Presentation is loading. Please wait.

Presentation is loading. Please wait.

Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency 

Published byたみえ あみおか Modified over 5 years ago

Similar presentations

Presentation on theme: "Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency "— Presentation transcript:

1 Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency  Marcella Visentini, MD, PhD, Ramona Marrapodi, ScD, Valentina Conti, MD, PhD, Milica Mitrevski, MD, Alessandro Camponeschi, ScD, Cristina Lazzeri, ScD, Maurizio Carbonari, ScD, Angela Catizone, ScD, PhD, Isabella Quinti, MD, PhD, Massimo Fiorilli, MD  Journal of Allergy and Clinical Immunology  Volume 134, Issue 2, Pages e10 (August 2014) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Increased constitutive ERK phosphorylation and attenuated BCR/ERK signaling in B cells from patients with CVID. A and B, Representative cytograms in 1 healthy donor (Fig 1, A) and 1 patient with CVID (Fig 1, B). Dot plots show the electronic gating of naive (IgM+CD27−), IgM memory (IgM+CD27+), and switched memory (IgM−CD27+) B cells. Histograms denote fluorescence intensities with control antibody (solid histograms) and anti-pERK antibody in unstimulated (thin lines) and BCR-induced (thick lines) B cells. C-E, Comparison of constitutive and BCR-induced ERK phosphorylation in naive B cells (Fig 1, C), IgM+ memory B cells (Fig 1, D), and switched memory B cells (Fig 1, E) of healthy donors and patients with CVID. Bars denote means. HD, Healthy donor. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 ERK signaling and BCR endocytosis are reduced in CD21low compared with CD21nor IgM+ memory B cells of patients with CVID with expansion of CD21low B cells (EUROclass4 group smB+/−CD21low). The CD21low and CD21nor cells with a naive (IgM+CD27−) or IgM+ memory (IgM+CD27+) phenotype are separately analyzed by using electronic gating. A and B, Comparison of constitutive and BCR-induced ERK phosphorylation in CD21nor and CD21low naive (Fig 2, A) and IgM+ memory (Fig 2, B) B cells of CVID patients. C, Rates of BCR endocytosis in CD21nor and CD21low naive and IgM memory B cells of CVID patients. Bars denote means. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Reduced endocytosis of the BCR in IgM+ memory B cells of patients with CVID. A, Representative cytograms of BCR endocytosis in normal B cells: BCR is cross-linked with goat anti-immunoglobulin at 4°C or 37°C for 30 minutes and stained for CD2, CD27, and IgM. B, Gating of naive (IgM+CD27−), IgM memory (IgM+CD27+), and switched (IgM−CD27+) B cells after endocytosis. C, Representative histograms of IgM-specific fluorescence in electronically gated B-cell subsets after BCR cross-linking at 4°C (solid histograms) or 37°C (open histograms). D, Rates of BCR endocytosis in naive, IgM+ memory, and switched B cells of healthy donors and patients with CVID. Bars denote means. HD, Healthy donors. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 BCR endocytosis depends on ERK signaling. A, Correlation of BCR-induced ERK activation with BCR endocytosis in naive and IgM+ memory B cells of patients with CVID. B-D, Effects of the ERK inhibitor U0126 on ERK phosphorylation and BCR endocytosis in mature B-cell subsets of healthy donors (open symbols) and patients with CVID (solid symbols). Each symbol denotes a single subject. Note that patients with CVID lack switched B cells. Fig 4, B, Effects of U0126 on constitutive and BCR-induced ERK phosphorylation expressed as MFI. Fig 4, C, Effects of U0126 on BCR-induced ERK activation expressed as fold a increase of pERK from baseline. Fig 4, D, Effects of U0126 on BCR endocytosis. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Normal trafficking of endocytosed BCR to Lamp-1+ late endosomes in B cells from a representative patient with CVID with attenuated ERK signaling. A, Cross-linked IgM (green) aggregates at 37°C in B cells of healthy donors and patients with CVID but in the latter cells tends to remain at the plasma membrane. Lamp-1 (red) largely colocalizes with endocytosed IgM (yellow) in normal B cells, whereas only a minor fraction of aggregated IgM colocalizes with Lamp-1 in B cells from patients with CVID. B, Unlike in normal B cells, in many B cells from patients with CVID, part of IgM appears to remain at the plasma membrane and does not colocalize with Lamp-1, whereas the fraction of IgM that enters the cytoplasm colocalizes efficiently with Lamp-1. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E1 IgM+ and switched memory B cells have increased ERK activation and endocytosis than naive B cells. A, Constitutive and BCR-induced phosphorylation of ERK (expressed as MFI) in B-cell subsets of healthy donors. B, BCR-induced pERK activation (expressed as a fold increase from baseline) in B-cell subsets of healthy donors. C, Rates of BCR endocytosis in B-cell subsets of healthy donors and patients with CVID. Bars denote means. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E2 High constitutive ERK phosphorylation is associated with low BCR-induced ERK activation in normal B cells but not in B cells from patients with CVID. Linear regression analysis of the correlation between constitutive and BCR-induced ERK phosphorylation in B-cell subsets of healthy donors (A) and patients with CVID (B). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E3 In patients with CVID with expansion of CD21low B cells (EUROclassE1 group smB+/−CD21low), IgM+ memory B cells expressing normal levels of CD21 (CD21nor) have attenuated pERK responses and reduced BCR endocytosis compared with the B cells of healthy donors. A and B, Comparison of constitutive and BCR-induced ERK phosphorylation in CD21nor naive B cells of CVID patients and naive B cells from healthy donors (Fig E3, A) and in CD21nor IgM+ memory B cells of CVID patients and IgM+ memory B cells from healthy donors (Fig E3, B). C, Rates of BCR endocytosis in CD21nor naive B cells of CVID patients and naive B cells from healthy donors and in CD21nor IgM+ memory B cells of CVID patients and IgM+ memory B cells from healthy donors. Bars denote means. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E4 IVIG therapy deregulates ERK signaling in B cells from patients with CVID. A and B, Constitutive and BCR-induced ERK phosphorylation in naive B cells (Fig E4, A) and IgM+ memory B cells (Fig E4, B) before and after IVIG therapy. Circles denote patients with CVID receiving replacement IVIG treatment, and triangles denote patients treated with IVIG for CIDP. Numbers on the x-axis refer to numbering of patients with CVID in Tables E1 to E4. Data indicate the values obtained immediately before (solid symbols) and after (open symbols) IVIG infusion. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E5 Patterns of constitutive (A) and BCR-induced (B) ERK activation are consistent over time in patients with CVID. Cell samples were obtained immediately before IVIG infusions. Patient numbering corresponds to Tables E1 to E4. The intervals between the first and the subsequent test(s) were as follows: patient 1, 10 months; patient 6, 6 and 9 months; patient 13, 4 months; patient 16, 4 months; and patient 18, 3 and 7 months. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Download ppt "Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency "

Similar presentations

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy  Erik Wambre, PhD, Jonathan.

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy  Erik Wambre, PhD, Jonathan.
Immacolata Brigida, PhD, Aisha V

Immacolata Brigida, PhD, Aisha V
The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency  Rita Carsetti, MD, Maria Manuela Rosado, PhD, Simona.

The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency  Rita Carsetti, MD, Maria Manuela Rosado, PhD, Simona.
Defective calcium signaling and disrupted CD20–B-cell receptor dissociation in patients with common variable immunodeficiency disorders  Annick A.J.M.

Defective calcium signaling and disrupted CD20–B-cell receptor dissociation in patients with common variable immunodeficiency disorders  Annick A.J.M.
Expression of IL-9 receptor α chain on human germinal center B cells modulates IgE secretion  Lama M. Fawaz, PhD, Ehssan Sharif-Askari, PhD, Oumnia Hajoui,

Expression of IL-9 receptor α chain on human germinal center B cells modulates IgE secretion  Lama M. Fawaz, PhD, Ehssan Sharif-Askari, PhD, Oumnia Hajoui,
Flow cytometry imaging identifies rare TH2 cells expressing thymic stromal lymphopoietin receptor in a “proallergic” milieu  Amanda J. Reefer, MS, Kathryn.

Flow cytometry imaging identifies rare TH2 cells expressing thymic stromal lymphopoietin receptor in a “proallergic” milieu  Amanda J. Reefer, MS, Kathryn.
Combined immunodeficiency due to JAK3 mutation in a child presenting with skin granuloma  Alessia Scarselli, MD, Silvia Di Cesare, BSc, Gigliola Di Matteo,

Combined immunodeficiency due to JAK3 mutation in a child presenting with skin granuloma  Alessia Scarselli, MD, Silvia Di Cesare, BSc, Gigliola Di Matteo,
Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma  Chun-Yu Lo, MD, Charalambos Michaeloudes,

Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma  Chun-Yu Lo, MD, Charalambos Michaeloudes,
Airway fibroblasts exhibit a synthetic phenotype in severe asthma

Airway fibroblasts exhibit a synthetic phenotype in severe asthma
Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy  Yin Yao, MD, Cai-Ling.

Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy  Yin Yao, MD, Cai-Ling.
Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.

Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.
IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation  Regina K. Rowe, MD, PhD, David M. Pyle, MD,

IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation  Regina K. Rowe, MD, PhD, David M. Pyle, MD,
CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion  Theresa Frenz, PhD, Elena Grabski, PhD, Daniela.

CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion  Theresa Frenz, PhD, Elena Grabski, PhD, Daniela.
Immunologic defects in 22q11.2 deletion syndrome

Immunologic defects in 22q11.2 deletion syndrome
T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity  Peter Szodoray, MD, PhD,

T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity  Peter Szodoray, MD, PhD,
Toll-like receptor 7–induced naive human B-cell differentiation and immunoglobulin production  Mark C. Glaum, MD, PhD, Shilpi Narula, MD, Decheng Song,

Toll-like receptor 7–induced naive human B-cell differentiation and immunoglobulin production  Mark C. Glaum, MD, PhD, Shilpi Narula, MD, Decheng Song,
Magdalena A. Berkowska, PhD, Jorn J

Magdalena A. Berkowska, PhD, Jorn J
Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation  Vassilios Lougaris, MD, Manuela Baronio, PhD, Massimiliano Vitali, PhD,

Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation  Vassilios Lougaris, MD, Manuela Baronio, PhD, Massimiliano Vitali, PhD,
Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation  Almut Meyer-Bahlburg,

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation  Almut Meyer-Bahlburg,
Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis  Kaori Mukai, PhD, Nicolas Gaudenzio,

Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis  Kaori Mukai, PhD, Nicolas Gaudenzio,

Similar presentations

Ads by Google