Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency Elisabeth Salzer, MD, Aydan Kansu,

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Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency Elisabeth Salzer, MD, Aydan Kansu, MD, Heiko Sic, PhD, Peter Májek, PhD, Aydan Ikincioğullari, MD, Figen E. Dogu, MD, Nina Kathrin Prengemann, MSc, Elisangela Santos-Valente, MD, MSc, Winfried F. Pickl, PhD, Ivan Bilic, PhD, Sol A Ban, Zarife Kuloğlu, MD, Arzu Meltem Demir, MD, Arzu Ensari, MD, Jacques Colinge, PhD, Marta Rizzi, PhD, Hermann Eibel, PhD, Kaan Boztug, MD Journal of Allergy and Clinical Immunology Volume 133, Issue 6, Pages 1651-1659.e12 (June 2014) DOI: 10.1016/j.jaci.2014.02.034 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Identification of IL-21 deficiency. A, Colonoscopy. B, Histology consistent with Crohn disease. C, Pedigree of index family. Solid portions of symbols mark IL-21Leu49Pro segregation pattern. D, Sanger chromatograms displaying the missense mutation in IL21 in the patient (II-8) and a healthy sibling (II-6). E, Amino acid sequence conservation of IL-21Leu49Pro among different species. F, Structure of mutant IL-21Leu49Pro (blue) overlapped with IL-21WT (brown). G, Orientation of residue 49 in simulations of WT (brown) and IL-21Leu49Pro (blue). Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Immunologic phenotype of the patient. A and B, Proportion of total B cells and IgD+CD27+ and IgD−CD27+ memory B cells in peripheral blood from the patient (Fig 2, A, upper panel) and transitional B cells (Fig 2, B) compared with a healthy donor. C, Percentage of IgG+ and IgA+ class-switched cells in peripheral blood from patients and control subjects. D, T-cell proliferation: stimulation for 3 (left panel) and 7 (right panel) days. Iono, Ionomycin; PMA, phorbol 12-myristate 13-acetate; PPD, purified protein derivative; SEA, staphylococcal enterotoxin A; SEB, staphylococcal enterotoxin; TT, tetanus toxoid. Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Functional consequences of IL-21 deficiency. A, Western blot of phospho-STAT3 in Jurkat cells after stimulation with IL-21WT, IL-21Leu49Pro, and commercially available IL-21 (IL-21rec). GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. B, Flow cytometry–based proliferation analysis of carboxyfluorescein succinimidyl ester–labeled cord blood–derived CD19+ B cells after stimulation with IL-21WT (open circles) and IL-21Leu49Pro (solid circles). C, IL-21–dependent proliferation of cord blood–derived B cells 6 days after stimulation with IL-21WT (open circles) or IL-21Leu49Pro (solid circles). Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Normal activation and class-switch recombination potential of IL-21–deficient B cells. A, Flow cytometric analysis of PBMCs from control subjects and patients stimulated with either CD40L and IL-21 (upper panel) or CD40L and IL-4 (lower panel). CD19+ B cells were stained for the activation markers CD69, CD86, and CD95 after 3 days of stimulation. B, Capacity of CD19+ B cells from control subjects and patients to undergo class-switch recombination into IgG+ and IgA+ cells after 6 days of stimulation. Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Flow cytometric analysis gated on CD19+ cells displaying decreased IgM+CD27+ non–class-switched memory B cells in the patient compared with a healthy shipment control, as well as a healthy donor (top) and increased immature early transitional CD38+CD10+ B cells (bottom). Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Flow cytometric analysis displaying increased proportion of TCRγδ+CD3+ cells. SSC, Side scatter. Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 TCR Vβ spectratyping analysis. Analysis of the patient shows a normal polyclonal use of the TCR Vβ repertoire. Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 IL-21 production by HEK293 cells. A, Flow cytometric analysis of IL-21R expression on Jurkat cells. B, Western blot analysis of supernatant of IL-21–producing HEK293 cells blotted for the His-tag attached to both with IL-21Leu49Pro and IL-21WT. Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Proliferation capacity of the cord blood–derived plasmablast and memory B-cell populations in response to WT (open circles) or mutant (solid circles) IL-21. Data were gated on CD19+ cells and analyzed for expression of either CD38 and CD27 (A) or CD38 and CD138 (B). Journal of Allergy and Clinical Immunology 2014 133, 1651-1659.e12DOI: (10.1016/j.jaci.2014.02.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions