Research

Modeling altered T-cell development with human induced pluripotent stem cells from patients with RAG1 mutations and distinct immunological phenotypes.

Blood. 2016 Jun 14;

Authors: Brauer PM, Pessach IM, Clarke E, Rowe JH, Ott de Bruin L, Lee YN, Dominguez-Brauer C, Comeau AM, Awong G, Felgentreff K, Zhang YH, Bredemeyer A, Al-Herz W, Du L, Ververs F, Kennedy M, Giliani S, Keller G, Sleckman BP, Schatz DG, Bushman FD, Notarangelo LD, Zúñiga-Pflücker JC

Abstract
Primary immunodeficiency diseases (PIDs) comprise a group of heterogeneous genetic defects that affect immune system development and/or function. Here we use in vitro differentiation of human induced pluripotent stem cells (iPSCs) generated from patients with different RAG1 mutations to assess T-cell development and T-cell receptor (TCR) V(D)J recombination. RAG1-mutants from severe-combined immune-deficient (SCID) patient cells showed a failure to sustain progression beyond the CD3(-)CD4(-)CD8(-)CD7(+)CD5(+)CD38(-)CD31(-/lo)CD45RA(+) stage of T-cell development to reach the CD3(-/+)CD4(+)CD8(+)CD7(+)CD5(+)CD38(+)CD31(+)CD45RA(-) stage. Despite residual mutant RAG1 recombination activity from an Omenn syndrome (OS) patient, similar impaired T-cell differentiation was observed, due to increased single-strand DNA breaks that likely occur due to heterodimers consisting of both an N-terminal truncated and a catalytically dead RAG1. Furthermore, deep-sequencing analysis of TCRβ and TCRα rearrangements of CD3(-)CD4(+)CD8(-) immature single-positive and CD3(+)CD4(+)CD8(+) double-positive cells showed severe restriction of repertoire diversity with preferential usage of few V-D-J genes, and skewed length distribution of the TCRβ and TCRα complementary-determining-region-3 (CDR3) sequences from SCID and OS iPSC-derived cells, whereas control iPSCs yielded T-cell progenitors with a broadly diversified repertoire. Finally, no TCR-excision-circles (TRECs), a marker of TCRα/δ locus rearrangements, were detected in SCID and OS-derived T-lineage cells, consistent with a pre-TCR block in T-cell development. This study compares human T-cell development of SCID versus OS patients, and elucidates important differences that help to explain the wide range of immunological phenotypes that result from different mutations within the same gene of various patients.

PMID: 27301863 [PubMed – as supplied by publisher]

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Managing Inflammatory Manifestations in Patients with Chronic Granulomatous Disease.

Paediatr Drugs. 2016 Jun 14;

Authors: Magnani A, Mahlaoui N

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by lack of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which results in inflammatory dysregulation and increased susceptibility to infections. Patients with CGD may develop severe obstructive disorders of the digestive tract as a result of their dysregulated inflammatory response. Despite a growing focus on inflammatory manifestations in CGD, the literature data on obstructive complications are far less extensive than those on infectious complications. Diagnosis and management of patients with concomitant predispositions to infections and hyperinflammation are particularly challenging. Although the inflammatory and granulomatous manifestations of CGD usually respond rapidly to steroid treatment, second-line therapies (immunosuppressants and biologics) may be required in refractory cases. Indeed, immunosuppressants (such as anti-tumor necrosis factor agents, thalidomide, and anakinra) have shown some efficacy, but the value of this approach is controversial, given the questionable risk-to-benefit ratio and the small numbers of patients treated to date. Significant progress in allogeneic hematopoietic stem cell transplantation (the only curative treatment for CGD) has been made through better supportive care and implementation of improved, reduced-intensity conditioning regimens. Gene therapy may eventually be an option for patients lacking a suitable donor; clinical trials with new, safer vectors are ongoing at a few centers.

PMID: 27299584 [PubMed – as supplied by publisher]

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Evaluation of cytokine genetic polymorphisms in adult patients with common variable immunodeficiency: A single-center study.

Immunol Lett. 2016 Jun 8;

Authors: Perovic D, Perovic V, Pravica V, Bonaci-Nikolic B, Mijanovic R, Bunjevacki V

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (-308G/A), IFNG (+874 T/A), IL10 (-1082G/A, -819T/C and -592A/C), and IL6 (-174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p=0.006; OR=2.27; 95%CI=1.24-4.17 and p=0.038, OR=15.64; 95%CI=1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p=0.019, OR=0.43, 95%CI=0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p=0.037, OR=1.78, 95% CI=1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p=0.032; OR=2.86; 95% CI=1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms -308G/A TNF and -174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings.

PMID: 27288995 [PubMed – as supplied by publisher]

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Proinflammatory cytokine response toward fungi but not bacteria in chronic granulomatous disease.

