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Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions.

J Allergy Clin Immunol. 2016 Feb 4;

Authors: Weisser M, Demel UM, Stein S, Chen-Wichmann L, Touzot F, Santilli G, Sujer S, Brendel C, Siler U, Cavazzana M, Thrasher AJ, Reichenbach J, Essers MA, Schwäble J, Grez M

Abstract
BACKGROUND: Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by dysfunctional microbicidal activity and chronic inflammation.
OBJECTIVE: We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD).
METHODS: We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD.
RESULTS: An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs.
CONCLUSIONS: Persistent chronic inflammation in patients with CGD is associated with hematopoietic proliferative stress, leading to a decrease in the functional activity of HSCs. Our observations have clinical implications for the development of successful autologous cell therapy approaches.

PMID: 26853280 [PubMed – as supplied by publisher]

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Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey.

J Clin Immunol. 2016 Feb 6;

Authors: Sterlin D, Velasco G, Moshous D, Touzot F, Mahlaoui N, Fischer A, Suarez F, Francastel C, Picard C

Abstract
PURPOSE: Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome.
METHODS: Demographic, genetic, immunological, and clinical features were recorded for each patient.
RESULTS: In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1 patients were also detected in two of our ICF1 patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICF patients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1 patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant.
CONCLUSION: Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICF patients has been improved by the combination of IgG replacement and antibiotic prophylaxis.

PMID: 26851945 [PubMed – as supplied by publisher]

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Adverse events following immunization in patients with primary immunodeficiencies.

Vaccine. 2016 Feb 2;

Authors: Sarmiento JD, Villada F, Orrego JC, Franco JL, Trujillo-Vargas CM

Abstract
BACKGROUND: Adverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a “red flag” for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients.
METHODS: Medical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria.
RESULTS: Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients.
CONCLUSIONS: Our study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT).

PMID: 26850760 [PubMed – as supplied by publisher]

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O-003 Understanding the Relevance of Whole Exome Sequencing Identified Variants in Patients with Very Early-Onset-IBD.

Inflamm Bowel Dis. 2016 Mar;22 Suppl 1:S1-S2

Authors: Kelsen J, Dawany N, Conrad M, Martinez A, Mamula P, Piccoli D, Artis D, Sonnenberg G, Baldassano R, Sullivan K, Devoto M

Abstract
BACKGROUND: Very early onset inflammatory bowel disease (VEO-IBD) is frequently considered a different disease process than older onset IBD. The severe phenotype and young age of onset suggest a more pronounced genetic susceptibility and dysregulated immune response. We hypothesized that rare or novel variants involving pathways in barrier defense, autoimmunity as well as both B and T cell development and activation, were enriched in patients with VEO-IBD. In turn, these variants result in altered gene expression, impaired immunological responses, and aberrant host-microbe interactions. Our primary aim is to identify dysregulation in the gene expression profiles of VEO-IBD patients, to determine the down-stream impact of candidate causal variants on the affected immune pathways and to delineate their role in disease pathogenesis.
METHODS: IBD patients 5 years and younger, and parents were recruited. Exome capture was performed by Agilent SureSelect V4, and sequencing was accomplished using the Illumina HiSeq platform. Following functional annotation, single base substitutions likely to alter protein function, such as missense and loss of function mutations, were kept for subsequent analysis. RNA isolated from whole blood collected in Tempus tubes was hybridized to Illumina HumanHT-12v4 arrays to evaluate the downstream effects of the variants on the mRNA product through changes in gene expression.
RESULTS: Three hundred eleven samples were analyzed, including 71 trios. Patients’ age ranged from 3 weeks to 4 years. 4 trios were analyzed for gene expression. WES identified compound heterozygous mutations in FAT1, and a heterozygous variant in BIRC6 in a male diagnosed with severe VEO-IBD at age 2, unresponsive to medical and surgical therapy. FAT1 is an antagonist of caspase-8, and BIRC6 is a member of the Inhibitors of Apoptosis protein (IAP) family. Gene expression demonstrated upregulation of genes involved in leukocyte apoptosis, including CASP7 and CASP8. This increased apoptotic activity is similar to the mechanism seen in XIAP deficiency, a known primary immunodeficiency that can result in VEO-IBD. In addition, there was an upregulation of NAIP, and subsequent down-stream increased anti-microbial activity. NAIP is a component of the NLRC4 inflammasome.
CONCLUSIONS: The association of candidate risk variants with gene expression provides a powerful method to mine WES identified variants. This case illustrates the ability to detect downstream effects of suspected causal variants. Currently there is a paucity of data utilizing this strategy in patients with VEO-IBD. This systems biology-based approach may provide further understanding of the interacting pathways responsible for a subset of disease in VEO-IBD.

