Mikael Eriksson

Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case-control study.

The use of oral snuff is a widespread habit in Sweden. We investigated whether the use of Swedish moist snuff leads to an increasing risk of oral cancer. Other risk factors such as smoking tobacco and alcoholic beverages were also investigated. Our study comprised 410 patients with oral cancer, from the period 1980–1989, and 410 matched controls. All subjects received a mailed questionnaire. The response rates were 96% and 91% for cases and controls, respectively. In the study, a total of 20% of all subjects, cases and controls, were active or ex‐snuff users. The univariate analysis did not show any increased risk [odds ratio (OR) 0.7, 95% confidence interval (CI) 0.4–1.1] for active snuff users. We found an increased risk (OR 1.8, CI 1.1–2.7) for oral cancer among active smokers. Alcohol consumption showed the strongest risk for oral cancer. Among consumers of beer, an increased risk of 1.9 (CI 0.9–3.9) was found. Corresponding ORs for wine and liquor were 1.3 (CI 0.9–1.8) and 1.6 (CI 1.1–2.3), respectively. A dose‐response effect was observed. Although not statistically significant, a multivariate analysis similarly suggested that the most important risk factors were beer and liquor consumption, followed by smoking. Int. J. Cancer 77:341–346, 1998.

Effects of Human Cytomegalovirus Infection on Ligands for the Activating NKG2D Receptor of NK Cells: Up-Regulation of UL16-Binding Protein (ULBP)1 and ULBP2 Is Counteracted by the Viral UL16 Protein

Human CMV (HCMV) interferes with NK cell functions at various levels. The HCMV glycoprotein UL16 binds some of the ligands recognized by the NK-activating receptor NKG2D, namely UL16-binding proteins (ULBP) 1 and 2 and MHC class I-related chain B, possibly representing another mechanism of viral immune escape. This study addressed the expression and function of these proteins in infected cells. HCMV induced the expression of all three ULBPs, which were predominantly localized in the endoplasmic reticulum of infected fibroblasts together with UL16. However, while at a lower viral dose ULBP1 and 2 surface expression was completely inhibited compared to ULBP3, at a higher viral dose cell surface expression of ULBP1 and ULBP2 was delayed. The induction of ULBPs correlated with an increased dependency on NKG2D for recognition; however, the overall NK sensitivity did not change (suggesting that additional viral mechanisms interfere with NKG2D-independent pathways for recognition). Infection with a UL16 deletion mutant virus resulted in a different pattern compared to the wild type: all three ULBP molecules were induced with similar kinetics at the cell surface, accompanied by a pronounced, entirely NKG2D-dependent increase in NK sensitivity. Together our findings show that upon infection with HCMV, the host cell responds by expression of ULBPs and increased susceptibility to the NKG2D-mediated component of NK cell recognition, but UL16 limits these effects by interfering with the surface expression of ULBP1 and ULBP2.

Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-β

Natural killer (NK) cells are a major population of lymphocytes in the human endometrium (EM), and NK cells can be a significant source of cytokines that alter local immune responses. The aim of this study was to determine the expression of NK cell receptors in situ and to test whether uterine NK (uNK) cells produce cytokines and how this activity may be regulated by transforming growth factor‐β (TGF‐β). We observed that human uNK cells were CD56+, CD3−, CD57−, CD9+, CD94+, killer inhibitory receptor+, and CD16+/− in situ by confocal microscopy. We examined cytokine production by uNK cells and uNK cell clones derived from human EM. Stimulation of uNK cells with interleukin (IL)‐12 and IL‐15, both of which are expressed in the human EM, induced interferon‐γ (IFN‐γ) and IL‐10 production. IFN‐γ production by uNK cell clones was completely inhibited by TGF‐β1 in a dose‐dependent manner with an inhibitory concentration 50% value of 20 pg/ml. IL‐10 secretion by uNK cell clones was also inhibited by TGF‐β1 at similar concentrations. Furthermore, blocking endogenous TGF‐β in fresh human endometrial cell cultures increased the production of IFN‐γ by uNK cells. These data indicate that uNK cells have a unique phenotype that is distinct from blood NK cells. Further, data demonstrate that uNK cells can produce immunoregulatory cytokines and that inhibition of uNK cells by locally produced TGF‐β1 is a likely mechanism to regulate NK cell function in the human EM.

Recruitment of Uterine NK Cells: Induction of CXC Chemokine Ligands 10 and 11 in Human Endometrium by Estradiol and Progesterone

Uterine NK (uNK) cells express a unique set of markers compared with blood NK cells. However, recent studies suggest that uNK cells may be derived from the recruitment of blood NK cells into the endometrium. In this study, we used an in vitro organ culture system to demonstrate that estradiol induces expression of chemokines CXCL10 and/or CXCL11 within human endometrium in 85% of patient samples tested. The average increase in gene expression after 10−9 M estradiol treatment was 8.5-fold for CXCL10 and 7.7-fold for CXCL11 compared with medium alone. We observed that a specific estrogen receptor antagonist (ICI182780) was able to prevent chemokine gene induction, indicating that the effect of estradiol was receptor mediated. Moreover, our study showed that progesterone induced CXCL10 and CXCL11 expression in 83% of endometrial samples tested. We have also found that uNK cells and blood NK cells express the receptor for CXCL10 and CXCL11, CXCR3, with the highest expression found on uNK cells and CD56bright blood NK cells. These data indicate that sex hormones induce specific chemokines in nonpregnant human endometrium that can activate NK cell migration, and suggest that this mechanism may account for the increased NK cell numbers in endometrium during the menstrual cycle.