J Allergy Clin Immunol. 2016 May 5;

Authors: Gazendam RP, van de Geer A, van Hamme JL, Helgers L, Rohr J, Chrabieh M, Picard C, Roos D, van den Berg JM, van den Berg TK, Kuijpers TW

PMID: 27283382 [PubMed – as supplied by publisher]

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Flebogamma(®) 5 % DIF Intravenous Immunoglobulin for Replacement Therapy in Children with Primary Immunodeficiency Diseases.

J Clin Immunol. 2016 Jun 8;

Authors: Ballow M, Pinciaro PJ, Craig T, Kleiner G, Moy J, Ochs HD, Sleasman J, Smits W

Abstract
PURPOSE: The previous studies with Flebogamma(®) 5 % DIF intravenous immunoglobulin (IVIG) contained insufficient numbers of pediatric subjects to fully warrant a pediatric indication by the FDA. The objective of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma® 5 % DIF for replacement therapy in children (age 2-16) with primary immunodeficiency diseases (PIDD).
METHODS: IVIG was administered at eight clinical sites to 24 subjects with well-defined PIDD at a dose of 300-800 mg/kg every 21-28 days for 12 months. The pharmacokinetics endpoint in this study was the dose-adjusted increment of the serum IgG trough levels.
RESULTS: The calculated serious bacterial infection rate was 0.05/subject/year. The incidence of adverse events considered potentially related to IVIG during or within 72 h after completing an infusion was within the FDA guidance threshold of <40 % at each time point. Dose-adjusted incremental IgG levels remained approximately equal to or slightly greater than pre-study IgG levels (between 800 and 1000 mg/dL throughout) when the subjects were treated with IVIG therapy other than Flebogamma(®) DIF 5 % indicating no evidence of a different pharmacokinetic profile in this pediatric population if compared to those profiles in previous Flebogamma studies in predominately adult populations.
CONCLUSIONS: Flebogamma(®) 5 % DIF is efficacious and safe, has adequate pharmacokinetic properties, is well-tolerated, and maintains the profile of Flebogamma(®) 5 % for the treatment of children with primary humoral immunodeficiency diseases.

PMID: 27279130 [PubMed – as supplied by publisher]

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High frequency of immunodeficiency-like states in systemic lupus erythematosus: a cross-sectional study in 300 consecutive patients.

Rheumatology (Oxford). 2016 Jun 5;

Authors: Perazzio SF, Granados Á, Salomão R, Silva NP, Carneiro-Sampaio M, Andrade LE

Abstract
OBJECTIVE: To determine the frequency of immunodeficiency-like states in SLE and related clinical features.
METHODS: Three hundred and fifteen SLE patients and 301 controls were evaluated for C4A and C4B gene copy number, immunoglobulin isotypes, IgG subclasses, total haemolytic complement (CH50), C2, C3 and neutrophil oxidative burst. C2 and C3 genes were sequenced in cases of low C2 or C3 levels. Those presenting abnormal CH50 with normal C2 and C3 underwent C1q-C9 determination. Patients with active SLE and abnormal results were re-tested after the flare or were excluded if no remission was attained. Fifteen patients were excluded on this basis. Persistent abnormal results characterized an immunodeficiency-like state.
RESULTS: A significantly higher percentage of SLE patients presented an immunodeficiency-like state compared with controls (28.7% vs 3.3%; P < 0.001), especially low immunoglobulin serum levels. Rigorous testing confirmed only two cases of C2 deficiency carriers among the SLE patients. There were significantly more SLE patients with less than two C4A copies compared with controls. SLE patients had higher frequency of low IgG2, IgG3, IgG4 and IgM levels compared with controls. Patients with low IgG3 or IgG4 presented higher frequency of lupus nephropathy. Patients with low IgM had longer disease duration, older age at SLE onset and lower frequency of oral ulcers.
CONCLUSION: An immunodeficiency-like state is present in a sizable fraction of SLE patients. Further studies are warranted to determine the impact of these immunodeficiency states and whether they are a primary condition or are secondary to confounding factors, including SLE itself.

PMID: 27274095 [PubMed – as supplied by publisher]

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Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil.

Rev Bras Reumatol (Rio J). 2016 Jan-Feb;56(1):58-68

Authors: Errante PR, Perazzio SF, Frazão JB, da Silva NP, Andrade LE

Abstract
Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott-Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4(+) lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

PMID: 27267335 [PubMed – as supplied by publisher]

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[Innate immunity primary immunodeficiencies and infections].

Arch Pediatr. 2016 Jun 3;

Authors: Duchamp M, Miot C, Bustamante JC, Picard C

Abstract
The diagnosis of primary immunodeficiency diseases (PIDs) is important for the early and adaptive care of patients and their families. Among the various known PIDs, a number of them concern the innate immune system, which involve a set of cells and mechanisms involved in the host defense by a nonspecific and fast response. The majority of patients with innate immunity defects have a predisposition to one isolated type of infection (bacterial, viral, or fungal), dependent on the genetic defect involved. This article describes the different PIDs involving innate immunity and the immunological investigations allowing for their diagnosis.

PMID: 27266636 [PubMed – as supplied by publisher]

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