Dimitra E. Zazara

A strong sex-bias characterizes many respiratory immune diseases and has been attributed to sexually dimorphic immune responses. However, the role of lung-resident immunity in this context remains elusive. Here, we thoroughly characterized the lung-resident immune landscape in male and female mice, with a special focus on sex hormone effects in this context. Androgens were found to exert the strongest effects, markedly impacting B cells and neutrophils in both male and female lungs. Castrated males exhibited increased, while testosterone-treated females and males decreased lung-residing B cells. Testosterone supplementation of castrated males and females resulted in increased lung-residing neutrophils. Sex-mismatched orthotopic lung transplantation further supported these findings, since lungs isolated from female donors exhibited reduced tissue-residing B cells after their transplantation into male recipients. For the remaining lung-resident immune cell populations, sex differences were observed at the level of cell frequencies, with male lungs exhibiting higher frequencies of alveolar macrophages and lower frequencies of lung-resident dendritic cells and CD4⁺ tissue-resident memory T cells. Castration reversed some of these findings. Our findings highlight that the sexual dimorphism of the lung-resident immune landscape is modulated by sex hormones and especially androgens, thereby providing insights into the sex-specific manifestation of respiratory immune diseases.

In solid organ transplantation, chimerism inevitably occurs via the coexistence of donor-derived cells from the graft and host cells throughout the recipient. However, long-term immunosuppressive treatment is needed to suppress host immune responses to the foreign organ graft. The deliberate induction of stable mixed bone marrow chimerism to achieve donor-specific immunological tolerance in solid organ graft recipients is an ambitious goal that may significantly contribute to the long-term survival of solid organ grafts and their recipients. While this strategy has been effectively established in laboratory animals and some promising clinical case series have been reported, widespread clinical application is still limited by the toxicity of the necessary conditioning regimens. On the other hand, the naturally occurring chimeric state resulting from the bidirectional transplacental cell trafficking during pregnancy, the so-called feto-maternal microchimerism, can also induce immune tolerance and thus influence the outcome of mother-to-child or child-to-mother organ transplantation. This review provides an overview of the field's historical development, clinical results, and underlying principles of (micro) chimerism-based tolerance.

Background: Respiratory diseases, such as infections and asthma, are major health burdens in childhood (Eder W et al. N Engl J Med 2006;355:2226-35). Markers predicting an increased risk for childhood respiratory diseases, e.g. during fetal life, are sparse. Aim: We aimed to examine if ultrasound-monitored fetal lung growth trajectories can predict the risk for respiratory infections and asthma early in life. Methods: Fetal lung size was serially assessed at standardized timepoints by ultrasound in pregnant women within the pregnancy cohort PRINCE (PRenatal determINants of Children’s hEalth). The number of respiratory infections in infancy was reported. Early-onset asthma risk was determined based on standardized universally used criteria (Asher MI et al. Eur Respir J 1995;8:483-91). Correlations among fetal lung growth, early-life respiratory infections and asthma were examined. Finally, machine-learning models were developed to predict the risk for early-life respiratory infections or early-onset asthma based on fetal lung growth. Results: Enhanced fetal lung growth throughout pregnancy predicted a lower risk for early-life respiratory infections. Male sex was associated with a higher risk for respiratory infections in infancy. Based on these findings, we developed novel accurate machine-learning models to predict the risk for early-life respiratory infections and early-onset asthma manifestation. Model variants included known influential factors and novel predictors, such as the ultrasound-monitored fetal lung growth. Conclusions: A non-invasive serial assessment of fetal lung growth can predict respiratory health risks, such as early-life respiratory infections and childhood asthma.

Background: Respiratory diseases, such as infections and asthma, are major health burdens in childhood (Eder W et al. N Engl J Med 2006;355:2226-35). Markers predicting an increased risk for childhood respiratory diseases, e.g. during fetal life, are sparse. Aim: We aimed to examine if ultrasound-monitored fetal lung growth trajectories can predict the risk for respiratory infections and asthma early in life. Methods: Fetal lung size was serially assessed at standardized timepoints by ultrasound in pregnant women within the pregnancy cohort PRINCE (PRenatal determINants of Children’s hEalth). The number of respiratory infections in infancy was reported. Early-onset asthma risk was determined based on standardized universally used criteria (Asher MI et al. Eur Respir J 1995;8:483-91). Correlations among fetal lung growth, early-life respiratory infections and asthma were examined. Finally, machine-learning models were developed to predict the risk for early-life respiratory infections or early-onset asthma based on fetal lung growth. Results: Enhanced fetal lung growth throughout pregnancy predicted a lower risk for early-life respiratory infections. Male sex was associated with a higher risk for respiratory infections in infancy. Based on these findings, we developed novel accurate machine-learning models to predict the risk for early-life respiratory infections and early-onset asthma manifestation. Model variants included known influential factors and novel predictors, such as the ultrasound-monitored fetal lung growth. Conclusions: A non-invasive serial assessment of fetal lung growth can predict respiratory health risks, such as early-life respiratory infections and childhood asthma.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4⁺ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1^flox/flox × Alb^Cre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC.

The lung is a vital organ that incessantly faces external environmental challenges. Its homeostasis and unimpeded vital function are ensured by the respiratory epithelium working hand in hand with an intricate fine-tuned tissue-resident immune cell network. Lung tissue-resident immune cells span across the innate and adaptive immunity and protect from infectious agents but can also prove to be pathogenic if dysregulated. Here, we review the innate and adaptive immune cell subtypes comprising lung-resident immunity and discuss their ontogeny and role in distinct respiratory diseases. An improved understanding of the role of lung-resident immunity and how its function is dysregulated under pathological conditions can shed light on the pathogenesis of respiratory diseases.