Seminars in Immunopathology最新文献

The transfer of a small number of cells between parent and offspring during pregnancy, commonly referred to as microchimerism, is thought to occur in all human pregnancies. The impact of microchimeric cells on health outcomes in mothers and offspring with respect to cancer, remains unknown. Molecular and epidemiological studies yield conflicting results on the link between microchimerism and cancer, underscoring the complexity of this phenomenon. Further, most studies on microchimerism and cancer focus on the relationship between circulating fetal cells in parous women. Given that the cellular exchange between the mother and offspring is thought to have arisen due to the evolution of internal gestation, we provide an evolutionary perspective on how internal gestation may impact the risk of cancer in humans. We highlight the potential mechanisms that may play a role in cancer vulnerability in mammals, such as genomic conflict and placental invasion. We then review the literature to investigate the effects of microchimerism on cancer outcomes in parous women, highlighting each study's interpretation of the role microchimeric cells play in cancer development, whether it is a protective or contributing role. We conclude that our current understanding of the relationship between microchimerism and cancer is poorly understood and propose mechanisms for when we would expect to see microchimerism contribute to a role in protecting the host from cancer and when microchimerism may contribute to tumor development. Future studies, including more advanced methods to detect and identify microchimerism, will be important for elucidating the link between microchimerism and cancer initiation and progression.

Tumors constantly shed cancer cells that are considered the mediators of metastasis via the blood stream. Analysis of circulating cells and circulating cell-free DNA (cfDNA) in liquid biopsies, mostly taken from peripheral blood, have emerged as powerful biomarkers in oncology, as they enable the detection of genomic aberrations. Similarly, liquid biopsies taken from pregnant women serve as prenatal screening test for an abnormal number of chromosomes in the fetus, e.g., via the analysis of microchimeric fetal cells and cfDNA circulating in maternal blood. Liquid biopsies are minimally invasive and, consequently, associated with reduced risks for the patients. However, different challenges arise in oncology and pregnancy-acquired liquid biopsies with regard to the analyte concentration and biological (background) noise among other factors. In this review, we highlight the unique biological properties of circulating tumor cells (CTC), summarize the various techniques that have been developed for the enrichment, detection and analysis of CTCs as well as for analysis of genetic and epigenetic aberrations in cfDNA and highlight the range of possible clinical applications. Lastly, the potential, but also the challenges of liquid biopsies in oncology as well as their translational value for the analysis of pregnancy-acquired microchimerism are discussed.

The development of the fetal immune response is a highly complex process. In the present review, we describe the development of the fetal immune response and the role of the maternal gut bacteria in this process. In contrast to the previous belief that the fetal immune response is inert, it is now thought that the fetal immune response is uniquely tolerant to maternal and allo-antigens, but able to respond to infectious agents, such as bacteria. This is accomplished by the development of T cells toward regulatory T cells rather than toward effector T cells, but also by the presence of functional innate immune cells, such as monocytes and NK cells. Moreover, in fetuses there is different programming of CD8 + T cells and memory T cells toward innate immune cells rather than to adaptive immune cells. The maternal gut bacteria are important in shaping the fetal immune response by producing bacterial products and metabolites that pass the placenta into the fetus and influence development of the fetal immune response. Insight into how and when these products affect the fetal immune response may open new treatment options with pre- or probiotics to affect the maternal gut bacteria and therewith the fetal immune response.

The brain-gut axis constitutes the basis for the bidirectional communication between the central nervous system and the gastrointestinal tract driven by neural, hormonal, metabolic, immunological, and microbial signals. Alterations in the gut microbiome composition as observed in inflammatory bowel diseases can modulate brain function and emerging empirical evidence has indicated that interactions among the brain-gut microbiome-axis seem to play a significant role in the pathogenesis of both inflammatory bowel diseases and psychiatric disorders and their comorbidity. Yet, the immunological and molecular mechanisms underlying the co-occurrence of inflammatory bowel diseases and psychological symptoms are still poorly understood. The aim of this narrative review is to highlight contemporary empirical findings supporting a pivotal role of the gut microbiome in the pathophysiology of highly prevalent neuropsychiatric symptoms in inflammatory bowel diseases such as fatigue, depression, and anxiety. Finally, we focus on microbiome modulation as potential treatment option for comorbid neuropsychiatric symptoms in immune-mediated diseases and especially in inflammatory bowel diseases. High-quality clinical trials are required to clarify how microbiome modulation through dietary interventions or probiotic, prebiotic or synbiotic treatment can be used clinically to improve mental health and thus quality of life of patients with inflammatory bowel diseases.

Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.

Overweight and obesity (OWO) are linked to dyslipidemia and low-grade chronic inflammation, which is fueled by lipotoxicity and oxidative stress. In the context of pregnancy, maternal OWO has long been known to negatively impact on pregnancy outcomes and maternal health, as well as to imprint a higher risk for diseases in offspring later in life. Emerging research suggests that individual lipid metabolites, which collectively form the lipidome, may play a causal role in the pathogenesis of OWO-related diseases. This can be applied to the onset of pregnancy complications such as gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP), which in fact occur more frequently in women affected by OWO. In this review, we summarize current knowledge on maternal lipid metabolites in pregnancy and highlight associations between the maternal lipidome and the risk to develop GDM, HDP and childhood OWO. Emerging data underpin that dysregulations in maternal triglyceride, phospholipid and polyunsaturated fatty acid (PUFA) metabolism may play a role in modulating the risk for adverse pregnancy outcomes and childhood OWO, but it is yet premature to convert currently available insights into clinical guidelines. Well-designed large-scale lipidomic studies, combined with translational approaches including animal models of obesity, will likely facilitate the recognition of underling pathways of OWO-related pregnancy complications and child's health outcomes, based on which clinical guidelines and recommendations can be updated.

The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria.

Microchimerism is defined as the presence of a small population of genetically distinct cells within a host that is derived from another individual. Throughout pregnancy, maternal and fetal cells are known to traffic across the feto-maternal interface and result in maternal and fetal microchimerism, respectively. However, the routes of cell transfer, the molecular signaling as well as the timing in which trafficking takes place are still not completely understood. Recently, the presence of inflammation at the feto-maternal interface has been linked with maternal microchimeric cells modulating organ development in the fetus. Here, we review the current literature and suggest that inflammatory processes at the feto-maternal interface tissues are a physiological prerequisite for the establishment of microchimerism. We further propose a spatio-temporal corridor of microchimeric cell migration to potentially explain some biological effects of microchimerism. Additionally, we elaborate on the possible consequences of a shift in this spatio-temporal corridor, potentially responsible for the development of pathologies in the neonate.

The management of autoimmune diseases is currently limited by therapies that largely suppress the immune system, often resulting in partial and temporary remissions. Cellular immunotherapies offer a targeted approach by redirecting immune cells to correct the underlying autoimmunity. This review explores the latest advances in cellular immunotherapies for autoimmune diseases, focusing on various strategies, such as the use of chimeric antigen receptor (CAR) T cells, chimeric auto-antibody receptor (CAAR) T cells, regulatory T cells (Tregs), and tolerogenic dendritic cells (TolDCs). We review recent preclinical studies and results from clinical trials that demonstrate the potential for these therapies to either deplete autoreactive cells or promote immune tolerance through broad or selective targeting of immune cell populations. Key challenges such as ensuring specificity, preventing off-target effects, and improving the longevity of therapeutic effects are discussed. The evolving landscape of cellular immunotherapies holds promise for more durable treatment responses and increased specificity for autoimmune disease treatment.

Despite advances in medicine and antimicrobial research, viral infections continue to pose a major threat to human health. While major strides have been made in generating vaccines and small molecules to combat emerging pathogens, new modalities of treatment are warranted in diseases where there is a lack of treatment options, or where treatment cannot fully eradicate pathogens, as in HIV infection. Cellular therapies, some of which are FDA approved for treating cancer, take advantage of our developing understanding of the immune system, and harness this knowledge to enhance, or direct, immune responses toward infectious agents. As with cancer, viruses that evade immunity, do so by avoiding immune recognition or by redirecting the cellular responses that would eradicate them. As such, infusing virus specific immune cells has the potential to improve patient outcomes and should be investigated as a potential tool in the arsenal to fight infection. The present manuscript summarizes key findings made using cellular therapies for the treatment of viral infections, focusing on the potential that these strategies might have in controlling disease.