Research

Overview of Infections in the Immunocompromised Host.

Microbiol Spectr. 2016 Aug;4(4):

Authors: Dropulic LK, Lederman HM

Abstract
Understanding the components of the immune system that contribute to host defense against infection is key to recognizing infections that are more likely to occur in an immunocompromised patient. In this review, we discuss the integrated system of physical barriers and of innate and adaptive immunity that contributes to host defense. Specific defects in the components of this system that predispose to particular infections are presented. This is followed by a review of primary immunodeficiency diseases and secondary immunodeficiencies, the latter of which develop because of a specific illness or condition or are treatment-related. The effects of treatment for neoplasia, autoimmune diseases, solid organ and stem cell transplants on host defenses are reviewed and associated with susceptibility to particular infections. In conclusion, an approach to laboratory screening for a suspected immunodeficiency is presented. Knowledge of which host defects predispose to specific infections allows clinicians to prevent, diagnose, and manage infections in their immunocompromised patients most effectively.

PMID: 27726779 [PubMed – in process]

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Exome and genome sequencing for inborn errors of immunity.

J Allergy Clin Immunol. 2016 Oct;138(4):957-969

Authors: Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, Pedergnana V, Moens L, Picard C, Cobat A, Bossuyt X, Abel L, Casanova JL

Abstract
The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls. Variant- and gene-level computational methods, as well as immunologic hypotheses, can help narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on 3 key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and selection criteria for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches in order not to assign a condition to an irrelevant variant. Finding the needle in the haystack takes patience, prudence, and discernment.

PMID: 27720020 [PubMed – in process]

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Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency.

Nat Genet. 2016 Oct 10;:

Authors: Bronson PG, Chang D, Bhangale T, Seldin MF, Ortmann W, Ferreira RC, Urcelay E, Pereira LF, Martin J, Plebani A, Lougaris V, Friman V, Freiberger T, Litzman J, Thon V, Pan-Hammarström Q, Hammarström L, Graham RR, Behrens TW

Abstract
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10(-11); ATG13-AMBRA1, P = 6.7 × 10(-10); AHI1, P = 8.4 × 10(-10); CLEC16A, P = 1.4 × 10(-9)) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3(+) regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.

PMID: 27723758 [PubMed – as supplied by publisher]

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DNA ligase IV syndrome; a review.

Orphanet J Rare Dis. 2016 Oct 7;11(1):137

Authors: Altmann T, Gennery AR

Abstract
DNA ligase IV deficiency is a rare primary immunodeficiency, LIG4 syndrome, often associated with other systemic features. DNA ligase IV is part of the non-homologous end joining mechanism, required to repair DNA double stranded breaks. Ubiquitously expressed, it is required to prevent mutagenesis and apoptosis, which can result from DNA double strand breakage caused by intracellular events such as DNA replication and meiosis or extracellular events including damage by reactive oxygen species and ionising radiation.Within developing lymphocytes, DNA ligase IV is required to repair programmed DNA double stranded breaks induced during lymphocyte receptor development.Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to severe combined immunodeficiency. All, however, manifest sensitivity to ionising radiation. Commonly associated features include primordial growth failure with severe microcephaly and a spectrum of learning difficulties, marrow hypoplasia and a predisposition to lymphoid malignancy. Diagnostic investigations include immunophenotyping, and testing for radiosensitivity. Some patients present with microcephaly as a predominant feature, but seemingly normal immunity. Treatment is mainly supportive, although haematopoietic stem cell transplantation has been used in a few cases.

PMID: 27717373 [PubMed – in process]

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Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency.

