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Magdalena A. Berkowska, PhD, Jorn J

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1 Human IgE+ B cells are derived from T cell–dependent and T cell–independent pathways 
Magdalena A. Berkowska, PhD, Jorn J. Heeringa, MD, Enes Hajdarbegovic, MD, Mirjam van der Burg, PhD, H. Bing Thio, MD, PhD, P. Martin van Hagen, MD, PhD, Louis Boon, PhD, Alberto Orfao, MD, PhD, Jacques J.M. van Dongen, MD, PhD, Menno C. van Zelm, PhD  Journal of Allergy and Clinical Immunology  Volume 134, Issue 3, Pages e6 (September 2014) DOI: /j.jaci Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Detection of IgE+ plasma cells in tonsils and peripheral blood. A, Representative images from flow cytometric analysis of plasma cell subsets in childhood tonsils. IgM−IgD− cells were gated within the total CD19+CD38high plasma cell fraction and analyzed for surface IgG, IgA, and IgE expression. B and C, SHM frequencies in rearranged IGHV genes in IGHM, IGHG, IGHA, and IGHE transcripts from childhood tonsils (Fig 1, B) and adult blood (Fig 1, C). Each dot represents an individual sequence, red lines represent median values, and the dashed line indicates the median SHM frequency in centrocytes. Data were statistically analyzed with the Mann-Whitney test. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Two IgE+ memory B-cell subsets in blood. A, Stepwise gating strategy for identification of CD27+IgE+ and CD27−IgE+ subsets. B, CD27+IgE+ and CD27−IgE+ B-cell frequencies in healthy children and adults. Bars represent mean values with SEMs. C, Expression levels of CD79b on IgM+, IgG+, IgA+, and 2 IgE+ memory B-cell subsets. Each histogram is composed of merged data from 6 healthy donors and contains a light gray filled histogram representing CD3+ T cells and a dark gray histogram representing naive mature B cells. D, Median fluorescence intensity of CD79b on B-cell subsets and T cells from 6 individual donors. Data were statistically analyzed with the Mann-Whitney test. *P < .05 and **P < .01. E, Expression levels of selected markers on IgM+, IgG+, IgA+, and IgE+ memory B-cell subsets. Light gray filled histograms represent isotype controls, and dark gray histograms represent naive mature B cells. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Distinct levels of molecular maturation in CD27+IgE+ and CD27−IgE+ memory B cells. A, Replication histories of memory B-cell subsets, as measured with the kappa-deleting recombination excision circle assay.25,27 Bars represent mean values with SEMs. Dashed lines represent values for centrocytes (n = 55).27 B, Frequencies of mutated nucleotides in rearranged IGHV genes. Each gray dot represents a unique rearrangement, and red lines indicate median values. C, Frequencies of mutated IGKV3-20 genes as measured with the Igκ restriction enzyme hot-spot mutation assay assay.27 D, IgH-CDR3 size distributions in memory B-cell subsets. Differences between CD27+IgE+ and CD27−IgE+ cells were statistically analyzed with the Mann-Whitney test. **P < .01 E, Schematic representation of direct (solid lines) and indirect (dashed lines; through IgG1) class-switching to IGHE. Examples of hybrid Sμ-Sε switch regions generated from direct (upper sequence) and sequential (lower sequence) class-switching to IGHE. Frequencies of direct and indirect class-switching in CD27+IgE+ and CD27−IgE+ memory B cells. The numbers of analyzed sequences are indicated in the inner circles. Data were statistically analyzed with the χ2 test. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 GC-dependent and GC-independent origin of IgE+ memory B-cell subsets in blood. A, Representative images of flow cytometric analysis of circulating memory B-cell subsets in CD40L-deficient patients. B, CD27+IgE+ and CD27−IgE+ B-cell frequencies in CD40L-deficient patients and healthy age-matched donors (0-3 y). Bars represent mean values with SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 A, Expression levels of IL-4 receptor (IL4R), IL-13 receptor alpha (IL13Rα), and IL-21 receptor (IL21R) on naive mature and IgG+ and IgE+ memory B cells. B, Generation of plasma cells defined as CD38hiCD27+ after 6-day cultures. Average values for independent experiments with SEMs are shown, as well as paired analysis of CD27+IgE+ and CD27−IgE+ memory B-cell subsets (paired t test). Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Increased frequencies of CD27−IgE+ memory B cells in patients with atopic dermatitis. A, Frequencies of CD27+IgE+ and CD27−IgE+ memory B cells and IgE+ plasma cells in patients with atopic dermatitis (AD), patients with psoriasis (psor), and healthy age-matched donors (ctrl). Individual data points are shown as gray dots, with red lines indicating median values. B, Correlation between CD27+IgE+ and CD27−IgE+ memory B-cell numbers and IgE serum levels in 23 patients with atopic dermatitis. C, Frequencies of mutated nucleotides in rearranged IGHV genes. Data were statistically analyzed with the Mann-Whitney test: *P < .05. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Model for GC-dependent and GC-independent maturation of IgE+ B cells. Naive mature B cells scavenge the peripheral lymphoid system for antigens. Responses to peptide allergens with T-cell help result in extensive proliferation and affinity maturation in GCs, generating IgE+ plasma cells and CD27+IgE+ memory B cells, potentially through an IgG intermediate. Antigen responses independently from T-cell help in local tissue (eg, mucosa and skin) induce limited proliferation, SHM, and direct IgE switching, generating plasma cells or CD27−IgE+ memory B cells. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 Immunophenotyping details of IgE+ memory B cells and plasma cells. A-C, Back gating of IgE+ plasma cells from tonsils (Fig E1, A) and memory B cells from blood of a healthy control subject (Fig E1, B) and a CD40L-deficient patient (Fig E1, C) within the IgM−IgD− gate. D, Evaluation of steric hindrance of CD79b (left) and T-cell receptor αβ expression. Cells from 2 healthy donors were incubated simultaneously with anti-CD79b and anti-immunoglobulin isotypes or 3 minutes with CD79b before addition of anti-immunoglobulin isotypes. Preincubation with anti-CD79b before addition of the anti-immunoglobulin isotype antibodies did not lead to higher expression levels. In contrast, preincubation of T cells with the anti–T-cell receptor αβ clone IP26 before addition of the anti-CD3 clone OKT3 did lead to increased T-cell receptor αβ expression levels. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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