Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency Bianca Tesi, MD, Elena Sieni, MD, Conceição Neves, MD, Francesca.

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Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency Bianca Tesi, MD, Elena Sieni, MD, Conceição Neves, MD, Francesca Romano, BSc, Valentina Cetica, PhD, Ana Isabel Cordeiro, MD, Samuel Chiang, MSc, Heinrich Schlums, MSc, Luisa Galli, MD, Stefano Avenali, MD, Annalisa Tondo, MD, Clementina Canessa, MD, Jan-Inge Henter, MD, PhD, Magnus Nordenskjöld, MD, PhD, Amy P. Hsu, BA, Steven M. Holland, MD, João F. Neves, MD, Chiara Azzari, MD, PhD, Yenan T. Bryceson, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 6, Pages 1638-1641.e5 (June 2015) DOI: 10.1016/j.jaci.2014.11.030 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Immunologic analyses. Both patients (A and B) displayed a low number of NK cells. Neutrophil counts in patient B were lower at initial diagnosis of HLH compared with this later measurement. Flow-cytometric analyses of patient A showed abnormal NK-cell degranulation toward K562 (C), normal T-cell degranulation (D), and normal granule content (E). Granule content (F) and NK-cell degranulation toward K562 (G) were normal in patient B. Ctrl, Control; R-MFI, relative median fluorescence intensity; Trp, transport. Journal of Allergy and Clinical Immunology 2015 135, 1638-1641.e5DOI: (10.1016/j.jaci.2014.11.030) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Coverage analysis in patient A suggests an exonic deletion of exon 2 of IFNGR2 (A), validated by RT-PCR of IFNGR2 (B) and cDNA sequencing (C), which showed lack of exon 2. D, Sanger electropherograms of G219R IFNGR1 missense mutation in patient B. E, STAT1 phosphorylation on IFN-γ stimulation is defective in patient A, but not in the controls. Ctrl, Control; STAT1, signal transducer and activator of transcription 1; Trp, transport. Journal of Allergy and Clinical Immunology 2015 135, 1638-1641.e5DOI: (10.1016/j.jaci.2014.11.030) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Family pedigree of patient A (II-3) (A) and patient B (II-1) (B). Journal of Allergy and Clinical Immunology 2015 135, 1638-1641.e5DOI: (10.1016/j.jaci.2014.11.030) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 NK-cell cytotoxic activity measured in patient A in resting NK cells (A) and after stimulation with IL-2 (B). Flow-cytometry analyses of NK-cell (C) and T-cell degranulation (D) after stimulation with IL-2 in PBMCs from patient A. Ctrl, Control; Trp, transport. Journal of Allergy and Clinical Immunology 2015 135, 1638-1641.e5DOI: (10.1016/j.jaci.2014.11.030) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IFN-γ release by patient B and control PBMCs. IFN-γ release was evaluated with 2 different assays that quantified IFN-γ by active units (A) or concentration (B). Ctrl, Control. Journal of Allergy and Clinical Immunology 2015 135, 1638-1641.e5DOI: (10.1016/j.jaci.2014.11.030) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions