Research

IL-10-Producing Regulatory B Cells Are Decreased in Patients with Common Variable Immunodeficiency.

PLoS One. 2016;11(3):e0151761

Authors: Barsotti NS, Almeida RR, Costa PR, Barros MT, Kalil J, Kokron CM

Abstract
Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.

PMID: 26991898 [PubMed – as supplied by publisher]

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How to use immunoglobulin levels in investigating immune deficiencies.

Arch Dis Child Educ Pract Ed. 2016 Mar 17;

Authors: Ladomenou F, Gaspar B

Abstract
Children are often referred to immunologists for the evaluation of reduced serum immunoglobulins. Knowledge of the immunoglobulin levels in healthy children of different ages is necessary when estimating immunological deficiency states of various kinds. After the measurement of the serum levels of the three major isotypes, examination of the capacity of the child to form antibodies to several antigens is a reasonable next step in the evaluation. We can rely on vaccine responses to make the distinction between significant primary immunodeficiency diseases and transiently low immunoglobulin levels. On the other hand, normal values of IgM, IgG and IgA are not always enough to exclude a more serious condition. Regardless of immunoglobulin concentrations, if a child’s history indicates that further evaluation is warranted, a complete humoral immunity study should be carried out, including IgG subclasses, specific antibody responses and identification of B lymphocyte populations.

PMID: 26987724 [PubMed – as supplied by publisher]

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Dissecting Epigenetic Dysregulation of Primary Antibody Deficiencies.

J Clin Immunol. 2016 Mar 17;

Authors: Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, López-Granados E, Ballestar E

Abstract
Primary antibody deficiencies (PADs), the most prevalent inherited primary immunodeficiencies (PIDs), are associated with a wide range of genetic alterations (both monogenic or polygenic) in B cell-specific genes. However, correlations between the genotype and clinical manifestations are not evident in all cases indicating that genetic interactions, environmental and epigenetic factors may have a role in PAD pathogenesis. The recent identification of key defects in DNA methylation in common variable immunodeficiency as well as the multiple evidences on the role of epigenetic control during B cell differentiation, activation and during antibody formation highlight the importance of investing research efforts in dissecting the participation of epigenetic defects in this group of diseases. This review focuses on the role of epigenetic control in B cell biology which can provide clues for the study of potential novel pathogenic defects involved in PADs.

PMID: 26984849 [PubMed – as supplied by publisher]

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Chronic granulomatous disease.

Br Med Bull. 2016 Mar 16;

Authors: Roos D

Abstract
INTRODUCTION: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, the liver, the brain and the bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia, Serratia marcescens and Salmonella species.
SOURCES OF DATA: CGD is a rare (∼1:250 000 individuals) disease caused by mutations in any one of the five components of the NADPH oxidase in phagocytic leucocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes.
AREAS OF AGREEMENT: CGD patients suffer not only from life-threatening infections, but also from excessive inflammatory reactions.
AREAS OF CONTROVERSY: Neither the cause of these inflammatory reactions nor the way to treat them is clear.
AREAS TIMELY FOR DEVELOPING RESEARCH: Patient selection for and timing of bone marrow transplantation along with gene therapy.

PMID: 26983962 [PubMed – as supplied by publisher]

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Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation.

Mucosal Immunol. 2016 Mar 16;

Authors: Jørgensen SF, Trøseid M, Kummen M, Anmarkrud JA, Michelsen AE, Osnes LT, Holm K, Høivik ML, Rashidi A, Dahl CP, Vesterhus M, Halvorsen B, Mollnes TE, Berge RK, Moum B, Lundin KE, Fevang B, Ueland T, Karlsen TH, Aukrust P, Hov JR

Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.Mucosal Immunology advance online publication, 16 March 2016; doi:10.1038/mi.2016.18.

PMID: 26982597 [PubMed – as supplied by publisher]

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Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.

N Engl J Med. 2016 Mar 17;374(11):1032-1043

Authors: Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, Maffucci P, Pierce KR, Abbott JK, Voelkerding KV, South ST, Augustine NH, Bush JS, Dolen WK, Wray BB, Itan Y, Cobat A, Sorte HS, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova JL, Fleisher TA, Hill HR, Kumánovics A, Conley ME, Rosenzweig SD

Abstract
Background Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. Methods We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. Results Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. Conclusions Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

PMID: 26981933 [PubMed – as supplied by publisher]

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Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency.

