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

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Presentation transcript:

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 401-410.e10 (August 2014) DOI: 10.1016/j.jaci.2014.03.017 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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 2014 134, 401-410.e10DOI: (10.1016/j.jaci.2014.03.017) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions