Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation Christian Klemann, MD,

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Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation Christian Klemann, MD, Sandra Ammann, PhD, Miriam Heizmann, MBiol, Sebastian Fuchs, PhD, Sebastian F. Bode, MD, Maximilian Heeg, MD, Hans Fuchs, MD, Kai Lehmberg, MD, Udo zur Stadt, MD, Claudia Roll, MD, Thomas Vraetz, MD, Carsten Speckmann, MD, Myriam Ricarda Lorenz, PhD, Klaus Schwarz, MD, Jan Rohr, MD, Stefan Feske, MD, Stephan Ehl, MD Journal of Allergy and Clinical Immunology Volume 140, Issue 6, Pages 1721-1724 (December 2017) DOI: 10.1016/j.jaci.2017.05.039 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Impaired NK-cell degranulation: PBMCs from the ORAI1-deficient patient (Pat I148S) or healthy control (Ctrl) were stained with fluorochrome-conjugated lineage markers and anti-CD107 mAbs following stimulation with K562 target cells for 2 hours (left plots) or after preactivation with PHA (1.25 μg/mL) and IL-2 (200 U/mL) (right plots). Lymphocytes were analyzed by flow cytometry and gated on forward scatter/side scatter characteristics and CD56 vs CD107a expression is plotted on CD3−CD56+ NK cells. The assay was performed twice with similar results. B, Impaired NK-cell degranulation in CRAC channelopathies: The upper panel shows the results of fresh NK-cell degranulation expressed as delta CD107a (difference in the percentage of CD107a+CD3−CD56+ NK cells among PBMCs after incubation with K562 cells or medium) in controls, 10 patients with 1° HLH due to mutations in MUNC13-4 or MUNC18-2, the current ORAI1 patient (I148S) (triangle, repeated measures), and previously published patients with ORAI1 deficiency (R91W3) (diamond) or STIM1 deficiency (R429C4) (square). The shaded gray area indicates normal values. The lower panel shows NK-cell degranulation after preactivation with PHA (1.25 μg/mL) and IL-2 (200 U/mL). C, Increased monocyte activation: Frozen PBMCs from the ORAI1-deficient patient and a healthy control as well as a perforin-deficient infant with acute HLH and a healthy control were stained with antibodies to lymphocyte lineages, CD45, HLA-DR, CD14, and CD16 and assessed by flowcytometry. The plots are gated on CD45+lin−HLA-DR+ cells. The 3 gates show CD14+CD16− classical monocytes, CD14+CD16dim intermediate monocytes (high cytokine producers), and CD14−CD16bright nonclassical monocytes (poor cytokine producers). D, Impaired T-cell proliferation: CFSE-labeled PBMCs were stimulated with PHA, plate-bound anti-CD3 (300 ng/mL) or plate-bound anti-CD3, and soluble CD28 or incubated in medium. After 5 days, CFSE dilution was analyzed by flow cytometry. Histograms show CFSE levels in nonstimulated CD4+ T cells (gray lines) and stimulated cells (black lines). E, Impaired T-cell activation: Expression of CD69 and CD40L on CD4+ T cells after incubation of patient and control PBMCs in medium alone (gray lines) or following stimulation (black lines) with anti-CD3/Cd28 beads for 24 hours (CD69) or inomycin/phorbol 12-myristate 13-acetate for 3 hours (CD40L). CFSE, Carboxyfluorescein succinimidyl ester; PRF1, Perforin 1. Journal of Allergy and Clinical Immunology 2017 140, 1721-1724DOI: (10.1016/j.jaci.2017.05.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Impaired calcium flux in T cells: PBMCs from the patient (black line) or a healthy control (gray line) were loaded with the Ca2+ indicator Indo-1-AM, incubated in Ca2+-free PBS (0 mM), and stimulated with Fab(2) of anti-CD3, followed by readdition of 2 mM of CaCl2 to induce store-operated calcium entry (left plot). Alternatively, cells were stimulated with 1 μM thapsigargin (TG) followed by readdition of CaCl2 (right plot). The graph shows the ratio of unbound to bound Indo-1-AM as a measure of Ca2+ influx during the experiment. The assay was performed twice with similar results. B, ORAI1 p.I148S mutation: Forward genomic DNA sequence of the index patient, his brother, and a control. The wild-type codon ATC is mutated to AGC resulting in a homozygous p.Ile148Ser missense mutation in the patient. C, Normal ORAI1 expression in T cells: CD3+ cells of the index patient, a healthy donor (Ctrl), and a previously reported patient with the R91W mutation3 were fixed, permeabilized, and stained without (left plot) or with primary anti-ORAI1 antibodies (all other plots). For this, a polyclonal antibody against the C terminus of ORAI1 raised by immunizing rabbits with a conserved 17-amino-acid peptide corresponding to amino acids 278 to 294 of human ORAI1 (NP_116179) was used. Intracellular ORAI1 was detected with a fluorescent secondary antibody by flow cytometry. D, Localization of p.I148S mutation in ORAI1: ORAI1 forms the pore-forming subunit of the CRAC channel in the plasma membrane. It contains 4 alpha-helical transmembrane domains (TM 1-4) and an intracellular N and C termini. The mutant I148S residue (depicted in red) is located in the TM II-III intracellular loop connecting TM2 and TM3. The localization of the protein changes resulting from previously published patients is also indicated (orange lines). Bro, Brother; Ctrl, control; Pat, patient. Journal of Allergy and Clinical Immunology 2017 140, 1721-1724DOI: (10.1016/j.jaci.2017.05.039) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions