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. Objectives 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.

Immune modules shared by innate lymphoid cells and T cells

“…It is deregulated in the development of psoriasis, Crohn’s disease, and other forms of autoimmunity such as the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE). Consistent with this, investigators have reported ILC3 expansion in: skin and blood of patients with psoriasis (97–99); blood, gut, synovial fluid, and bone marrow of patients with ankylosing spondylitis (100); and blood, lung, and gut of patients with common variable immunodeficiency (CVID) (101). Interestingly, several labs have reported that ILC3 are reduced rather than increased in Crohn’s disease relative to ILC1 (17, 18, 57, 58), and that remaining ILC3 are phenotypically altered and express less MHC-II (102).…”

Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD)

“…Similarly, Innate lymphoid cells (ILC) have also been identified to play a crucial role in IBD pathogenesis [26]. The number of inflammatory ILC have remarkably been found increased in blood, respiratory and gastrointestinal mucosa of CVID patients with inflammatory conditions compared to patients without CVID inflammatory disorders [27] although, to date ILC have not been studied in detail in the GI mucosa of CVID patients with intestinal manifestations.…”

Loss of Circulating Mucosal-Associated Invariant T Cells in Common Variable Immunodeficiency Is Associated with Immune Activation and Loss of Eomes and PLZF

“…IgG replacement therapy reduces immune activation in CVID patients (13), but invariant NK T cells and regulatory T cells remain low in CVID patients on treatment (14)(15)(16). Chronic upregulation of the IFN pathway, due to expansion of proinflammatory group 3 innate lymphoid cells, has been reported in a subset of CVID patients with inflammatory complications (17,18).…”