Impaired natural killer cell subset phenotypes in human obesity.

Obesity is associated with alterations in functionality of immune cells, like macrophages and natural killer (NK) cells, leading to an increased risk for severe infections and several cancer types. This study aimed to examine immune cell populations and functional NK cell parameters focusing on NK cell subset phenotypes in normal-weight and obese humans. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from normal-weight and obese individuals and analyzed by flow cytometry. Results show no significant changes in the frequency of monocytes, B lymphocytes, or NKT cells but a significantly increased frequency of T lymphocytes in obesity. The frequency of total NK cells was unaltered, whereas the number of low cytotoxic CD56bright NK cell subset was increased, and the number of high cytotoxic CD56dim NK cell subset was decreased in obese subjects. In addition, the frequency of CD56bright NK cells expressing the activating NK cell receptor NKG2D as well as intracellular interferon (IFN)-γ was elevated in the obese study group. In contrast, the frequency of NKG2D- and IFN-γ-positive CD56dim NK cells was lower in obesity compared to normal-weight individuals. Moreover, the expression of the activation marker CD69 was decreased in NK cells, which can be attributed to a reduction of CD69-positive CD56dim NK cells in obese subjects. In conclusion, data reveal an impaired NK cell phenotype and NK cell subset alterations in obese individuals. This NK cell dysfunction might be one link to the higher cancer risk and the elevated susceptibility for viral infections in obesity.

Expression and Regulation of S100 Fused-Type Protein Hornerin at the Ocular Surface and Lacrimal Apparatus.

Purpose: The S100 fused-type proteins hornerin (HRNR) and filaggrin-2 (FLG2) are members of the epidermal differentiation complex, which is involved in terminal differentiation of keratinocytes via cornification as well as maintenance of the epidermal antimicrobial barrier. We investigated the expression and possible regulation of HRNR and FLG2 at the ocular surface and in the lacrimal apparatus. Methods: Tissues of the lacrimal apparatus and ocular surface were analyzed systematically by means of RT-PCR, immunohistochemistry, and immuntransmission electron microscopy (iTEM) for their ability to express and produce HRNR and FLG2. In addition, inducibility and regulation of HRNR were studied in cultivated human corneal (HCE), conjunctival (HCjE), as well as meibomian gland (HMGEC) epithelial cell line by real-time RT-PCR. Results: RT-PCR, immunohistochemistry, and iTEM revealed constitutive expression of HRNR in the epithelium of cornea, conjunctiva, nasolacrimal ducts, and acinus cells of lacrimal and meibomian glands. HRNR also was detected in tears of healthy volunteers. No expression of FLG2 could be detected in tissue samples of the ocular surface and lacrimal apparatus. Real-time RT-PCR revealed a decreased HRNR gene expression after challenge with proinflammatory cytokines and supernatants of Escherichia coli and Pseudomonas aeroginosa in HCE cells, whereas HCjE cells revealed no changes. In HMGECs serum-induced differentiation and application of all-trans retinoic acid significantly increased HRNR gene expression. Conclusions: The data suggest that HRNR, but not FLG2, is a component of the ocular surface and lacrimal apparatus, including meibomian glands. HRNR seems to contribute to the maintenance of the epithelial barrier at the ocular surface and, thus, also may be involved in ocular surface diseases.

Impact of the body mass index on perioperative immunological disturbances in patients with hip and knee arthroplasty.

BACKGROUND: Obesity increases the risk for knee and hip joint implantation and negatively contributes to wound healing. In this study, in 52 patients undergoing hip and knee arthroplasty the amount of peripheral immune effector cells pre- and post-operative, as well as the expression of certain soluble factors affecting the functions of immune effector cells were investigated. METHODS: The peripheral immune cells and the expression of the soluble factors were determined by flow cytometry and correlated to each other in dependency of the BMI, the sex, and the kind of arthroplasty. RESULTS: The pre-operative amounts of peripheral NK cells and cytotoxic T cells significantly decreased with increasing BMI. Furthermore, the expression of the immunomodulatory adipokine leptin nicely correlated to the BMI. These effects were stronger in males than in females. Furthermore, the correlation of the activation marker sTNF-R and peripheral T cells strongly decreased with increasing BMI. While IL-6, CD40L, and MPO were significantly induced after surgery, there were no correlations to the BMI. CONCLUSIONS: The known wound-healing problems in obese patients and the osteoarthritis per se can be linked to the BMI. While obese patients exerted reduced peripheral NK cells and cytotoxic T cells (CTLs), IL-6 showed no involvement. However, the adipokine leptin strongly increased with the BMI strengthening its role as immunomodulatory molecule negatively interfering the functions of immune effector cells.

