Patient-reported assessment of medical care for chronic inflammatory skin diseases: an enterprise-based survey.

Background: Chronic inflammatory skin diseases (CISDs) are among the most common diseases in the Western world. Current estimates of medical care for CISDs are primarily based on surveys among patients in medical care facilities and on health insurance data. Aim: Survey-based examination to what extent CISD patients in health-aware environment consider their skin disease to be controlled. Methods: The survey of CISD patients was carried out in 2022 among the employees of a pharmaceutical company located in Germany and Switzerland. Software-based, anonymous, self-reported questionnaires were used. Results: The number of employees, who answered the questionnaire, was 905. Of these, 222 participants (24.5%) reported having at least one CISD. 28.7% of participants with CISD described their disease as being hardly or not controlled. Regarding the nature of disease, more than one third of participants suffering from hidradenitis suppurativa (HS) or psoriasis fell into the hardly/not controlled category. In contrast, the largest proportion of participants with chronic spontaneous urticaria (43%) or atopic dermatitis (42%) considered their CISD to be completely or well controlled. Only 35.5% of CISD sufferers stated that they were currently under medical care for their skin condition. Being under medical care, however, had no influence on the extent CISD sufferers considered their skin disease to be controlled. The number of active CISD episodes but not the total number of symptomatic days per year was negatively associated with poor disease control (p = 0.042 and p = 0.856, respectively). Poor disease control had a negative effect on the personal and professional lives of those affected, as deduced from its positive association with the extent of daily activity impairment and presenteeism (p = 0.005 and p = 0.005, respectively). Moreover, 41.4 and 20.7% of participants with hardly/not controlled disease stated that their CISD had a moderate and severe or very severe impact on their overall lives (p < 0.001), respectively. A severe or very severe impact of their CISD on their overall life was most commonly reported by participants with HS. Conclusion: Medical care for CISDs, even in an environment with high socio-economic standard and high health-awareness, still appears to be limited and has a negative impact on individuals and society.

Primary immune responses are negatively impacted by persistent herpesvirus infections in older people: results from an observational study on healthy subjects and a vaccination trial on subjects aged more than 70 years old.

BACKGROUND: Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood. We aimed here at establishing the influence of persistent viral infections on the naive T-cell compartment and primary immune responsiveness in older adults. METHODS: We assessed immunological parameters, related to CD8+ and CD4+ T-cell responsiveness, according to the serological status for common latent herpesviruses in two independent cohorts: 1) healthy individuals aged 19y to 95y (n = 150) and 2) individuals above 70y old enrolled in a primo-vaccination clinical trial (n = 137). FINDINGS: We demonstrate a prevalent effect of age and CMV infection on CD8+ and CD4+ naive T cells, respectively. CMV seropositivity was associated with blunted CD4+ T-cell and antibody responses to primary vaccination. INTERPRETATION: These data provide insights on the changes in adaptive immunity over time and the associated decline in vaccine efficacy with ageing. This knowledge is important for the management of emerging infectious diseases in elderly populations. FUNDING: This work was supported by the ANR (Project ANR-14-CE14-0030-01) and by Universita ItaloFrancese/Univeriste FrancoItalienne (Galileo Project G10-718; PHC Galilee Project 39582TJ), by the Swiss National Science Foundation (grant PP0033-110737 to UK), by the Heuberg Foundation (Zurich, Switzerland), by the AETAS Foundation (Geneva, Switzerland) and by a Senior IdEx Chair of the University of Bordeaux (France). EC, VB, CA, MA, DD and AT were supported by the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence "Milieu Interieur" Grant ANR-10-LABX-69-01. EC and AT are supported by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02).

Pre-existing yellow fever immunity impairs and modulates the antibody response to tick-borne encephalitis vaccination.

Flaviviruses have an increasing global impact as arthropod-transmitted human pathogens, exemplified by Zika, dengue, yellow fever (YF), West Nile, Japanese encephalitis, and tick-borne encephalitis (TBE) viruses. Since all flaviviruses are antigenically related, they are prone to phenomena of immunological memory ('original antigenic sin'), which can modulate immune responses in the course of sequential infections and/or vaccinations. In our study, we analyzed the influence of pre-existing YF vaccine-derived immunity on the antibody response to TBE vaccination. By comparing samples from YF pre-vaccinated and flavivirus-naive individuals, we show that YF immunity not only caused a significant impairment of the neutralizing antibody response to TBE vaccination but also a reduction of the specific TBE virus neutralizing activities (NT/ELISA-titer ratios). Our results point to a possible negative effect of pre-existing cross-reactive immunity on the outcome of flavivirus vaccination that may also pertain to other combinations of sequential flavivirus infections and/or vaccinations.

Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients.

BACKGROUND: Tight junctions (TJs) form a barrier on the apical side of neighboring epithelial cells in the bronchial mucosa. Changes in their integrity might play a role in asthma pathogenesis by enabling the paracellular influx of allergens, toxins, and microbes to the submucosal tissue. OBJECTIVE: The regulation of bronchial epithelial TJs by TH2 cells and their cytokines and their involvement in epigenetic regulation of barrier function were investigated. METHODS: The expression, regulation, and function of TJs were determined in air-liquid interface (ALI) cultures of control and asthmatic primary human bronchial epithelial cells (HBECs) by means of analysis of transepithelial electrical resistance, paracellular flux, mRNA expression, Western blotting, and immunofluorescence staining. RESULTS: HBECs from asthmatic patients showed a significantly low TJ integrity in ALI cultures compared with HBECs from healthy subjects. TH2 cell numbers and levels of their cytokines, IL-4 and IL-13, decreased barrier integrity in ALI cultures of HBECs from control subjects but not in HBECs from asthmatic patients. They induced a physical separation of the TJs of adjacent cells in immunofluorescence staining of the TJ molecules occludin and zonula occludens-1. We observed that expression of histone deacetylases (HDACs) 1 and 9, and Silent information regulator genes (sirtuins [SIRTs]) 6 and 7 were significantly high in HBECs from asthmatic patients. IL-4 and IL-13 significantly increased the expression of HDACs and SIRTs. The role of HDAC activation on epithelial barrier leakiness was confirmed by HDAC inhibition, which improved barrier integrity through increased synthesis of TJ molecules in epithelium from asthmatic patients to the level seen in HBECs from control subjects. CONCLUSION: Our data demonstrate that barrier leakiness in asthmatic patients is induced by TH2 cells, IL-4, and IL-13 and HDAC activity. The inhibition of endogenous HDAC activity reconstitutes defective barrier by increasing TJ expression.

