B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency

Driessen, Gertjan J.; Zelm, Menno C. van; Hagen, P. Martin van; Hartwig, Nico G.; Trip, Margreet; Warris, Adilia; Vries, Esther de; Barendregt, Barbara H.; Pico, Ingrid; Hop, W. C. J.; Dongen, Jacques J. M. van; Burg, Mirjam van der

doi:10.1182/blood-2011-06-361881

Cited by 107 publications

(118 citation statements)

References 49 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…In line with the clinical differences, analysis of the earlier presented B-cell patterns 9 revealed that defective B-cell production and early peripheral B-cell maturation or survival defect (B-cell patterns 1 and 2, respectively) were seen exclusively in CVID. In addition, we showed that these two B-cell patterns are associated with non-infectious disease-related clinical complications.…”

Section: Discussionmentioning

confidence: 83%

“…9 The patterns are based on the composition of the peripheral B-cell compartment and the replication history and somatic hypermutation frequency of the individual Bcell subsets and are indicative for the pathophysiological background of the antibody deficiency. 9 The B-cell patterns can be easily determined by flow cytometry. Our earlier detailed molecular assays on sorted peripheral Bcell subsets were used to characterize the patterns, but are not used to define the pattern in individual patients.…”

Section: Peripheral B-cell Subset Patterns Are Different In Cvid and Iphmentioning

confidence: 99%

“…A decrease or increase of a B-cell subset was defined as a value below the 5 th or above the 95 th percentile. B-cell patterns were determined as described previously 9 and are summarized together with their pathophysiological background in Table 1.…”

Section: Flow Cytometric Analysis and Assignment Of B-cell Patternsmentioning

confidence: 99%

“…The group of CVID patients includes the 37 patients who were reported in our original description of the B-cell patterns. 9 In addition, we collected blood from 130 healthy age-matched controls and 26 cord blood samples. This study was approved by the Medical Ethics Committee of the Erasmus MC.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum

et al. 2013

View full text Add to dashboard Cite

ABSTRACTical practice, but information concerning the prevalence and the clinical and immunological characteristics is not available. It is important to obtain insight into the frequency and severity of the clinical complications of IPH, to clarify whether IPH is a clinically relevant antibody deficiency, and to develop appropriate treatment strategies. In addition, analysis of immunological parameters will enable the comparison of pathophysiological aspects of IPH and CVID.Therefore, we aimed to determine the position of IPH in the spectrum of idiopathic antibody deficiencies through clinical and immunological comparison with CVID. First, we recorded the patients with the clinical phenotypes as established by Chapel et al. 2,7 In addition, we performed flow cytometric immunophenotyping in order to analyze T-cell dependent and independent memory B-cell subset counts 8 and blood B-cell patterns, which are associated with differences in pathophysiological background. 9 Methods PatientsPeripheral blood samples and clinical data were collected for 44 CVID patients and 21 IPH patients. IPH was diagnosed if patients had a reduction of IgG at least 2 SD below the mean for age, an onset of the immunodeficiency after two years of age, exclusion of defined causes of hypogammaglobulinemia and if they did not fulfill the CVID diagnostic criteria with respect to a reduction of two immunoglobulin isotypes and/or a reduced response to vaccination. The group of CVID patients includes the 37 patients who were reported in our original description of the B-cell patterns. 9 In addition, we collected blood from 130 healthy age-matched controls and 26 cord blood samples. This study was approved by the Medical Ethics Committee of the Erasmus MC. Clinical phenotypingClinical data were collected from all IPH and CVID patients to record their clinical phenotypes as previously described by Chapel et al. 2,5 These phenotypes are: 1) no disease-related complications (infections only); 2) autoimmune cytopenias; 3) polyclonal lymphoproliferation (granuloma/LIP/persistent unexplained lympadenopathy); and 4) unexplained persistent enteropathy. In addition, data were collected concerning the frequency and severity of infections and modes of treatment. Pneumococcal polysaccharide vaccination responses were interpreted according to Borgers et al. 10 as an adequate response to half of the measured pneumococcal serotypes. Flow cytometric analysis and assignment of B-cell patternsSix-color flow cytometric immunophenotyping of peripheral blood was performed on a CantoII (BD Biosiences) and data were analyzed using FACS Diva software (BD Biosiences). The following monoclonal antibodies were used: CD19-PerCP-Cy5.5, CD19-PE-Cy7, CD19-APC (all SJ25C1), CD5-APC ( L17F12 ), CD45-PerCP (2D1), CD19-APC (SJ25C1), CD38-PE, CD38-APC and CD38-PE-Cy7 ( HB7), CD27-APC (L128), CD3-PerCP-Cy5.5 (SK7) and CD8-APC-Cy7 (SK1) (all from BD Biosciences), polyclonal IgD-FITC, IgD-PE and IgM-PE (all from Southern Biotechnologies), polyclonal IgG-FITC (Kallestad), IgA-FITC a...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Peripheral B-cell Subset Patterns Are Different In Cvid and Iphmentioning

confidence: 99%

Section: Flow Cytometric Analysis and Assignment Of B-cell Patternsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum

et al. 2013

View full text Add to dashboard Cite

show abstract

“…As mutations in genes encoding T and B cell activation molecules and receptors, such as inducible T cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B cell activating factor-receptor (BAFF-R), B cell receptor complex (CD19, CD81, CD21), and CD20 have been detected in less than 10% of patients affected by CVID (30), the identification of genetic defects is limited by disease immunologic heterogeneity. A classification of CVID dependent of immune parameters of the B cell compartment with analysis of replication history and somatic hypermutation status has been proposed by Driessen et al (31). The pathophysiologic B cell pattern associated with peripheral maturation or survival defects was associated with a normal transitional B cell number and a reduction of naive mature and memory B cells in CVID patients and also in the hypogammaglobulinemic children studied.…”

