Research

Chemokine, cytokine and type I interferon production induced by Toll-like receptor activation in common variable immune deficiency.

Clin Immunol. 2016 Jul 5;

Authors: de Lollo C, de Moraes Vasconcelos D, da Silva Oliveira LM, Domingues R, de Carvalho GC, da Silva Duarte AJ, Sato MN

Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficiency and is associated with recurrent infections and chronic inflammatory diseases. We evaluated the ability of Toll-like receptor (TLR) ligands to induce secretion of chemokines, cytokines and type I interferons by peripheral blood mononuclear cells (PBMCs) from CVID patients. High levels of CXCL10, CCL2, CXCL9, CCL5, CXCL8, and IL-6 were detected in sera of CVID patients compared with healthy controls. Increased chemokine levels were observed in unstimulated PBMCs, but after stimulation with TLR2 and TLR4 agonists, equivalent chemokine and pro-inflammatory cytokine secretion, as in healthy controls, was observed, whereas TLR4 agonist induced a decreased secretion of CCL2 and CXCL8 and increased secretion of TNF. Decreased IFN-α secretion induced by TLR7/TLR8 activation was observed in CVID, which was recovered with TLR9 signaling. Our findings revealed that TLR9 activation has an adjuvant effect on the altered type I response in CVID.

PMID: 27392462 [PubMed – as supplied by publisher]

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Autoimmunity and infection in common variable immunodeficiency (CVID).

Autoimmun Rev. 2016 Jul 6;

Authors: Patuzzo G, Barbieri A, Tinazzi E, Veneri D, Argentino G, Moretta F, Puccetti A, Lunardi C

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of diseases, characterized by primary hypogammaglobulinemia. B and T cell abnormalities have been described in CVID. Typical clinical features of CVID are recurrent airway infections; lymphoproliferative, autoinflammatory, or neoplastic disorders; and autoimmune diseases among which autoimmune thrombocytopenia (ITP) is the most common. The coexistence of immunodeficiency and autoimmunity appears paradoxical, since one represents a hypoimmune state and the other a hyperimmune state. Considering both innate and adaptive immune response abnormalities in CVID, it is easier to understand the mechanisms that lead to a breakdown of self-tolerance. CD21(low) B cells derive from mature B cells that have undergone chronic immune stimulation; they are increased in CVID patients. The expansion of CD21(low) B cells is also observed in certain autoimmune diseases. We have studied CD21(low) B cells in patients with CVID, CVID, and ITP and with ITP only. We observed a statistically significant increase in the CD21(low) population in the three pathological groups. Moreover, we found statistical differences between the two groups of CVID patients: patients with ITP had a higher percentage of CD21(low) cells. Our data suggest that CD21(low) cells are related to autoimmunity and may represent a link between infection and autoimmunity.

PMID: 27392505 [PubMed – as supplied by publisher]

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Expanding the Phenotype of TRNT1-Related Immunodeficiency to Include Childhood Cataract and Inner Retinal Dysfunction.

JAMA Ophthalmol. 2016 Jul 7;

Authors: Hull S, Malik AN, Arno G, Mackay DS, Plagnol V, Michaelides M, Mansour S, Albanese A, Brown KT, Holder GE, Webster AR, Heath PT, Moore AT

Abstract
Importance: A multiorgan syndromic disorder characterized by sideroblastic anemia, immunodeficiency, periodic fever, and developmental delay with an uncharacterized retinal dystrophy is caused by TRNT1. This report of a family with a homozygous mutation in TRNT1 expands the ocular phenotype to include cataract and inner retinal dysfunction and details a mild systemic phenotype.
Observations: A consanguineous family with 3 affected children was investigated. Key clinical features comprised hypogammaglobulinemia, short stature with microcephaly, cataract, and inner retinal dysfunction without sideroblastic anemia or developmental delay. Two siblings had poor balance and 1 sibling had sensorineural hearing loss. The oldest sibling had primary ovarian failure diagnosed at age 14.5 years. Exome sequencing identified a homozygous missense variant in TRNT1, c.295C>T (p.Arg99Trp) in all 3 patients. The sibling with hearing loss also harbored a homozygous mutation in GJB2, c.71G>A (p.Trp24*), which is an established cause of sensorineural hearing loss.
Conclusions and Relevance: This family expands the ocular and systemic phenotypes associated with mutations in TRNT1, demonstrating phenotypic variability and highlighting the need for ophthalmic review of these patients.

