ABSTRACTAtherosclerotic cardiovascular disease (ASCVD) is increasingly recognized not just as a lipid‐driven disease, but as a complex interplay between vascular cells and the immune system. Accumulating evidence highlights a central, yet heterogeneous role for B cells in atherogenesis, with distinct subsets displaying opposing roles. In this review, we provide an in‐depth overview of the contributions of B cell subsets to ASCVD, including emerging insights into the roles and pathways of atheroprotective innate B cells producing IgM against oxidation‐specific epitopes (IgMOSE) and newly appreciated age‐associated B cells (ABCs), a distinct subset that accumulates with aging and potentially exacerbates atherosclerosis. By integrating insights from preclinical models and human studies, we describe the mechanisms through which B cell subsets influence ASCVD, including antigen presentation and immune checkpoint‐mediated communication, secretion of cytokines and chemokines, and we highlight that humoral immunity in atherosclerosis reflects a context‐dependent interplay between antibody effector properties and antigenic targets rather than antibody class alone. Finally, we explore how the advances in our understanding of B cells may guide the development of more targeted immunomodulatory therapies that enhance atheroprotective B cell functions while limiting atherogenic responses.

ABSTRACTBiological sex has a significant impact on how the immune system develops and responds to foreign and self‐antigens. Sex differences exist in innate and adaptive immune cells, both at homeostasis and in the context of infection and inflammatory diseases such as asthma, cancer, and autoimmune disorders. Women generate stronger immune responses and are more susceptible to developing autoimmune conditions, while males are more prone to acute viral infections and developing certain cancers. Some immunological differences persist throughout life, while others emerge only after puberty and before reproductive senescence. Additionally, environmental exposures can affect the influence of biological sex in regulating immune function. This is particularly pertinent at mucosal surfaces such as the lungs, where lung immune defenses are constantly exposed to foreign material during respiration. Consequently, environmental factors together with genetics, age and sex hormones play a vital role in governing lung tissue immune responses between the sexes. In this context, we highlight studies that support the need for considering sex as an important biological variable in lung immunological research. This knowledge will provide a benchmark for understanding sex‐driven immunological mechanisms that underpin disease development and may inform new avenues targeted for generating sex‐specific therapies in lung disease.

ABSTRACTSystemic 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.

Dendritic cells (DCs) demonstrate remarkable functional and metabolic heterogeneity that governs the balance between immune tolerance and autoimmune pathogenesis. Under homeostatic conditions, tolerogenic DC subsets maintain immunological equilibrium through distinct metabolic programs and the production of immunoregulatory metabolites, promoting T cell anergy and regulatory T cell (Treg) differentiation. In contrast, autoimmune conditions trigger pathogenic metabolic rewiring, shifting DCs toward glycolysis and enhanced lipid synthesis, which drives DC hyperactivation and breakdown of self-tolerance. This metabolic reprogramming is coordinately regulated by external microenvironmental cues and internal signaling pathways, leading to heterogeneous DC responses in diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis. Targeting metabolic regulators offers promising therapeutic strategies to restore immune tolerance and prevent harmful autoimmunity and inflammation. The review highlights the intricate interplay between DC metabolism and function, emphasizing how metabolic heterogeneity underpins their dual roles in immune regulation and autoimmunity. Future exploration of subset-specific metabolic preferences and spatiotemporal metabolic dynamics will facilitate the development of precision immunotherapies for autoimmune diseases.

ABSTRACTDendritic cells comprise several populations with distinct ontogeny that share core features including a typical dendritic morphology and the ability to present antigens and stimulate T cells. Dendritic cells originating from monocytes have been reported in steady‐state and in different inflammatory contexts, in mouse models and in human clinical samples. However, because of their phenotypical and transcriptional proximity with other dendritic cell subsets and with monocyte‐derived macrophages, whether monocyte‐derived dendritic cells (mo‐DCs) represent a distinct population has been controversial. Here, we summarize the evidence supporting the existence of mo‐DCs in vivo and we review work addressing the molecular regulation of mo‐DCs differentiation and their role in immune responses. We also discuss the potential for harnessing mo‐DCs differentiation for therapy.

ABSTRACTType‐2 inflammation is driven by the production of canonical type‐2 cytokines IL‐4, IL‐5, and IL‐13. Type‐2 cytokines promote mucus production, innate immune cell recruitment, and smooth muscle contractility in mucosal tissues. These hallmarks of type‐2 inflammation are important contributors to the weep‐and‐sweep responses observed in the lung and intestine after epithelial insults. While these type‐2 cytokines are generated by a number of innate and adaptive immune cells, group 2 innate lymphoid cells (ILC2) are key early producers of these cytokines and are critical in shaping immune responses in the lung. This review summarizes the role of ILC2 in the lung with specific emphasis on their origins as part of the gut‐lung axis, their heterogeneity with respect to unique identities of circulating and tissue resident ILC2 populations, and how these relatively rare immune cells can significantly impact the course of pulmonary disease. We also explore factors that influence ILC2 behavior with respect to activation, migration, and communication with their environment.

ABSTRACTAsthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy‐resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4+ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)‐4, IL‐5, IL‐9, and IL‐13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8+ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy‐resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids—the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid‐resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non‐type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non‐type 2 lymphocytes, placing special emphasis on severe disease forms.