Immune Netw.  2017 Oct;17(5):352-364. 10.4110/in.2017.17.5.352.

Functional Defects in Type 3 Innate Lymphoid Cells and Classical Monocytes in a Patient with Hyper-IgE Syndrome

• Chang Y
• Kang SY
• Kim J
• Kang HR
• Kim HY

• KMID: 2400640
• DOI: http://doi.org/10.4110/in.2017.17.5.352

Abstract

Hyper-IgE syndrome (HIES) is a very rare primary immune deficiency characterized by elevated serum IgE levels, recurrent bacterial infections, chronic dermatitis, and connective tissue abnormalities. Autosomal dominant (AD) HIES involves a mutation in signal transducer and activator of transcription 3 (STAT3) that leads to an impaired T(H)17 response. STAT3 signaling is also involved in the function of RORγt⁺ type 3 innate lymphoid cells (ILC3s) and RORγt⁺T(H)17 cells. The aim of this study was to investigate the role of innate immune cells such as innate lymphoid cells (ILCs), granulocytes, and monocytes in a patient with HIES. Peripheral blood mononuclear cells (PBMCs) from a patient with HIES and three age-matched healthy controls were obtained for the analysis of the innate and adaptive immune cells. The frequencies of ILCs in PBMCs were lower in the patient with HIES than in the controls. Moreover, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A produced by ILC3s in PBMCs were lower in the patient with HIES than the controls. Compared with the controls, classical monocytes (CD14⁺CD16(low)), which have a high antimicrobial capability, were also lower in the patient with HIES, while non-classical monocytes (CD14(low)CD16⁺) as well as intermediate monocytes (CD14⁺CD16(intermediate)) were higher. Taken together, these results indicate that the impaired immune defense against pathogenic microbes in the patient with HIES might be partially explained by functional defects in ILC3s and inflammatory monocytes.

Keyword

Hyper-IgE syndrome; STAT3 transcription factor; Innate immunity; Innate lymphoid cells; Monocytes; Cytokines

MeSH Terms

Bacterial Infections
Connective Tissue
Cytokines
Dermatitis
Granulocyte-Macrophage Colony-Stimulating Factor
Granulocytes
Humans
Immunity, Innate
Immunoglobulin E
Interleukin-17
Job Syndrome*
Lymphocytes*
Monocytes*
STAT3 Transcription Factor
Cytokines
Granulocyte-Macrophage Colony-Stimulating Factor
Immunoglobulin E
Interleukin-17
STAT3 Transcription Factor

Figure

• 

  Figure 1 Chest computed tomography scan (A, B). Images showing necrotic lesions in right axillary lymph nodes, subcutaneous tissue of the right buttock (A, white arrows), and multifocal air cysts or bullae of the both lungs (B).

• 

  Figure 2 Excisional biopsy specimen revealing inflamed granulation tissue with abscess formation from the right axillary area (A, ×100; B, ×400).

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  Figure 3 The distribution of T cells in PBMCs from healthy controls and a patient with HIES. (A, B) CD4+ T cells, CD8+ T cells, and Treg cells were analyzed by flow cytometry. (A) Representative flow cytometric profiles of the T cell population. (B) Graphs show the mean percentages of CD3+ T cells, CD4+ T cells, CD8+ T cells, and Treg cells±SEM (n=3). (C, D) Intracellular IFN-γ, IL-5, IL-13, GM-CSF, IL-17, and IL-22 expression in T cells was analyzed by flow cytometry. (C) Representative flow cytometric profiles of cytokine expression by T cells. (D) Graphs show the mean percentage of positive cells±SEM (n=3). CTRL, control; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIES, hyper-IgE syndrome; IFN, interferon; PBMC, peripheral blood mononuclear cell; SEM, standard error of the mean; Treg, regulatory T.

• 

  Figure 4 The distribution of ILCs in PBMCs from healthy controls and a patient with HIES. (A, B) ILC1s (CD45+Lin−CD127+CRTH2−c-kit−NKp44−), ILC2s (CD45+Lin−CD127+CRTH2+), and ILC3s (CD45+Lin−CD127+CRTH2−c-kit+) were analyzed by flow cytometry. (A) Representative flow cytometric profiles of ILC subsets. (B) Graphs show the mean percentage of total ILCs, ILC1s, ILC2s, and ILC3s±SEM (n=3). (C, D) Intracellular IFN-γ, IL-5, IL-13, GM-CSF, IL-17, and IL-22 expression in ILCs was analyzed by flow cytometry. (C) Representative flow cytometric profiles of cytokine expression in ILCs. (D) Graphs show the mean percentage of positive cells±SEM (n=3). CTRL, control; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIES, hyper-IgE syndrome; ILC, innate lymphoid cell; PBMC, peripheral blood mononuclear cell; SEM, standard error of the mean.

• 

  Figure 5 The distribution of monocytes in PBMCs from healthy controls and a patient with HIES. (A, B) Monocytes (CD45+CD15−CD14+) were analyzed by flow cytometry. (A) Representative flow cytometric profiles of monocyte populations. (B) Graphs show the mean percentages of monocytes, classical monocytes (CD14+CD16low), intermediate monocytes (CD14+CD16intermediate), and non-classical monocytes (CD14lowCD16+)±SEM (n=3). (C) The correlations between ILC1s and classical monocytes, intermediate monocytes, and non-classical monocytes were analyzed in healthy controls (black) and a patient with HIES (red). CTRL, control; HIES, hyper-IgE syndrome; ILC, innate lymphoid cell; SEM, standard error of the mean.

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