PMID: 27389523 [PubMed – as supplied by publisher]

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An orthotopic mouse model of small cell lung cancer reflects the clinical course in patients.

Clin Exp Metastasis. 2016 Jul 6;

Authors: Taromi S, Kayser G, von Elverfeldt D, Reichardt W, Braun F, Weber WA, Zeiser R, Burger M

Abstract
Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with very poor prognosis due to early metastatic spread and development of chemoresistance. In the last 30 years the study of SCLC has been constrained by a lack of primary human tumor specimen thus highlighting the need of a suitable mouse model. In this article we present the establishment of an orthotopic xenograft mouse model which accurately reproduced the clinical course of SCLC. Orthotopic implantation enabled engraftment of primary lung tumors in all injected mice. Furthermore, immunodeficiency of mice allowed formation of spontaneous metastases in characteristic organs. Bioluminescence Imaging, Magnetic Resonance Imaging and Positron emission tomography were applied to monitor engraftment, metabolism and the exact growth of tumors over time. In order to mimic the extensive disease stage, mice were injected with aggressive human chemoresistant cells leading to development of chemoresistant tumors and early metastatic spread. As a proof of concept treatment of tumor-bearing mice with conventional chemotherapeutics reduced tumor volumes, but a complete regression of tumors was not achieved. By mimicking the extensive disease stage our mouse model can facilitate the study of mechanisms contributing to chemoresistance and metastasis formation, as well as drug screening and evaluation of new treatment strategies for SCLC patients.

PMID: 27380917 [PubMed – as supplied by publisher]

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Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.

Front Immunol. 2016;7:220

Authors: Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, Cunningham-Rundles C

Abstract
Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.

PMID: 27379089 [PubMed – as supplied by publisher]

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T Cell Abnormalities in Common Variable Immunodeficiency.

J Investig Allergol Clin Immunol. 2016 Apr 15;26(4)

Authors: Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, Aghamohammadi A

Abstract
Common variable immunodeficiency (CVID) is the most common clinical primary immunodeficiency, which characterized by defect in B cells differentiation to plasma and memory B cells. Moreover, numerous T cell abnormalities have been described in these patients such as, decreased T cell count and proliferative response, increased of T cell activation and apoptosis, and abnormalities in cytokine production. The aim of this review is to describe phenotypic and functional defects of T cells in CVID patients, and to review the literature with respect to the effects of immunoglobulin substitution on the T cell component of CVID patients.

PMID: 27374799 [PubMed – as supplied by publisher]

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Comprehensive activities to increase recognition of primary immunodeficiency and access to immunoglobulin replacement therapy in Poland.

Eur J Pediatr. 2016 Jun 29;