J Allergy Clin Immunol Pract. 2016 Oct 1;:

Authors: Ramakrishnan KA, Pengelly RJ, Gao Y, Morgan M, Patel SV, Davies EG, Ennis S, Faust SN, Williams AP

Abstract
BACKGROUND: Methylenetetrahydrofolate dehydrogenase (MTHFD1) deficiency has recently been reported to cause a folate-responsive syndrome displaying a phenotype that includes megaloblastic anemia and severe combined immunodeficiency.
OBJECTIVE: To describe our investigative approach to the molecular diagnosis and evaluation of immune dysfunction in a family with MTHFD1 deficiency.
METHODS: The methods used were exome sequencing and analysis of variants in genes involved in the folate metabolic pathway in a family with 2 affected siblings. Routine laboratory and research data were analyzed to gain an in-depth understanding of innate, humoral, and cell-mediated immune function before and after folinic acid supplementation.
RESULTS: Interrogation of exome data for concordant variants between the siblings in the genes involved in folate metabolic pathway identified a heterozygous mutation in exon 3 of the MTHFD1 gene that was shared with their mother. In view of highly suggestive phenotype, we extended our bioinformatics interrogation for structural variants in the MTHFD1 gene by manual evaluation of the exome data for sequence depth coverage of all the exons. A deletion involving exon 13 that was shared with their father was identified. Routine laboratory data showed lymphopenia involving all subsets and poor response to vaccines. In vitro analysis of dendritic cell and lymphocyte function was comparable to that in healthy volunteers. Treatment with folinic acid led to immune reconstitution, enabling discontinuation of all prophylactic therapies.
CONCLUSIONS: Exome sequencing demonstrated MTHFD1 deficiency as a novel cause of a combined immunodeficiency. Folinic acid was established as precision therapy to reverse the clinical and laboratory phenotype of this primary immunodeficiency.

PMID: 27707659 [PubMed – as supplied by publisher]

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Primary immunodeficiencies : Report of 33 Pediatric Tunisian cases.

Tunis Med. 2016 Apr;94(4):320-325

Authors: Halioui-Louhaichi S, Azzabi O, Mattoussi N, Labiadh H, Bousseta K, Tebib N, Gargah T, Ben Becher S, Barbouch MR, Bejaoui M, Maherzi A

Abstract
Background Primary immunodeficiencies (PID) are a group of heterogeneous and relatively rare diseases. Aim to determine the clinical characteristics, outcome and genetic data of primary immunodeficiencies in pediatrics patients. Methods A retrospective, descriptive and multicentered study, enrolling 33 children presenting a PID in Tunis, during a period of 22 years (1991-2012). Resultats a masculine predominance has been noticed with a sex ratio at 2,3. Consanguinity was found in 71% of family cases. History of early infant deaths was found in 42% of cases. The media age of diagnosis was of 1 year 2 months. The median diagnosis delay was of 11 months and 1/2. Most frenquently observed PID were combined immunodeficiency (36%), mostly severe combined immunodeficiency (SCID) (21%), followed by congenial defects of phagocyte function (33%), mostly chronic granulomatosis disease (21%). Antibody defects were found in 21% of cases. Most frequently observed out comes were lung infections (66%) recurrent oral thrush (57%) and diarrhea (42%). Most important complications were severe infections and bronchiectasis. 30% of patients were dead by the end of the study. A molecular characterization was performed in 33% of patients, and an antenatal diagnosis was performed in 10% of cases. Conclusion The PID are a group of disease with variable expressions and etiologies. Their frequency remains understimated in Tunisia, and their management, difficult and insufficient. We suggest the establishment of systematic genetic consulting visit, the creation of a national registry and developing bone marrow transplantation in children in Tunisia.

PMID: 27704518 [PubMed – in process]

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ANNALS EXPRESS: CHITOTRIOSIDASE ENZYME ACTIVITY: IS THIS A POSSIBLE CHRONIC INFLAMMATION MARKER IN CHILDREN WITH COMMON VARIABLE IMMUNODEFICIENCY AND EARLY ATHEROSCLEROSIS?”

Ann Clin Biochem. 2016 Oct 4;:

Authors: Azarsız E, Karaca N, Levent E, Kutukculer N, Sozmen E

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is a rare clinically symptomatic primary immunodeficiency disorder which manifests a wide variability of symptoms, complications. Atherosclerosis in CVID patients have not been investigated yet contrary to other severe clinical complications. We aimed to investigate the chitotriosidase enzyme’s role as an inflammation and atherosclerosis marker in pediatric CVID patients.
METHODS: CVID patients (n =24) and healthy controls (n = 23) evaluated for chitotriosidase activity with other inflammation markers (hsCRP, myeloperoxidase, serum amyloid A, ferritin), lipid profile and echocardiographic findings (carotid artery intima media thickness – cIMT, brachial artery flow-mediated vazodilatation – FMD%).
RESULTS: In patients, mean chitotriosidase activity (8.98 ± 6.28) was significantly higher than controls (5.17 ± 3.42) (p = 0.014). Chitotriosidase showed positive relation with hs-CRP (p = 0.011) and SAA (p = 0.011) but had no relation with ferritin (p = 0.155), HDL (p = 0.152) or LDL – cholesterol (p = 0.380). Mean cIMT increased in patients compared to the controls (p < 0.001) but did not show any relation with chitotriosidase (p = 0.546). FMD% decreased in patients (p < 0.001) also showing no relation with chitotriosidase (p = 0.298). Ventricular myocardial performance indexes had no significant difference, but RV EF% decreased in patients (p = 0.043).
CONCLUSIONS: High chitotriosidase activity in CVID patients demonstrated in vivo the presence of activated macrophages indicating ongoing inflammation. Echocardiographic diastolic functional deficiency, increased cIMT and decreased FMD% may be accepted as early atherosclerotic findings; but none of them showed relationship with chitotriosidase activities. KEY: WORDS: : primary immunodeficiency, chitotriosidase, atherosclerosis, inflammation.

PMID: 27705887 [PubMed – as supplied by publisher]

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mTOR inhibition counterbalances the inflammatory status of immune cells in Chronic Granulomatous Disease.

J Allergy Clin Immunol. 2016 Oct 1;:

Authors: Gabrion A, Hmitou I, Moshous D, Neven B, Lefèvre-Utile A, Diana JS, Suarez F, Picard C, Blanche S, Fischer A, Cavazzana M, Touzot F

Abstract
BACKGROUND: Chronic granulomatous disease (CGD) is primary immunodeficiency caused by defective production of reactive oxygen species in phagocytic cells that results in life-threatening infections and severe inflammatory manifestations. The treatment of inflammatory manifestations remains challenging, as it can be associated with an increased risk of infections. Previous studies have shown that CGD phagocytes display a defect in autophagy and a reactive oxygen species-independent activation of the inflammasome.
OBJECTIVE: Since the intersections between autophagy and inflammasome have been observed in various diseases and microbial infections, we investigated the possible benefit of restoring the autophagy defect through rapamycin – a potent autophagy inducer -in the setting of CGD.
METHODS: We studied fifteen patients diagnosed with CGD and followed in our institution. All patients were free of any active infection at the time of the study.
RESULTS: We show that CGD patients present a consistent inflammatory phenotype defined by (i) increased ‘non-classical’ and ‘intermediate’ monocytes (ii) a pro-inflammatory state of mononuclear phagocytes with increased IL-1β and TNF-α content (iii) a TH17 bias of CD4+ T-cells (iv) and an increase in IL-17A secreting neutrophils. We document the reversion of CGD inflammatory status by the mTOR inhibitor rapamycin on the different immune cell subsets. We also provide evidence for the enhancement of rapamycin inhibitory effect on IL-1β secretion by the IL-1 receptor antagonist anakinra in CGD phagocytes.
CONCLUSION: Altogether these data open new therapeutic approaches for CGD inflammatory manifestations.

PMID: 27702670 [PubMed – as supplied by publisher]

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