HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease.

Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on HIF-1, a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our present studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrated a strong cytotoxic signature at the transcript and protein levels, and HIF-1 inhibition abrogated skin and systemic diseases in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell-rich inflammatory infiltrate exhibited increased amounts of HIF-1 and a cytotoxic signature. Granzyme B-expressing T cells were concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections.

BACKGROUND: Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections. METHODS: We used data on insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital records in the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 392,000). We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and performed Mendelian randomization analyses to assess causality. FINDINGS: Utilizing 23 years of registry data and follow-up, we discovered that insomnia diagnosis associated with increased risk for infections (FinnGen influenza Cox's proportional hazard (CPH) HR = 4.34 [3.90, 4.83], P = 4.16 × 10-159, UK Biobank influenza CPH HR = 1.54 [1.37, 1.73], P = 2.49 × 10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (inverse-variance weighted (IVW) OR = 1.65, P = 5.86 × 10-7), URI (IVW OR = 1.94, P = 8.14 × 10-31), COVID-19 infection (IVW OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (IVW OR = 1.47, P = 4.96 × 10-5). INTERPRETATION: Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens. FUNDING: Instrumentarium Science Foundation, Academy of Finland, Signe and Ane Gyllenberg Foundation, National Institutes of Health.

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections.

Background: Poor sleep is associated with an increased risk of infections and all-cause mortality, and acute sleep loss and disruption have been linked with inflammation and poorer immune control. Previous studies, however, have been unable to evidence causality between the chronic effects of poor sleep and respiratory infection risk. In light of the ongoing COVID-19 pandemic and potential future disease outbreaks, understanding the risk factors for these infections is of great importance. Aim: Our goal was to understand if chronic poor sleep could be identified as a causal risk factor for respiratory infections including influenza, upper respiratory infections and COVID-19. Methods: We used population cohorts from the UK Biobank (N ≈ 231,000) and FinnGen (N ≈ 327,000) with ICD-10 based electronic health records and obtained diagnoses of insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital settings. We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and used summary statistics from genome-wide association studies of insomnia, influenza, URI and COVID-19 to perform Mendelian randomization analyses and assess causality. Findings: Utilizing 23 years of registry data and follow-up, we saw that insomnia diagnosis associated with increased risk for infections in FinnGen and in UK Biobank (FinnGen influenza HR = 5.32 [4.09, 6.92], P = 1.02×10-35, UK Biobank influenza HR = 1.54 [1.37, 1.73], P = 2.49×10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (OR = 1.59, P = 6.23×10-4), upper respiratory infections (OR = 1.71, P = 7.60×10-13), COVID-19 infection (OR = 1.08, P = 0.037) and risk of hospitalization from COVID-19 (OR = 1.47, P = 4.96×10-5). Conclusions: Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens as suggested by earlier work. As the current COVID-19 pandemic has increased the number of people suffering from poor sleep, safe interventions such as sleep management and treating individuals with insomnia could be promoted to reduce infections and save lives.