lung function, and subsequently poor prognosis.

PMID: 27550483 [PubMed – in process]

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Cancer and mTOR inhibitors in Transplant Recipients.

Transplantation. 2016 Aug 10;

Authors: de Fijter JW

Abstract
Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma and posttransplant lymphoproliferative disease (PTLD) have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated post-transplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors such as Kaposi sarcoma and mantle cell lymphoma. Since mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. Nonmelanoma skin cancers, in particular cutaneous squamous cell carcinoma (SCC), have the highest standardized incidence ratios in transplant recipients. Recent meta-analyses and randomized trials on secondary prevention of SCC observed a reduction in cumulative tumor load, suggesting most benefit to be gained by early conversion to an mTOR inhibitor-based maintenance regime. There is ongoing debate on the mechanisms involved including withdrawal of the carcinogenic effects of calcineurin inhibitors and/or their impact on chronic (oncogenic) viral infections. At the present there is, however, insufficient evidence for the primary use of mTORis as protective agents against most other cancer types.

PMID: 27547865 [PubMed – as supplied by publisher]

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Important Factors Influencing Severity of Common Variable Immunodeficiency.

Arch Iran Med. 2016 Aug;19(8):544-550

Authors: Mokhtari M, Shakeri A, Mirminachi B, Abolhassani H, Yazdani R, Grimbacher B, Aghamohammadi A

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is a primary immune deficiency with heterogeneous complications. The purpose of this study is to determine disease severity in a cohort of CVID patients based on the suggested scoring system and investigate predisposing factors which would be helpful to predict the severity of the disease.
METHODS: The study population comprised 113 CVID patients (69 males and 44 females) who were visited at Children’s Medical Center (Pediatrics Center of Excellence affiliated to Tehran University of Medical Sciences, Tehran, Iran) during the last 30 years (from 1984-2014). According to a suggested severity scoring system, patients were divided into two groups, A and B. The clinical severity of the disease in patients was assessed with severity scores including 15 unlucky complications of the disease such as numbers of past meningitis, encephalitis or pneumonias, development of bronchopulmonary pathologies, presence of lymphoproliferative disorders, autoimmunity or malignancy.
RESULTS: The mean serum IgG level was significantly higher in group B (308.6±195.9) compared to group A (177.8 ± 151.9; P = 0.03). Patients in group B had a significantly higher percentage of CD8 (P = 0.003). However, they had lower percentage of CD4 lymphocytes (P = 0.08), switched memory B cells (CD27+IgM-IgD-) (P < 0.01) and regulatory T cells (P = 0.02) than group A.
CONCLUSION: Using standard and universal scoring system and understanding of related factors can be applicable in clinical settings for prognosis assessment of CVID patients.

PMID: 27544362 [PubMed – as supplied by publisher]

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