Authors: Pac M, Bernatowska E

Abstract
The study presents an overview on current situation of primary immunodeficiency (PID) patients in Poland and the 2014 annual report of the Polish Working Group for Immunodeficiency (PWGID). The group was set up in 2005 to improve diagnosis, treatment, and care of patients with immunodeficiencies and currently includes 15 pediatric and 13 adult centers. According to PWGID report 4099, PID patients are recognized in Poland, with the prevalence 10.6/100,000. The majority of them (54.2 %) have predominantly antibody deficiency (PAD). In 2014 alone, a total number of 731 newly diagnosed individuals are reported. As predicted, the vast majority (70 %) of them have PAD. Approximately one third of PAD patients require immunoglobulin replacement therapy. Within the entire cohort, an intravenous route of immunoglobulin therapy dominates (67.3 %). However, within the age groups, distribution of immunoglobulin therapy varies and seems to be age related. Among children, 36 % receive subcutaneous immunoglobulin, while with adults 26 %.
CONCLUSION: Analysis of numbers of either newly recognized or treated patients indicates its dynamic increase in recent years. This is the result of comprehensive activities by PWGID supported by governmental institutions, outstanding foundations, and patient’s organization.
WHAT IS KNOWN: • Immunoglobulins’ treatment has substantially changed the life of individuals with PAD. Patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinemia (XLA) can live and lead a near normal life. Early diagnosis of the disease followed by earlier implementation of appropriate treatment, including gammaglobulin replacement therapy, improves the quality of life. • Targeted efforts of health care professionals and government are required to optimize diagnostic and therapeutic approach for PAD. What is New: • Comprehensive activities of PWGID lead to better recognition of PID individuals and should improve reporting Polish PIDs to the ESID database. • Following the joint efforts of immunologists, patient’s, and governmental organizations in the end of 2014, the Therapeutic Program for Treatment Adults with PID was introduced, leading to universal access to currently available treatment options and to improve the quality of life.

PMID: 27357411 [PubMed – as supplied by publisher]

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Seroprevalence and Risk Factors of Varicella Zoster Infection in Iranian Adolescents: A Multilevel Analysis; The CASPIAN-III Study.

PLoS One. 2016;11(6):e0158398

Authors: Hoseini SG, Kelishadi R, Kasaeian A, Ataei B, Yaran M, Motlagh ME, Heshmat R, Ardalan G, Safari O, Qorbani M, Mostafavi SN

Abstract
The objective of this study was to evaluate the varicella zoster virus (VZV) immunity in Iranian adolescents. It was conducted as a primary study for vaccine implementation, and to investigate the association of climatic and socioeconomic factors with the epidemiology of this infection. In this cross- sectional study, anti VZV antibodies were measured in serum samples obtained in a national school-based health survey (CASPIAN- III). Association of demographic, socio-economic, and climate of the living region with the frequency of VZV was investigated by multivariate multilevel analysis. Overall, sera of 2753 individuals aged 10-18 were tested for VZV antibodies, from those 87.4% were positive. The prevalence was statistically different in four socio-geographic regions (P<0.001), varying between 85.24% in West region (mostly mountainous areas with cold climate) to 94.59% in Southeast region (subtropical climate). Among variables studied, only age and mean daily temperature of the living area were positively associated with the VZV seroprevalence. Our findings show that most Iranians develop immunity to VZV before the age of 10, but a substantial proportion of them are yet susceptible to the infection. Therefore, it seems that the best strategy to reduce the burden of the disease is to vaccinate high- risk adults, i.e. those without a history of varicella infection. The regional temperature might be the only determinant of VZV epidemiology in Iran.

PMID: 27355931 [PubMed – as supplied by publisher]

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Secondary hypogammaglobulinemia in Waldmann’s disease treated with subcutaneous immunoglobulins.

Eur Ann Allergy Clin Immunol. 2016 Mar;48(2):55-7

Authors: Patuzzo G, Tinazzi E, Micheletti M, Puccetti A, Lunardi C

Abstract
Primary intestinal lymphangiectasia (PIL) is rare disorder characterized by congenital malformation or obstruction of intestinal lymphatic drainage; it is responsible for protein losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL management. The administration of intravenous immunoglobulins does not always lead to satisfactory plasma levels and therefore the replacement therapy with immunoglobulins is controversial. We describe here the case of a patient with PIL and severe hypogammaglobulinemia treated with immunoglobulins. The striking aspect of this case is the clinical and serological benefit obtained with the subcutaneous compared to the intravenous immunoglobulins administration.

PMID: 26934740 [PubMed – indexed for MEDLINE]

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