Abstract Long-lived plasma cells have traditionally been viewed through the lens of bone marrow-resident IgG-secreting cells that maintain systemic serological memory. However, recent timestamping approaches and isotype-specific analyses have revealed diverse trajectories toward plasma-cell longevity. Plasma-cell longevity is not specified at a single developmental checkpoint, but emerges through a multistep process involving the timing and site of plasma-cell generation, migratory competence, entry into and adaptation to tissue niches, and progressive maturation. Moreover, emerging studies of non-IgG plasma cells indicate that distinct antibody isotypes use different anatomical and molecular strategies to sustain antibody production. In particular, the recent identification of IgE long-lived plasma cells in secondary lymphoid tissues suggests that the bone marrow is not the only anatomical site capable of supporting durable plasma-cell survival. Together, these findings argue against a single, universal model of plasma-cell longevity and instead support a framework in which antibody persistence is achieved through isotype-specific and tissue-specific logic.
Recent pandemics, the increasing incidence of cancer and an inversion of the age pyramid towards an older society fuels the need for an in depth understanding of the field of inflammaging and changes in the immune system, in particular of the T cell compartment, which is the most impacted during ageing. Starting from quantitative and qualitative changes that occur in T cells during ageing, this review discusses pathophysiological factors that lead to or accelerate these processes. Furthermore, it highlights emerging strategies aimed at overcoming age-related T-cell dysfunction, with a focus on recent advances in the field. Together, these insights may contribute to a better understanding of how healthy ageing can be promoted through the preservation or rejuvenation of T-cell "youthfulness", which is central for healthy ageing.
Primary sclerosing cholangitis (PSC) is a chronic autoimmune cholestatic liver disease characterized by progressive inflammation and fibrosis, but the role of neutrophils in PSC remains poorly understood. To define neutrophil states in the PSC liver microenvironment, we performed single-cell RNA sequencing of leukocytes isolated from liver perfusate obtained from healthy donor grafts and explanted PSC livers. We identified a marked expansion of transcriptionally diverse neutrophil subclusters in PSC liver perfusate. Importantly, PSC livers were enriched for four neutrophil subclusters: RHOB-high, immediate early gene-high, heat shock protein-high, and CXCL8-high liver neutrophil-like subclusters. These PSC-associated neutrophil subclusters showed increased activity of the TNF and IL-17 signaling pathways, consistent with current views of PSC pathogenesis. They also displayed activation of inflammatory transcriptional regulators, including CEBPB, JUN, FOS, and RELA. Pseudotime analysis suggested that RHOB and immediate early gene subsets were derived from immature neutrophils, whereas liver neutrophil-like and heat shock protein-high subsets exhibited more mature and tissue-adapted features. Together, these data reveal previously unrecognized heterogeneity of liver neutrophils in PSC and identify inflammatory neutrophil programs that may contribute to sustained hepatic inflammation and represent potential therapeutic targets.
Vaccine reactogenicity refers to the capacity of a vaccine to induce transient local and systemic adverse reactions (ARs). Although these ARs are often attributed to vaccine-induced innate inflammation, accumulating evidence indicates that the inflammatory pathways causing symptoms are not necessarily identical to those required for protective immunity. mRNA-lipid nanoparticle (LNP) vaccines provide a valuable framework for examining this relationship, because both the mRNA cargo and the LNP delivery system can contribute to innate immune activation. Early inflammatory responses following mRNA-LNP vaccination appear to reflect the interplay of multiple signals, including ionizable lipid-driven signaling, mRNA-associated interferon (IFN) responses, endosomal membrane perturbation, and tissue-derived danger signals. These upstream events can be amplified through cytokine networks that promote systemic symptoms. Interleukin-1 (IL-1) has emerged as a major contributor to this process, although IL-6, tumor necrosis factor-alpha (TNF-α), type I IFN, and prostaglandin-related pathways also contribute, depending on the experimental model and context. In this review, we summarize recent evidence linking upstream sensing pathways to local and systemic ARs, and discuss how these pathways intersect with vaccine-induced adaptive immunity. We also consider booster-associated amplification of ARs as an example in which immune memory may reshape innate cytokine responses after repeated vaccination. Understanding these relationships will help delineate the shared and distinct inflammatory circuits underlying ARs and protective immunity. These mechanistic insights may also inform the rational design of low-reactogenic mRNA-LNP formulations that retain sufficient immunogenicity.
Humans possess various blood cell types, such as T cells, B cells, monocytes/macrophages, neutrophils, dendritic cells, erythrocytes, and platelets/thrombocytes, and these lineages are shared by nearly all vertebrates. Although invertebrates such as tunicates, sea urchins, flies, and sponges possess different blood cell lineages, some homology exists between vertebrate and invertebrate blood cells. Comparing cell lineages between different species can help estimate the evolution of blood cell lineages and immune systems across more than 600 million years of animal history. Studies on blood cells in vertebrate and invertebrate species have put some mile stones in the roads of blood cell evolution, but a comprehensive map has not been drawn. Recent advances in sequencing and bioinformatic technologies and the accumulation of genomic information for various animal species enabled us to develop an analytical method to compare cell lineages between far different species. Our recent work suggested one probable evolutionary history of blood cell lineages, in which T cells, NK cells, ILC, mast cells, erythrocytes, and thrombocytes evolved from prototypic mast cells. In addition, a vestige of this history was detected in our body as a linage restriction process in blood cell differentiation. Thus, studying evolution can help clarify current biological systems, and vice versa.