J Clin Immunol. 2016 Mar 15;

Authors: Wirsum C, Glaser C, Gutenberger S, Keller B, Unger S, Voll RE, Vach W, Ness T, Warnatz K

Abstract
PURPOSE: The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency.
METHODS: We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base.
RESULTS: 21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T-cell subtypes.
CONCLUSION: Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID).

PMID: 26980224 [PubMed – as supplied by publisher]

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A comparison of B cell subsets in primary immune deficiencies that progress with antibody deficiency and age-matched healthy children.

Allergol Immunopathol (Madr). 2016 Mar 11;

Authors: Celiksoy MH, Yildiran A

Abstract
BACKGROUND: The objective of this study was to examine the B lymphocyte subsets in primary immunodeficiency that progress with antibody deficiency.
METHODS: The patients’ naive, memory, class-switched memory and non-switched memory B cells were compared with those of healthy individuals of matching ages using flow cytometry.
RESULTS: A total of 67 patients with antibody deficiency and 28 healthy children of matching ages were included in the study. The median age of the patients was six years (min-max: 1-24) and 40 (59.7%) were male. The median age of the healthy controls was again six years (min-max: 1-17) and 12 (42.8%) were male. Patients with common variable immunodeficiency had higher relative counts of naive cells when compared with the control group; however, they were found to have lower relative counts of memory, relative and absolute counts of non-switched and relative counts of switched B lymphocytes (p=0.001, 0.023, 0.003-0.003, 0.001, respectively). In patients with selective IgA deficiency, similar to patients with common variable immunodeficiency, the relative counts of naive cells were found to be higher, while the relative counts of memory and relative and absolute counts of non-switched B lymphocytes were found to be lower when compared with the control group (p=0.011, 0.032, 0.006-0.009, respectively). Although patients with selective IgM deficiency had higher relative counts of naive B cells when compared with the control group, they had lower relative and absolute counts of non-switched B lymphocytes (p=0.008-0.016).
CONCLUSIONS: The B lymphocyte subsets of patients with selective IgA deficiency are largely similar to those of patients with common variable immunodeficiency. Both illness groups exhibit low levels of memory B cells.

PMID: 26976550 [PubMed – as supplied by publisher]

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Prevalence and pattern of humoral immunodeficiency in chronic refractory sinusitis.

Eur Arch Otorhinolaryngol. 2016 Mar 14;

Authors: Odat H, Alqudah M

Abstract
The purpose of this study is to readdress the issue of primary humoral immunodeficiency frequency and pattern in medically resistant chronic rhinosinusitis (CRS) based on the new guidelines for CRS diagnosis and management. Two hundred and fifty-seven consecutive patients with refractory CRS were included in this study. The results of their IgA, IgM, IgG, and IgG subclasses were analyzed and compared with 75 age- and gender-matched control groups. The average age of CRS patients was 34 years (SD ± 13). In the refractory CRS group, there was no significant difference between patients with or without humoral immunodeficiency based on age, gender and status of allergy, polyps and revision. Low level of one of the major immunoglobulin isotypes was found in 15 patients (6 %). Six patients had low IgG, two had low IgA, and seven had low IgM. IgG subclasses were low in 37 patients (14 %), and IgG4 was the most common deficient subclass. Multiple immunoglobulins deficiencies were found in eight patients. Compared with the control group, CRS patients had a significant higher prevalence of major immunoglobulins as well as total major immunoglobulins and IgG subclasses deficiency. Because of high prevalence of subtle humoral immunodeficiency in medically resistant CRS and inability to find unique clinical and demographic characteristic of these patients, we recommend routine screening of major immunoglobulins and IgG subclasses on the group of CRS patients who failed medical treatment.

PMID: 26975445 [PubMed – as supplied by publisher]

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Genetic predisposition and hematopoietic malignancies in children: Primary Immunodeficiency.

Eur J Med Genet. 2016 Mar 11;

Authors: van der Werff Ten Bosch J, van den Akker M

Abstract
It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID.

PMID: 26975585 [PubMed – as supplied by publisher]

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