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Jeff Choi, BSc, Rosemary Fernandez, PhD, Holden T

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1 Systems approach to uncover signaling networks in primary immunodeficiency diseases 
Jeff Choi, BSc, Rosemary Fernandez, PhD, Holden T. Maecker, PhD, Manish J. Butte, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 140, Issue 3, Pages e8 (September 2017) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Signaling responses of immune cell subtypes to canonical stimuli. Fold changes of phospho signaling proteins after stimulation compared with baseline across 9 pathways, shown according to stimuli and cell subtype. All responses were measured 15 minutes after stimulation. This signaling map compiled from 5 healthy subjects provides a comprehensive view of well-established, recently described, and previously undescribed signaling changes. mDC, Myeloid dendritic cells; NK, natural killer; pDC, plasmacytoid dendritic cell. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Defects in baseline signals and responses to signals in PID. Baseline phosphorylation levels of subjects with GOF STAT1 (A) and STAT3 (B) deficiency that are greater than 1.5-fold or less than 0.75-fold of corresponding baseline phosphorylation levels in controls. Signaling fold changes in GOF STAT1 (C) and STAT3 (D) deficiency subjects that fall outside of the 95% CI of corresponding fold changes in controls (indicated by boxes) with P value of less than .05 are shown. Unstimulated points are scaled to the unstimulated value for the subject with GOF STAT1 (Fig 2, C) or STAT3 deficiency (Fig 2, D) or the average for the 5 healthy subjects. Stimulation responses are shown for the subjects with PID (purple or green circle) and the healthy controls (gray circles). Stimuli and signals are across the top, and cell type is across the side. Only the responses that are statistically significant are shown. mDC, Myeloid dendritic cell; NK, natural killer; pSTAT1, phospho-STAT1; unstim, unstimulated. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 Schematic of the gating strategy used to identify the various cell types. Shown are CyTOF data from a control subject. Gates were manually adjusted for each subject starting from these representative gates. Cell subsets were gated as follows: basophils (CD123+ HLA−DR−); eosinophils (CD45+ CD66+ CD16−); neutrophils (CD45+ CD66+ CD16+); CD16+ monocytes (CD45+ CD66− CD14+ CD11c+ CD16+); CD16− monocytes (CD45+ CD66− CD14+ CD11c+ CD16−); switched memory B cells (CD45+ CD3− CD20+ CD19+ CD27+ IgD−); unswitched memory B cells (CD45+ CD3− CD20+ CD19+ CD27+ IgD+); naive B cells (CD45+ CD3− CD20+ CD19+ CD27− IgD+); plasmablasts (CD45+ CD3− CD19low IgD− CD38+ CD27+); myeloid dendritic cell (mDC) (CD45+ CD3− CD20− CD19− CD56− CD11c+); plasmacytoid dendritic cell (pDC) (CD45+ CD3− CD20− CD19− CD56− CD11c− CD123+); note that true pDCs are a subset of this population that also express CD303, which was not included in this panel. CD4+ naive T cell (CD45+ CD3+ CD4+ CD45RA+ CD45RO−); CD4+ memory T cell (CD45+ CD3+ CD4+ CD45RO+ CD45RA−); activated CD4+ T cell (CD45+ CD3+ CD4+ CD38+ HLA−DR+); regulatory T cells (CD45+ CD3+ CD4+ CD25+ CD127−); CD8+ naive T cell (CD45+ CD3+ CD8+ CD45RA+ CD45RO−); CD8+ memory T cell (CD45+ CD3+ CD8+ CD45RO+ CD45RA−); activated CD8+ T cell (CD45+ CD3+ CD8+ CD38+ HLA−DR+); natural killer T (NKT) cells (CD45+ CD3+ CD56+); natural killer (NK) cells (CD45+ CD3− CD19− CD20− CD56+). Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E2 Hierarchical clustering by signal responsiveness largely mirrors developmental lineages. mDC, Myeloid dendritic cell; NK, natural killer; pDC, plasmacytoid dendritic cell. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E3 Stimulation responses for subject with GOF STAT1 disease. Responses are scaled to the unstimulated value for the subject with GOF STAT1 and the average for the 5 healthy controls. Stimulation responses are shown for the GOF STAT1 subject (orange circle) and the healthy controls (green circles). Stimuli and signals are across the top, and cell type is across the side. Only the responses that are statistically significant are shown. Boxes show the bootstrapped mean and 95% CI. NK, Natural killer. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E4 Stimulation responses for subject with STAT3 deficiency disease. Responses are scaled to the unstimulated value for the subject with PI and the average for the 5 healthy controls. Stimulation responses are shown for the STAT3 deficiency subject (orange circle) and the healthy controls (green circles). Stimulation and response are across the top, and cell type is across the side. Only the responses that are statistically significant are shown. Boxes show the bootstrapped mean and 95% CI. pDC, Plasmacytoid dendritic cell. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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