PMID: 26849720 [PubMed – as supplied by publisher]

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[Hereditary angioedema in Medellín (Colombia): Clinical evaluation and quality of life appraisal].

Biomedica. 2015 Sep;35(3):419-428

Authors: Sánchez MD, Cuervo J, Rave D, Clemen G, Yepes-Núñez JJ, Ortiz-Reyes B, Sus S, Cardona R

Abstract
INTRODUCTION: Hereditary angioedema is an autosomal dominant primary immunodeficiency caused by a deficiency of the C1 inhibitor protein and characterized by recurrent episodes of subcutaneous and mucosal edema. Unpredictable and frequent crisis of angioedema affect the quality of life of individuals suffering this kind of disorder.
OBJECTIVE: To analyze the clinical characteristics of a family with an index case of hereditary angioedema and to determine the impact of this disease on their quality of life.
MATERIALS AND METHODS: Twenty six members of the family were included in the trial; 25 of them were analyzed for C4 complement and antigenic and functional C1 inhibitor blood levels. Two instruments (SF-365 and KIDSCREEN-27) were used to evaluate adult health quality and children and teenagers quality of life, respectively.
RESULTS: Eighty three percent (83%) of individuals reporting symptoms of the condition exhibited serological criteria of hereditary angioedema type I: low levels of both C4 complement and quantitative (antigenic) and qualitative (functional) C1 inhibitor. In relation to patients’ psychological and emotional performance, their quality of life was significantly affected by the symptoms of hereditary angioedema.
CONCLUSION: This study provides evidence of the first family in Valle de Aburrá (Colombia) characterized as having hereditary angioedema type I. Despite the use of a generic instrument, the negative impact on the quality of life of individuals suffering this disease was also confirmed.

PMID: 26849703 [PubMed – as supplied by publisher]

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Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients.

PLoS One. 2016;11(2):e0145888

Authors: Moorhouse AJ, Rennison C, Raza M, Lilic D, Gow NA

Abstract
Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder characterised by susceptibility to chronic Candida and fungal dermatophyte infections of the skin, nails and mucous membranes. Molecular epidemiology studies of CMC infection are limited in number and scope and it is not clear whether single or multiple strains inducing CMC persist stably or are exchanged and replaced. We subjected 42 C. albicans individual single colony isolates from 6 unrelated CMC patients to multilocus sequence typing (MLST). Multiple colonies were typed from swabs taken from multiple body sites across multiple time points over a 17-month period. Among isolates from each individual patient, our data show clonal and persistent diploid sequence types (DSTs) that were stable over time, identical between multiple infection sites and exhibit azole resistant phenotypes. No shared origin or common source of infection was identified among isolates from these patients. Additionally, we performed C. albicans MLST SNP genotype frequency analysis to identify signatures of past loss of heterozygosity (LOH) events among persistent and azole resistant isolates retrieved from patients with autoimmune disorders including CMC.

PMID: 26849050 [PubMed – as supplied by publisher]

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The Challenge of Immunoglobulin-G Subclass Deficiency and Specific Polysaccharide Antibody Deficiency – a Dutch Pediatric Cohort Study.

J Clin Immunol. 2016 Feb 4;

Authors: Schatorjé EJ, de Jong E, van Hout RW, García Vivas Y, de Vries E

Abstract
PURPOSE: Immunoglobulin(Ig)G-subclass deficiency and specific polysaccharide antibody deficiency (SPAD) are among the most frequent causes of recurrent respiratory infections in children. Little is known about their prevalence, clinical presentation and prognosis. No study has been published in a Western-European nor in a mainly non-tertiary cohort until now. Therefore, we performed this observational cohort study in children recruited from secondary and tertiary pediatric practices all over The Netherlands.
METHODS: Dutch pediatricians were monthly asked to report patients with IgG-subclass deficiency and/or SPAD. Demographic, clinical and laboratory characteristics were collected. Separate informed consent was asked from parents and children (≥12 years of age) for annual update of the medical status.
RESULTS: 49 children with confirmed IgG-subclass deficiency and/or SPAD were included. The majority of children (69 %) was reported by four (out of 12) secondary hospitals with a pediatric immunologist in the staff. 45 children had ≥1 low IgG-subclass level and 11 had SPAD. IgG2 deficiency was the most prevalent IgG-subclass deficiency (37/49;76 %). 10 % of these children already showed bronchiectasis. Two-thirds were male (33/49;67 %, p = 0.015). From 10 years of age, only boys were left and only boys showed progressive immunodeficiency during follow-up (11/24; 46 %).
CONCLUSIONS: This is the first Western-European mainly non-tertiary cohort of children with IgG-subclass deficiency and/or SPAD. The disease course is not always benign, especially in boys. Most children were reported and managed in secondary hospitals with a pediatric immunologist in the staff. To identify more patients, the awareness of these diseases among general pediatricians should increase.

PMID: 26846287 [PubMed – as supplied by publisher]

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Eosinophilic gastroenteritis in a patient with Bruton’s tyrosine kinase deficiency.

Pediatr Int. 2016 Feb 3;

Authors: Yamazaki S, Ohtsuka Y, Yokokura T, Yokota R, Honjo A, Inage E, Baba Y, Mori M, Suzuki R, Iwata T, Shimizu T

Abstract
Eosinophilic gastrointestinal diseases (EGID) are relatively rare diseases characterized by eosinophilic infiltration of the gastrointestinal tract resulting in various gastrointestinal symptoms. EGID are often caused by allergic reactions or systemic eosinophilic disorders, but their comorbidity with Bruton’s tyrosine kinase (BTK) deficiency has not been previously documented. Here, we report a case of eosinophilic gastroenteritis (EG) in a patient with BTK deficiency. Despite adequate replacement immunoglobulin (Ig) therapy, trough serum IgG was not maintained. To identify the underlying cause of the low trough level and chronic diarrhea, the intestine was investigated on endoscopy. We also screened for the variable number of tandem repeat polymorphism in FCGRT. Genetic analysis could not explain the low trough IgG, but endoscopy indicated eosinophilic enterocolitis. EG may be an important differential diagnosis when primary immunodeficiency patients have chronic diarrhea or continued low serum IgG.

PMID: 26840762 [PubMed – as supplied by publisher]

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Disorganisation of the splenic microanatomy in ageing mice.

Immunology. 2016 Feb 3;

Authors: Aw D, Hilliard L, Nishikawa Y, Cadman ET, Lawrence RA, Palmer DB

Abstract
The precise mechanisms responsible for immunosenescence still remain to be determined, however considering the evidence that disruption of the organisation of primary and secondary lymphoid organs results in immunodeficiency, we propose this could be involved in the decline of immune responses with age. Therefore, we investigated the integrity of the splenic microarchitecture in mice of increasing age and its reorganisation following immune challenge in young and old mice. Several differences in the anatomy of the spleen with age in both the immune and stromal cells were observed. There is an age-related increase in the overall size of the white pulp, which occurs primarily within the T cell zone and mirrored by the enlargement of the T cell stromal area, concurrent to the distinct boundary between T cells and B cells becoming less defined in older mice. In conjunction, there appears to be a loss of marginal zone macrophages, which is accompanied by an accumulation of fibroblasts in the spleens from older animals. Furthermore, whereas the reorganisation of the white pulp is resolved after several days following antigenic challenge in young animals, it remains perturbed in older subjects. All these age-related changes within the spleen could potentially contribute to the age-dependent deficiencies in functional immunity. This article is protected by copyright. All rights reserved.

PMID: 26840375 [PubMed – as supplied by publisher]

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Reducing the risk of transfusion-transmitted cytomegalovirus infection: a systematic review and meta-analysis.

Transfusion. 2016 Jan 29;

Authors: Mainou M, Alahdab F, Tobian AA, Asi N, Mohammed K, Murad MH, Grossman BJ

Abstract
BACKGROUND: Leukoreduced (LR) or cytomegalovirus (CMV)-seronegative cellular blood components are commonly used to reduce the risk of transfusion-transmitted CMV infection in high-risk patients.
STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis to evaluate the evidence for the use of LR cellular blood components with or without concurrent CMV testing of donor units in patients undergoing chemotherapy or solid organ and hematopoietic stem cell transplantation, in pregnant women, in very-low-birthweight infants, and in patients with primary immunodeficiency. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1980 through February 2015. Studies were included if they had a comparison group. Two independent reviewers selected and appraised studies. Meta-analysis was performed when appropriate.
RESULTS: Of 457 studies screened, 11 were eligible. One study was excluded from the meta-analysis because the comparison performed differed significantly from the others. Meta-analysis of five studies that compared leukoreduction to transfusing CMV-untested blood components showed no significant difference in clinical CMV infection (relative risk [RR], 0.26; 95% confidence interval [CI], 0.04-1.57) or laboratory CMV infection (RR, 0.33; 95% CI, 0.08-1.37). Meta-analysis of three studies that compared leukoreduction to transfusing CMV-seronegative cellular components showed no significant difference in laboratory CMV infection (RR, 2.18; 95% CI, 0.96-4.98). Meta-analysis of two studies that compared adding CMV testing to leukoreduction (vs. leukoreduction alone) showed no significant difference in clinical or laboratory CMV infection. The certainty in estimates was low for all comparisons.
CONCLUSION: At present, the scientific evidence does not favor a single strategy for reducing the risk of transfusion-related CMV infection in high-risk patients.

PMID: 26826015 [PubMed – as supplied by publisher]

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