Langerhans cells in the development of skin cancer: A qualitative and quantitative comparison of cell markers in normal, acanthotic and neoplastic ovine skin

The distribution of Langerhans cells in normal, acanthotic and neoplastic ovine epithelium was examined using the enzyme marker Acetylcholinesterase (AchE) and monoclonal antibodies (MoAb) to CD1 (20.27) and MHC Class It (49.1 and 28.1) molecules. In normal skin, where Langerhans cells were regularly spaced within the basal layer, qualitative observations and direct pairwise testing showed that AChE was superior to the MoAb in detecting these cells. Significantly more (P < 0.01) dendritic cells were also detected with MoAb 49.1 than MoAb 20.27 or 28.1, suggesting differential expression of MHC Class II subsets and the presence of CD1– MHC Class II+ granule– dendritic cells in sheep analogous to indeterminate cells of man. In acanthotic skin, compared to normal skin, Langerhans cells were less numerous, irregular and more suprabasal in distribution and their morphology was occasionally swollen and indistinct. No difference was seen in the ability of AChE and MoAb in detecting Langerhans cells, however pairwise testing of markers did demonstrate that significantly more (P < 0.05) cells without dendritic processes were stained with MoAb 49.1 than with 20.27 or 28.1. In all squamous cell carcinomas examined dendritic cells that stained for ACHE, CD1 or MHC Class II antigens were concentrated at the peripheral areas of neoplastic epithelium. Many dendritic cells were detected with MoAb to MHC Class II antigens, whereas CD1 and AChE positive dendritic cells were rare in tumor bearing tissue. The quantitative differences in the immunohistochemical staining of Langerhans cells between normal, acanthotic and neoplastic epithelium were consistent with ultrastructural studies. When compared with those of a newborn lamb, which had had very little exposure to antigens or ultraviolet radiation (UVR), the Langerhans cells of the aged sheep were deformed and contained far fewer Birbeck granules. The abnormalities were progressively more severe in acanthotic and neoplastic skin. These observed changes may have resulted from UVR induced damage and may be indicative of impaired function involved in the development of skin cancer

COVID‐19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity?

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2

Hypoxia regulates DPP4 expression, proteolytic inactivation, and shedding from ovarian cancer cells

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.Laura R. Moffitt, Maree Bilandzic, Amy L. Wilson, Yiqian Chen, Mark D. Gorrell, Martin K. Oehler ... et al

Circulating fibroblast activation protein activity and antigen levels correlate strongly when measured in liver disease and coronary heart disease

textabstractBackground and aim: Circulating fibroblast activation protein (cFAP) is a constitutively active enzyme expressed by activated fibroblasts that has both dipeptidyl peptidase and endopeptidase activities. We aimed to assess the correlation between cFAP activity and antigen levels and to compare variations in levels. Methods: In plasma of 465 control individuals, 368 patients with coronary heart disease (CHD) and 102 hepatitis C virus (HCV) infected patients with severe liver disease before and after liver transplant, cFAP activity levels were measured with a newly developed cFAP activity assay. In the same samples, cFAP antigen levels were measured using a commercially available cFAP ELISA. Correlation analyses between activity and antigen levels were performed by calculating Pearson's correlation coefficient (ρ). Additionally, normal ranges, determinants and differences between cohorts and between anticoagulants were investigated. Results: cFAP activity and antigen levels significantly correlated in controls (ρ: 0.660, p<0.001) and in CHD patients (ρ: 0.709, p<0.001). cFAP activity and antigen levels in the HCV cohort were significantly lower in the samples taken after liver transplantation (p<0.001) and normalized toward levels of healthy individuals. Furthermore, cFAP activity and antigen levels were higher in men and significantly associated with body mass index. Also, cFAP activity and antigen levels were higher in EDTA plasma as compared to the levels in citrated plasma from the same healthy individuals. Conclusions: For analyzing cFAP levels, either activity levels or antigen levels can be measured to investigate differences between individuals. However, it is of importance that blood samples are collected in the same anticoagulant