Section: Discussionmentioning

confidence: 99%

Impaired Antigen-Specific Immune Response to Vaccines in Children with Antibody Production Defects

Szczawińska-Popłonyk

Bręborowicz

Samara

et al. 2015

Clin Vaccine Immunol

View full text Add to dashboard Cite

The impaired synthesis of antigen-specific antibodies, which is indispensable for an adaptive immune response to infections, is a fundamental pathomechanism that leads to clinical manifestations in children with antibody production defects. The aim of this study was to evaluate the synthesis of antigen-specific antibodies following immunization in relation to peripheral blood B cell subsets in young children with hypogammaglobulinemia. Twenty-two children, aged from 8 to 61 months, with a deficiency in one or more major immunoglobulin classes participated in the study. Postvaccination antibodies against tetanus and diphtheria toxoids, the surface antigen of the hepatitis B virus, and the capsular Haemophilus influenzae type b polysaccharide antigen were assessed along with an immunophenotypic evaluation of peripheral blood B lymph cell maturation. A deficiency of antibodies against the tetanus toxoid was assessed in 73% of cases and that against the diphtheria toxoid was assessed in 68% of cases, whereas a deficiency of antibodies against the surface antigen of the hepatitis B virus was revealed in 59% of the children included in the study. A defective response to immunization with a conjugate vaccine with the Haemophilus influenzae type b polysaccharide antigen was demonstrated in 55% of hypogammaglobulinemic patients. Increased proportions of transitional B lymph cells and an accumulation of plasmablasts accompanied antibody deficiencies. The defective response to vaccine protein and polysaccharide antigens is a predominating disorder of humoral immunity in children with hypogammaglobulinemia and may result from a dysfunctional state of the cellular elements of the immune system. A ntibody production defects are the most common category of pediatric primary immunodeficiencies (PIDs) (1, 2). The hallmark of these immunodeficiency conditions is the defective production of antigen-specific antibodies that are an indispensable element of the adaptive immune response to pathogens (3, 4). While the poor response to vaccines is another feature of humoral PIDs, the ability to synthesize postvaccination antibodies against toxoids and polysaccharides is the most specific expression of the immune response to antigens. In the evaluation of the immune response associated with antibody production, the response to vaccination against hepatitis B is not routinely recommended because of the large proportion of adults, up to between 1% and 3% of vaccinated individuals, who do not effectively synthesize antibodies against hepatitis B virus surface antigen (HBs). In infants and children, the efficiency of recombinant vaccines against hepatitis B, assessed on the basis of postvaccination anti-HBs antibody concentration over 10 mIU/ml, is estimated at 85% to 100% (5, 6). The minimal protective level of neutralizing antibodies against diphtheria and tetanus toxoids has been estimated at 0.01 to 0.1 IU/ml, whereas to achieve long-term immunity, a concentration of specific antibodies, up to 1.0 IU/ml, may be required. The synthesis of...

show abstract

Disturbed B Cell Homeostasis in Newly Diagnosed Giant Cell Arteritis and Polymyalgia Rheumatica

Geest

Abdulahad

Chalan

et al. 2014

Arthritis & Rheumatology

109

View full text Add to dashboard Cite

Objective. Several lines of evidence indicate that B cells may be involved in the immunopathology of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). This study was undertaken to examine the distribution of defined B cell subsets, including effector B (Beff) cells and regulatory B (Breg) cells, in patients with GCA and patients with PMR before and after corticosteroid treatment.Methods. Circulating B cells were analyzed in 34 newly diagnosed, untreated patients with GCA or PMR, and in 44 followup samples from patients with GCA or PMR who received corticosteroids for 2 weeks or 3 months. For comparison, 40 age-matched healthy controls and 11 rheumatoid arthritis (RA) patients were included. Serum BAFF levels were determined, and temporal arteries were studied by immunohistochemistry.Results Conclusion. We show for the first time that the distribution of B cells is highly disturbed in GCA and PMR and that B cells likely contribute to the enhanced IL-6 response in both diseases.

show abstract

B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency

Abstract: Common variable immunodeficiency disorder (CVID) is

Cited by 107 publications

References 49 publications

Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum

Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum

Impaired Antigen-Specific Immune Response to Vaccines in Children with Antibody Production Defects

Disturbed B Cell Homeostasis in Newly Diagnosed Giant Cell Arteritis and Polymyalgia Rheumatica

Contact Info

Product

Resources

About