TLRs Mediate IFN-γ Production by Human Uterine NK Cells in Endometrium

The human endometrium (EM) contains macrophages, NK cells, T cells, B cells, and neutrophils in contact with a variety of stromal and epithelial cells. The interplay between these different cell types and their roles in defense against pathogen invasion in this specialized tissue are important for controlling infection and reproduction. TLRs are a family of receptors able to recognize conserved pathogen-associated molecular patterns. In this study, we determined the expression of TLRs on uterine NK (uNK) cells from the human EM and the extent to which uNK cells responded to TLR agonist stimulation. uNK cells expressed TLRs 2, 3, and 4, and produced IFN-γ when total human endometrial cells were stimulated with agonists to TLR2 or TLR3 (peptidoglycan or poly(I:C), respectively). Activated uNK cell clones produced IFN-γ upon stimulation with peptidoglycan or poly(I:C). However, purified uNK cells did not respond directly to TLR agonists, but IFN-γ was produced by uNK cells in response to TLR stimulation when cocultured with APCs. These data indicate that uNK cells express TLRs and that they can respond to TLR agonists within EM by producing IFN-γ. These data also indicate that the uNK cells do not respond directly to TLR stimulation, but rather their production of IFN-γ is dependent upon interactions with other cells within EM.

The association between soft tissue sarcomas and exposure to phenoxyacetic acids. A new case-referent study.

A case‐referent study on soft tissue sarcomas (STS) was conducted, to see if previous findings regarding an association between exposure to phenoxyacetic acids or chlorophenols and this tumor type could be reproduced. Fifty‐five male STS patients were thereby compared with 220 living and 110 dead population‐based referents. Furthermore, another referent group consisting of 190 patients with another type of malignant disease was used in order to evaluate any influence of recall bias on the results. To obtain information about exposure to the studied chemicals, as well as about any other exposures that might be of interest, questionnaires were used, and if necessary these were completed over the phone by an interviewer who had no information regarding case‐referent status. All analysis and interpretation of exposure data were done in a blinded manner. Exposure to phenoxyacetic acids gave a roughly three‐fold increased risk for STS, thereby confirming previous findings, whereas exposure to chlorophenols was not associated with STS in this study.

Intravascular haemolysis and increased prevalence of myeloma and monoclonal gammopathy in congenital dyserythropoietic anaemia, type III

Abstract:  A family with congenital dyserythropoietic anaemia type III was studied. Twenty patients and 10 of their healthy siblings were clinically examined and questioned about their medical history. Blood sampling and bone marrow aspirations were also performed. Forty‐five percent of the patients reported symptoms of anaemia and 35% regularly felt weakness, fatigue, or headache. However, the majority of the patients regarded themselves as healthy. The bone marrow showed a uniform picture of erythroid hyperplasia with multinuclear erythroblasts and gigantoblasts with up to 12 nuclei. There was laboratory evidence of intravascular haemolysis and mild anaemia. We also observed a high prevalence of monoclonal gammopathy of undetermined significance (3 cases) and myeloma (1 case) among the patients.

PCNA, Ki‐67, p53, bcl‐2 and prognosis in intraoral squamous cell carcinoma of the head and neck

Eighty patients with primary intraoral squamous cell carcinomas of the head and neck, with a follow‐up of 4–14 years were analysed for clinical outcome in relation to immunohistochemical expression of PCNA, Ki‐67, p53, bcl‐2 and presence of mutations in the p53 gene. The tumour site was not associated with the different parameters calculated. PCNA and Ki‐67 labelling showed median values of 56% and 32%, respectively, and neither antigen was of predictive value. Fiftyfive percent of the tumours expressed p53, and 38 (48%) had mutations in the p53 gene. No association between the presence of p53 protein or mutations in the p53 gene and clinical outcome was found. Bcl‐2 positivity was detected in a minor fraction (10%) of the tumours.

Human uterine NK cells interact with uterine macrophages via NKG2D upon stimulation with PAMPs.

Problem  The initiation of an immune response often involves the cooperation of various innate immune cells. In the human endometrium, uterine natural killer (uNK) cells and uterine macrophages are present in significant numbers and in close proximity, yet how they cooperatively respond to infectious challenge is poorly understood.

Ly49A inhibitory receptors redistribute on natural killer cells during target cell interaction.

When T effector cells meet antigen‐bearing target cells, there is a specific accumulation of T‐cell receptors, co‐receptors and structural proteins at the point of cell–cell contact. Ly49 inhibitory receptors bind to murine major histocompatibility complex (MHC) class I molecules and prevent natural killer‐(NK) cell cytotoxicity. In this study we have tested whether inhibitory receptors accumulate at the point of cell–cell contact when NK cells encounter target cells bearing MHC class I ligands for those inhibitory receptors. We have used RNK‐16 effector cells that express Ly49A receptors and have found that there was a specific accumulation of Ly49A receptors at the point of NK cell–target cell contact when the target cells expressed H‐2Dd. We also observed that engagement of Ly49A on NK cells resulted in an altered redistribution of potential triggering receptors CD2 and NKR‐P1. These data indicate that inhibitory receptors, like activating receptors, may specifically aggregate at the point of cell–cell contact which may be necessary for them to mediate their full inhibitory effect.