High Interferon Signature Leads to Increased STAT1/3/5 Phosphorylation in PBMCs From SLE Patients by Single Cell Mass Cytometry

Gloria Yiu; Gloria Yiu; Tue Kruse Rasmussen; Tue Kruse Rasmussen; Tue Kruse Rasmussen; Brandon L. Tsai; Vivian K. Diep; David J. Haddon; Jennifer Tsoi; Gopika D. Miller; Begoña Comin-Anduix; Begoña Comin-Anduix; Begoña Comin-Anduix; Bent Deleuran; Bent Deleuran; Gay M. Crooks; Gay M. Crooks; Gay M. Crooks; Gay M. Crooks; Paul J. Utz; Paul J. Utz

doi:10.3389/fimmu.2022.833636

Frontiers in Immunology (Jan 2022)

High Interferon Signature Leads to Increased STAT1/3/5 Phosphorylation in PBMCs From SLE Patients by Single Cell Mass Cytometry

Gloria Yiu,
Gloria Yiu,
Tue Kruse Rasmussen,
Tue Kruse Rasmussen,
Tue Kruse Rasmussen,
Brandon L. Tsai,
Vivian K. Diep,
David J. Haddon,
Jennifer Tsoi,
Gopika D. Miller,
Begoña Comin-Anduix,
Begoña Comin-Anduix,
Begoña Comin-Anduix,
Bent Deleuran,
Bent Deleuran,
Gay M. Crooks,
Gay M. Crooks,
Gay M. Crooks,
Gay M. Crooks,
Paul J. Utz,
Paul J. Utz

Affiliations

Gloria Yiu: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
Gloria Yiu: Department of Rheumatology, University of California, Los Angeles, Los Angeles, CA, United States
Tue Kruse Rasmussen: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
Tue Kruse Rasmussen: Department of Biomedicine, Aarhus University, Aarhus, Denmark
Tue Kruse Rasmussen: Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
Brandon L. Tsai: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, United States
Vivian K. Diep: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
David J. Haddon: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
Jennifer Tsoi: Department of Surgery David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
Gopika D. Miller: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
Begoña Comin-Anduix: Department of Surgery David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, United States
Begoña Comin-Anduix: Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
Begoña Comin-Anduix: Parker Institute for Cancer Immunotherapy, San Francisco, CA, United States
Bent Deleuran: Department of Biomedicine, Aarhus University, Aarhus, Denmark
Bent Deleuran: Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
Gay M. Crooks: Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
Gay M. Crooks: Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
Gay M. Crooks: 0Eli and Edythe Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
Gay M. Crooks: 1Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
Paul J. Utz: Department of Medicine, Division of Immunology and Rheumatology, Stanford School of Medicine, Stanford, CA, United States
Paul J. Utz: 2Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, United States

DOI: https://doi.org/10.3389/fimmu.2022.833636
Journal volume & issue: Vol. 13

Abstract

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The establishment of an “interferon (IFN) signature” to subset SLE patients on disease severity has led to therapeutics targeting IFNα. Here, we investigate IFN signaling in SLE using multiplexed protein arrays and single cell cytometry by time of flight (CyTOF). First, the IFN signature for SLE patients (n=81) from the Stanford Lupus Registry is determined using fluidigm qPCR measuring 44 previously determined IFN-inducible transcripts. IFN-high (IFN-H) patients have increased SLE criteria and renal/CNS/immunologic involvement, and increased autoantibody reactivity against spliceosome-associated antigens. CyTOF analysis is performed on non-stimulated and stimulated (IFNα, IFNγ, IL-21) PBMCs from SLE patients (n=25) and HCs (n=9) in a panel identifying changes in phosphorylation of intracellular signaling proteins (pTOF). Another panel is utilized to detect changes in intracellular cytokine (ICTOF) production in non-stimulated and stimulated (PMA/ionomycin) PBMCs from SLE patients (n=31) and HCs (n=17). Bioinformatic analysis by MetaCyto and OMIQ reveal phenotypic changes in immune cell subsets between IFN-H and IFN-low (IFN-L) patients. Most notably, IFN-H patients exhibit increased STAT1/3/5 phosphorylation downstream of cytokine stimulation and increased phosphorylation of non-canonical STAT proteins. These results suggest that IFN signaling in SLE modulates STAT phosphorylation, potentially uncovering possible targets for future therapeutic approaches.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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