Diet-Induced Obesity Is Associated with an Impaired NK Cell Function and an Increased Colon Cancer Incidence.

Obesity is associated with an increased colon cancer incidence, but underlying mechanisms remained unclear. Previous studies showed altered Natural killer (NK) cell functions in obese individuals. Therefore, we studied the impact of an impaired NK cell functionality on the increased colon cancer risk in obesity. In vitro investigations demonstrated a decreased IFN-γ secretion and cytotoxicity of human NK cells against colon tumor cells after NK cell preincubation with the adipokine leptin. In addition, leptin incubation decreased the expression of activating NK cell receptors. In animal studies, colon cancer growth was induced by injection of azoxymethane (AOM) in normal weight and diet-induced obese rats. Body weight and visceral fat mass were increased in obese animals compared to normal weight rats. AOM-treated obese rats showed an increased quantity, size, and weight of colon tumors compared to the normal weight tumor group. Immunohistochemical analyses demonstrated a decreased number of NK cells in spleen and liver in obesity. Additionally, the expression levels of activating NK cell receptors were lower in spleen and liver of obese rats. The results show for the first time that the decreased number and impaired NK cell function may be one cause for the higher colon cancer risk in obesity.

Effect of therapeutic plasma exchange on plasma levels and total removal of adipokines and inflammatory markers.

BACKGROUND: Aside from well-established inflammatory mediators adipokines have recently been found to play an important role in a variety of immunologic diseases. Therapeutic plasma exchange (TPE) is an established treatment modality for the acute removal of pathophysiological relevant disease mediators. The aim of this study was to determine adipokine removal during TPE therapy. METHODS: 21 Caucasian patients (10 females, 11 males) with an indication for TPE using albumin as exchange fluid received two consecutive TPE sessions. Blood samples for measurement of resistin, leptin, sICAM-1, sCD40L, MCP-1, and sTNF-R were drawn before and at the end of each TPE session. Samples from the total removed plasma were collected at the end of every treatment. RESULTS: We found a significant reduction in pre- vs. post-TPE plasma concentrations for sICAM-1 (517 ± 246 vs. 260 ± 159 ng/ml, p < 0.0001), sTNF-R (8.1 ± 6.4 vs. 5.7 ± 3.9 ng/ml, p < 0.05), and resistin plasma levels (14.3 ± 6.9 vs. 9.5 ± 4.7 ng/ml, p < 0.001). Solely sICAM-1 reduction persisted for 25 ± 5 h between the first and second TPE treatment, while the other investigated mediators increased to baseline levels. Substantial amounts of all measured mediators could be recovered from the removed plasma. CONCLUSIONS: TPE provides a persistent reduction in sICAM-1 levels and temporarily affects several adipokine and cytokine plasma levels. Our findings are of importance not only for the interpretation of blood levels of cytokines in patients undergoing TPE but provide solid evidence that TPE markedly decreases sICAM-1.

Decreased NK cell functions in obesity can be reactivated by fat mass reduction.

OBJECTIVE: Natural killer (NK) cells are the first defense against malignant cells, and their functions are severely impaired in individuals with obesity. However, it is not known whether functions can be re-activated after weight loss. The alterations of NK cell functions after fat mass reduction were investigated. METHODS: Thirty-two healthy adults with obesity were divided into control and experimental groups. Participants of the experimental group performed a 3-month program of exercise training and nutrition. Anthropometric, physiological, and metabolic parameters and plasma adipocytokines were determined. Peripheral blood mononuclear cells were analyzed by means of flow cytometry and Western blot assay for various NK cell-specific functional parameters and leptin signaling components. NK cell-mediated cytotoxicity assay with leptin stimulation was performed. RESULTS: Male participants significantly decreased their body fat mass (P < 0.05) and increased physical fitness (P < 0.05). Plasma leptin levels were significantly reduced (P < 0.05) and intracellular interferon gamma (IFN-γ) expression in CD56(dim) NK cells was significantly increased (P < 0.001) 3 months after study end. Stimulation of NK-92 cells with different leptin dosages revealed a significant dose-dependent decrease of specific tumor cell lysis. CONCLUSIONS: The present study demonstrates a reactivation of NK cell functionality after body fat mass reduction in persons with obesity.