Immunological Reviews最新文献

Inflammation is increasingly recognized as a central driver of heart failure (HF), particularly in older adults, yet the underlying immune mechanisms remain diverse and incompletely understood. Clonal hematopoiesis (CH), defined by the expansion of somatically mutated hematopoietic clones, has emerged as a risk factor for the development of numerous age-related diseases including HF. Experimental and clinical evidence suggests that mutant clones carrying driver gene mutations promote a pro-inflammatory immune cell phenotype that contributes to cardiac injury, remodeling and adverse outcomes. Notably, CH has been implicated in HF across diverse etiologies, including both HFrEF and HFpEF, highlighting its broad impact on a vast array of HF syndromes. More recently, it has been discovered that hematopoietic loss of the Y chromosome (LOY) also contributes to HF. LOY appears to shift macrophages toward a fibrotic and away from a pro-inflammatory phenotype, contrasting with that observed for driver gene mutations and suggesting that different somatic alterations contribute to HF via divergent mechanisms. In this review, we examine the clinical and experimental associations between CH and HF. We also explore how CH may drive age-related immune heterogeneity in HF and highlight its potential to be leveraged for personalized interventions in patients with HF.

There is a sex difference in asthma prevalence and asthma-related morbidity that changes from childhood into different reproductive stages of life. The impact of sex hormone signaling on asthma pathogenesis has been partially elucidated using large cohort human studies, human cells, and animal models. Androgens decreased airway inflammation by reducing type 2 inflammation and eosinophil infiltration as well as reducing neutrophil-induced airway inflammation in animal models. Estrogen signaling through ER-α increased IL-33 production, an alarmin produced by airway epithelial cells that increases type 2 inflammation and increased Th17 cell-mediated neutrophilic inflammation. Additional studies are needed to determine what happens to asthma control and asthma-induced inflammation in women during pregnancy and menopause as well as how sex differences in immune cell development and airway inflammation affect asthma incidence and onset during childhood. Collectively, understanding that sex differences in asthma risk and control exist throughout life is important to personalize therapies for males and females with asthma.

Systemic inflammation is a key driver of atherogenesis and its complications. While anti-inflammatory therapies targeting pathways such as IL-1β and IL-6 have shown promise in established atherosclerotic cardiovascular disease (ASCVD), potential systemic effects raise concerns about immune suppression and infection, underscoring the need for more precise immunomodulatory approaches. Trained immunity—a form of innate immune memory—has emerged as a potential contributor linking ASCVD risk factors to chronic inflammation and disease progression. In this review, we discuss the evidence for trained immunity in ASCVD, its induction by several known risk factors (e.g., hyperglycaemia, hypercholesterolemia, diet, chronic stress, inflammatory diseases, and infection), and its potential role in sustaining vascular inflammation. Advancing our understanding of the metabolic and epigenetic mechanisms underlying trained immunity, as well as defining shared and cumulative effects across risk factors, will be critical to guide the development of next-generation targeted therapies for ASCVD prevention and treatment.

Central tolerance, established in the thymus, ensures T cells are nonreactive to self-antigens while maintaining a functional immune repertoire. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) play a crucial role in this mechanism by orchestrating the selection and deletion of autoreactive thymocytes, a process heavily influenced by the Autoimmune Regulator (AIRE). AIRE promotes the promiscuous expression of tissue-restricted antigens (TRAs) in mTECs, enabling the elimination of self-reactive T cells and the differentiation of regulatory T cells (Tregs). Studies on the role of AIRE in transcriptional regulation and nuclear body localization have significantly advanced our understanding of its mechanisms, revealing protein interactions with chromatin-associated complexes that facilitate broad transcriptomic complexity in mTECs. However, the discovery of neutralizing type 1 interferon (T1 IFN) autoantibodies in APECED patients, alongside recently identified AIRE-induced IFN signals in the thymus, suggests that AIRE's influence extends beyond its classical function in negative selection, potentially playing a broader role in thymic homeostasis via inflammatory signals. This review discusses recent advances in understanding AIRE's complexity, its role in transcriptional regulation and nuclear location, insights from studies in human APECED patients and rodent models, and the emerging concept of an IFN-mediated tonic inflammatory signal in the thymus.

The intestinal immune system is constantly challenged to distinguish between innocuous dietary antigens, commensal microbiota and intestinal self-antigens (self-Ags) versus harmful pathogens and malignant cells. It resides in the intestinal wall itself, Peyer's patches (PPs) and the draining lymph nodes (LNs). Dendritic cells (DCs) are found in all of these structures and are professional antigen-presenting cells (APCs) dictating and maintaining T cell fate. Here, we review how DCs contribute to immune homeostasis in the gastrointestinal system through multiple strategies: division in labor and strategic anatomical positioning between DC subtypes, plasticity and site-specific functional adaptation. While these properties of DCs are likely not unique to the gastrointestinal tract, it is the site where we have learned most about how this DC network operates.