Interleukins (from IL-1 to IL-38), interferons, transforming growth factor ß, and TNF-α: Receptors, functions, and roles in diseases.

There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-ß offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-ß, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.

Reduced naïve CD8(+) T-cell priming efficacy in elderly adults.

Aging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8(+) T-cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling naïve CD8(+) T-cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8(+) T-cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8(+) T-cell responses specific for a model antigen. Reduced CD8(+) T-cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the naïve CD8(+) T-cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging.

Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease with still unclear pathophysiologic mechanisms. Epithelial tight junctions (TJs) have been shown to be involved in different chronic disorders, including bronchial asthma, inflammatory bowel diseases, and skin disorders. The regulation of epithelial barrier function and TJ expression has not been extensively studied in patients with CRS and in the paranasal sinus epithelium thus far. OBJECTIVE: We sought to elucidate the TJ expression pattern in the epithelium of the sinonasal mucosa and its regulation in patients with CRS. METHODS: Trans-tissue resistance was measured in biopsy specimens from healthy control subjects and patients with CRS with and without nasal polyps. TJ protein expression was determined by using immunofluorescence, Western blotting, and real-time PCR. Primary epithelial cell cultures from patients with CRS and control subjects were used in air-liquid interface (ALI) cultures for the measurement of transepithelial resistance (TER) and TJ expression. The effect of IFN-γ, IL-4, and IL-17 on ALI cultures was assessed. RESULTS: A decreased trans-tissue resistance was found in biopsy specimens from patients with CRS with nasal polyps along with an irregular, patchy, and decreased expression of the TJ molecules occludin and zonula occludens 1. TER was reduced in ALI cultures from patients with CRS with nasal polyps. The cytokines IFN-γ and IL-4 decreased TER, whereas IL-17 did not have any influence on epithelial integrity. CONCLUSION: A defective epithelial barrier was found in patients with CRS with nasal polyps along with a decreased expression of TJ proteins. The disruption of epithelial integrity by IFN-γ and IL-4 in vitro indicates a possible role for these proinflammatory cytokines in the pathogenesis of patients with CRS.

Inhibition of angiogenesis by IL-32: possible role in asthma.

BACKGROUND: IL-32 is a proinflammatory cytokine involved in various chronic inflammatory diseases. Chronic airway inflammation in asthmatic patients results in structural airway changes, including angiogenesis. Vascular endothelial growth factor (VEGF) is a key inducer of angiogenesis in the airways of asthmatic patients. OBJECTIVE: The aim of the study was to investigate the expression and function of IL-32 in patients with angiogenesis and asthma. METHODS: The expression and regulation of IL-32 in normal human bronchial epithelial (NHBE) cells was analyzed by using RT-PCR, ELISA, Western blotting, immunofluorescent staining, and flow cytometry. After knockdown of IL-32 in NHBE cells by small interfering RNA (siRNA) transfections, VEGF secretion was quantified by means of ELISA. New blood vessel formation was determined with human umbilical vein endothelial cells by culturing with supernatants from IL-32 siRNA-transfected NHBE cells. IL-32 was determined in serum and induced sputum samples of asthmatic patients and healthy control subjects by means of ELISA. RESULTS: IL-32 is expressed in NHBE cells on stimulation with IFN-γ, TNF-α, T(H)1 cells, and rhinovirus. Inhibition of IL-32 expression resulted in significantly increased secretion of the proangiogenic factors VEGF and platelet-derived growth factor by NHBE cells. Human umbilical vein endothelial cells cultured in supernatants from IL-32 siRNA-transfected NHBE cells showed enhanced in vitro angiogenesis. IL-32 is detectable in induced sputum from asthmatic patients. IL-32 serum levels were significantly higher in asthmatic patients compared with those seen in healthy control subjects and correlated with response to asthma treatment. CONCLUSION: IL-32 is induced by IFN-γ, TNF-α, T(H)1 cells, and rhinovirus in bronchial epithelial cells. It inhibits angiogenesis, and its serum levels are associated with a good treatment response in asthmatic patients.

Cytomegalovirus and immune senescence: culprit or innocent bystander?

Immune senescence may be defined as the age-related reduction and dysregulation of immune function, and has been associated with increased incidence and severity of infectious diseases and with poor efficacy of prophylactic vaccines in the elderly. Several studies have demonstrated that persistent infections with Herpes viruses in general and Cytomegalovirus (CMV) in particular have a profound influence on subset distribution, phenotype and potentially also on the function of T cells in ageing individuals. The association of CMV-seropositivity and accumulation of CMV-specific CD8+ T cells with decreased survival in longitudinal studies of very elderly has fostered the hypothesis that CMV-infection may be an important causative factor for the development of immune senescence. Here, we have critically summarized the current body of evidence supporting this hypothesis, highlight some controversial issues about its relevance and mechanisms and propose areas of future research to demonstrate unequivocally whether and how persistent infections might compromise the ageing immune system.