title: Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency.
abstract: BACKGROUND
  Common variable immunodeficiency (CVID) is an antibody deficiency treated with immunoglobulin; however, patients can have noninfectious inflammatory conditions that lead to heightened morbidity and mortality.
  
  
  OBJECTIVE
  Modular analyses of RNA transcripts in whole blood previously identified an upregulation of many interferon-responsive genes. In this study we sought the cell populations leading to this signature.
  
  
  METHODS
  Lymphoid cells were measured in peripheral blood of 55 patients with CVID (31 with and 24 without inflammatory/autoimmune complications) by using mass cytometry and flow cytometry. Surface markers, cytokines, and transcriptional characteristics of sorted innate lymphoid cells (ILCs) were defined by using quantitative PCR. Gastrointestinal and lung biopsy specimens of subjects with inflammatory disease were stained to seek ILCs in tissues.
  
  
  RESULTS
  The linage-negative, CD127(+), CD161(+) lymphoid population containing T-box transcription factor, retinoic acid-related orphan receptor (ROR) γt, IFN-γ, IL-17A, and IL-22, all hallmarks of type 3 innate lymphoid cells, were expanded in the blood of patients with CVID with inflammatory conditions (mean, 3.7% of PBMCs). ILCs contained detectable amounts of the transcription factors inhibitor of DNA binding 2, T-box transcription factor, and RORγt and increased mRNA transcripts for IL-23 receptor (IL-23R) and IL-26, demonstrating inflammatory potential. In gastrointestinal and lung biopsy tissues of patients with CVID, numerous IFN-γ(+)RORγt(+)CD3(-) cells were identified, suggesting a role in these mucosal inflammatory states.
  
  
  CONCLUSIONS
  An expansion of this highly inflammatory ILC population is a characteristic of patients with CVID with inflammatory disease; ILCs and the interferon signature are markers for the uncontrolled inflammatory state in these patients.
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cols
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Adeeb
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Maglione
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Garcia-Carmona
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Noa
authors.initials: N
authors.lastname: Simchoni
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Huai-Bin M
authors.initials: HM
authors.lastname: Ko
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Lin
authors.initials: L
authors.lastname: Radigan
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Tex.
authors.forename: Derek
authors.initials: D
authors.lastname: Blankenship
authors.affiliation: Baylor Institute for Immunology Research, Dallas, Tex.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: Charlotte.Cunningham-Rundles@mssm.edu.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D017074:Common Variable Immunodeficiency / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines
keywords: Common variable immunodeficiency; inflammatory complications; innate lymphoid cells; mucosal disease