Allergen specificity of IgG4-expressing B cells in patients with grass pollen allergy undergoing immunotherapy Louisa K. James, PhD, Holly Bowen, PhD,

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Presentation transcript:

Allergen specificity of IgG4-expressing B cells in patients with grass pollen allergy undergoing immunotherapy Louisa K. James, PhD, Holly Bowen, PhD, Rosaleen A. Calvert, PhD, Tihomir S. Dodev, BSc, Mohamed H. Shamji, PhD, Andrew J. Beavil, PhD, James M. McDonnell, PhD, Stephen R. Durham, MD, FRCP, Hannah J. Gould, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 3, Pages 663-670.e3 (September 2012) DOI: 10.1016/j.jaci.2012.04.006 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 V gene mutation frequency. Heavy-chain (A) and light-chain (B) V gene sequences (excluding primer annealing regions) were analyzed with IMGT/V-Quest. The percentage of mutations in the FWRs and CDRs were determined from the total number of nucleotides. Comparisons were made by using a paired t test. ns, Not significant; r, replacement mutation; s, silent mutation. Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Depletion of allergen-specific IgG4 from serum has a modest effect on total IgG4 levels. Allergen-specific immunoglobulins were removed from diluted serum by means of incubation with P pratense-coupled Sepharose beads for 4 hours at room temperature. P pratense–specific (A) and total (B) IgG4 levels were measured in the depleted serum by means of ELISA. The percentage reduction (C) in total (tIgG4) and specific (sIgG4) IgG4 levels was determined from a control depletion by using BSA-coupled Sepharose beads. Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Binding analysis of Phl p 7 to recombinant IgG4. Recombinant IgG4 (102.1F10) was covalently immobilized on a sensor chip. Experiments were carried out in either buffer containing 2 mmol/L calcium chloride (left panel) with 2-fold serial dilutions of Phl p 7 from 16 nmol/L or in buffer containing 10 mmol/L EDTA (right panel) with 2-fold serial dilutions of Phl p 7 from 16 μmol/L. In the presence of calcium, high-affinity binding is observed. Curves were fit (red lines) to derive on and off rates. In the absence of calcium, the binding affinity is about 10,000 times weaker, and the interaction displays fast-on/fast-off kinetics. Consequently, affinities were estimated by using equilibrium methods (right panel inset). Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Inhibition of IgE-facilitated allergen presentation and basophil activation by monoclonal IgG4. A, Serum containing Phl p 7–specific IgE was incubated with Phl p 7 in the additional presence of either Phl p 7–specific IgG4 (102.1F10) or an isotype control (101.C6). Postimmunotherapy serum from patient 102 and assay media were included as positive and negative controls, respectively. Binding of IgE–Phl p 7 complexes were detected by using flow cytometry. Data are shown as means ± SEMs. B, Basophil activation was detected by using flow cytometry after incubation of whole blood with Phl p 7 and either Phl p 7–specific IgG4 (102.1F10) or an isotype control (101.C6). Postimmunotherapy serum from patient 102 and assay media were included as positive and negative controls, respectively. Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Serum IgE and IgG4 levels specific for grass pollen allergens. Serum samples taken at the same time as blood collection were tested for the presence of IgE and IgG4 specific for the grass pollen allergens Phl p 1, 2, 5, and 7 by means of ELISA. The dotted line represents the limit of detection. Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Cloning strategy for the generation of recombinant IgG4. Paired heavy- and light-chain variable regions from single IgG4+ memory B cells were amplified by means of RT-PCR and sequenced. Restriction enzyme sites were introduced by using PCR to permit cloning into modified pTT3 vectors containing human leader and constant region genes. Journal of Allergy and Clinical Immunology 2012 130, 663-670.e3DOI: (10.1016/j.jaci.2012.04.006) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions