Defective regulatory B-cell compartment in patients with immune thrombocytopenia

Li, Xiaojuan; Zhong, Hui; Bao, Weili; Boulad, Nayla; Evangelista, Jessie; Haider, Muhammad A.; Bussel, James B.; Yazdanbakhsh, Karina

doi:10.1182/blood-2012-05-432575

Cited by 165 publications

(162 citation statements)

References 42 publications

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“…Khoder et al used CD40L-transfected fibroblasts, whereas we used CpG, a TLR9 agonist, with or without recombinant human CD40L, as established by our group 6,57 and others. 7,23,43,58,59 In vitro-induced CD38 hi CD138 1 plasma cells were able to secrete large quantities of IL-10. These results are consistent with the work by Shen et al 29 and Matsumoto et al 31 who showed that CD138 1 plasma cells and plasmablast cells were the main IL-10 producers in mice with For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythematosus, 21 rheumatoid arthritis, 22 primary Sjögren syndrome, 7 and immune thrombocytopenia, 23 all of which share certain clinical features with human cGVHD. 1 Depending on the disease, the phenotypic markers and in vitro stimulation used, different B-cell subsets are enriched in Bregs, including CD24 hi CD27 1 B cells 7 and CD24 hi CD38 hi transitional B cells.…”

Section: Introductionmentioning

confidence: 99%

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CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

View full text Add to dashboard Cite

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“…[42][43][44][45] A variety of pathomechanisms underlying the antiplatelet autoimmunity in cITP has been suggested, ranging from dysfunctional Tregs and lacking regulatory B cells to cytokine gene polymorphisms, disturbed antigen presentation, and autoreactive B cells. [46][47][48][49][50] The detection of CVID-or ALPS-like immune phenotypical parameters in a subgroup of patients with ES has recently been reviewed. 9 SLE is a descriptive symptom complex mainly ascribed to humoral autoimmunity that may arise in PIDs, typically caused by deficiencies in the classical complement pathway (eg, C1q, C1R, Table 2 and Al-Herz et al …”

Section: Autoimmune-mediated Cytopenia In Pidmentioning

confidence: 99%

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Seidel

2014

Blood

129

140

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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“…6 However, the changes reported were subtle and only found in patients with a platelet count less than 50x10 9 /L. Comparatively small numbers restricted our ability to perform detailed subanalyses, and as such, it is possible that our cross-sectional cohort was not powered to replicate this observation.…”

Section: Expansion Of This Cd21mentioning

confidence: 79%

“…6,7 A modern view of ITP pathogenesis places these B-cell abnormalities within a complex network of abnormalities affecting multiple immune cell lineages. T cells, in particular, contribute to platelet destruction both by facilitating the production of class-switched, high affinity autoantibody and through B-cell independent mechanisms such as cell-mediated cytotoxicity directed against platelets.…”

Section: A Distinct Plasmablast and Naïve B-cell Phenotype In Primarymentioning

confidence: 99%

A distinct plasmablast and naive B-cell phenotype in primary immune thrombocytopenia

et al. 2016

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P rimary immune thrombocytopenia is an autoimmune disorder in which platelet destruction is a consequence of both B-and T-cell dysregulation. Flow cytometry was used to further characterize the B-and T-cell compartments in a cross-sectional cohort of 26 immune thrombocytopenia patients including antiplatelet antibody positive (n=14) and negative (n=12) patients exposed to a range of therapies, and a cohort of matched healthy volunteers. Markers for B-cell activating factor and its receptors, relevant B-cell activation markers (CD95 and CD21) and markers for CD4 + T-cell subsets, including circulating T-follicular helper-like cells, were included. Our results indicate that an expanded population of CD95 + naïve B cells correlated with disease activity in immune thrombocytopenia patients regardless of treatment status. A population of CD21-naïve B cells was specifically expanded in autoantibody-positive immune thrombocytopenia patients. Furthermore, the B-cell maturation antigen, a receptor for B-cell activating factor, was consistently and strongly up-regulated on plasmablasts from immune thrombocytopenia patients. These observations have parallels in other autoantibody-mediated diseases and suggest that loss of peripheral tolerance in naïve B cells may be an important component of immune thrombocytopenia pathogenesis. Moreover, the B-cell maturation antigen represents a potential target for plasma cell directed therapies in immune thrombocytopenia.

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Defective regulatory B-cell compartment in patients with immune thrombocytopenia

Cited by 165 publications

References 42 publications

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

A distinct plasmablast and naive B-cell phenotype in primary immune thrombocytopenia

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