Seminars in Immunopathology最新文献

Cells cross the placenta during pregnancy, resulting in proliferation of semiallogeneic cells in the mother and fetus decades later. This phenomenon, termed microchimerism, is documented across mammalian species, implying an evolutionary benefit. Still, short- and long-term effects remain uncertain. Here, we review the dynamics of microchimerism of fetal, maternal, and mother of the proband origin in relation to increasing gestational age and pregnancy complications associated with placental dysfunction including preeclampsia, fetal growth restriction, preterm labor, recurrent miscarriage, and diabetes. We use the two-stage model of preeclampsia as a framework. We recently published a series of papers independently linking increased fetal microchimerism to markers of placental dysfunction (stage 1), severe maternal hypertension (stage 2) and poor glucose control. Placental dysfunction may influence the intrinsic properties of fetal stem cells. Mesenchymal and hematopoietic stem cells isolated from cord blood during preeclampsia display reduced proliferative potential in vitro. Moreover, preeclampsia is shown to disrupt paracrine signaling in mesenchymal stem cells of the umbilical cord. Undesired properties in cells transferred to the mother could have profound negative effects on maternal health. Finally, recent studies indicate that microchimerism is involved in inducing maternal-fetal tolerance. Disruption of this process is associated with pregnancy complications. Long term, the persistence of microchimerism is necessary to sustain specific regulatory T cell populations in mice. This likely plays a role in the proband's future pregnancies and long-term maternal and offspring health. Current evidence indicates that advancements in our understanding of microchimerism could be instrumental in promoting reproductive and long-term health.

Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.

Decidualization, the transformation of endometrial stromal cells into specialized decidual cells, is essential for embryo implantation and pregnancy maintenance. This process involves immune cell infiltration, especially decidual natural killer (dNK) cells, which regulate immune responses and support tissue remodeling. Recent findings suggest that cellular senescence during decidualization is not just a byproduct but plays a functional role in enhancing uterine receptivity. However, excessive senescence leads to complications like recurrent pregnancy loss. dNK cells help maintain decidual homeostasis by clearing senescent cells, preventing their harmful accumulation. The balance between dNK activity and decidual stromal cell (DSC) senescence is crucial for successful implantation and pregnancy outcomes. Disruption of this balance may contribute to pathological conditions. This review delves into the pivotal roles of dNK cells in decidual senescence regulation and discusses therapeutic strategies targeting senescence to improve pregnancy outcomes, and new approaches for treating reproductive disorders.

Understanding the role of the gut microbiota in the pathogenesis of inflammatory bowel diseases (IBD) has been an area of intense research over the past decades. Patients with IBD exhibit alterations in their microbial composition compared to healthy controls. However, studies focusing solely on taxonomic analyses have struggled to deliver replicable findings across cohorts regarding which microbial species drive the distinct patterns in IBD. The focus of research has therefore shifted to studying the functionality of gut microbes, especially by investigating their effector molecules involved in the immunomodulatory functions of the microbiota, namely metabolites. Metabolic profiles are altered in IBD, and several metabolites have been shown to play a causative role in shaping immune functions in animal models. Therefore, understanding the complex communication between the microbiota, metabolites, and the host bears great potential to unlock new biomarkers for diagnosis, disease course and therapy response as well as novel therapeutic options in the treatment of IBD. In this review, we primarily focus on promising classes of metabolites which are thought to exert beneficial effects and are generally decreased in IBD. Though results from human trials are promising, they have not so far provided a large-scale break-through in IBD-therapy improvement. We therefore propose tailored personalized supplementation of microbiota and metabolites based on multi-omics analysis which accounts for the individual microbial and metabolic profiles in IBD patients rather than one-size-fits-all approaches.

Dyslipidemia is a common metabolic disorder around the world, with a higher incidence in the population of childbearing age and those experiencing infertility. Increasing research has been focused on the impact of dyslipidemia on female reproduction. This article reviews relevant clinical and basic science research on the effects of dyslipidemia on female reproduction, particularly paying attention to immune inflammatory changes in the endometrium. A comprehensive overview of the physiological effects of lipid metabolism on innate and adaptive immunity is provided, specifically examining the relationship between lipid metabolism and endometrial immune homeostasis, as well as the changes observed in women with reproductive failures. Moreover, the alterations in endometrial gene expressions and immune effectors in women with dyslipidemia and reproductive disorders are discussed, offering a new perspective on the reproductive disorders in women with dyslipidemia. Considering the significant involvement of lipid metabolism in human reproduction, gaining a deeper insight into dyslipidemia and female reproduction could have important clinical implications for the diagnosis and management of female reproductive disorders.

The impact of endometriosis and adenomyosis on reproduction and pregnancy is significant, with both conditions linked to increased rates of infertility, poor ovarian function in women with endometriosis, and elevated pregnancy complications in those with adenomyosis. However, the underlying mechanisms remain largely unclear. Both conditions share a similar pathophysiological process characterized by the growth of ectopic endometrium, which may originate from the eutopic endometrium. Notably, surgical removal of ectopic lesions does not appear to significantly improve reproductive and pregnancy outcomes, further underscoring the importance of eutopic endometrium in these adverse effects. Emerging evidence indicates substantial differences in endometrial NK cells, macrophages, and T cells, leading to inflammatory responses in women with endometriosis and adenomyosis. These alterations may contribute not only to disease progression but also to defective endometrial receptivity, insufficient angiogenesis remodeling, impaired maternal-fetal immune tolerance, and poor placentation, thereby influencing embryo implantation and pregnancy maintenance. This provides an immunological perspective to explain the higher rates of infertility and pregnancy complications observed in affected women. Therefore, we systematically review the alterations in endometrial immune cells in women with endometriosis and adenomyosis compared to healthy controls, exploring the potential impacts of these changes on reproduction and pregnancy. This review aims to lay the groundwork for future studies on the immunopathogenesis associated with endometriosis and adenomyosis-related reproductive failure and pregnancy complications, shedding lights on the development of immunotherapeutic strategies to mitigate these adverse impacts in affected women.

Natural chimeras are prevalent in nature (> 10 phyla of protists, plants, invertebrates, and vertebrates), disrupting the conventional believe that genetically homogeneous entities are selected to prevent conflicts within an organism. Chimerism emerges as a significant ecological/evolutionary mechanism, shaping the life history characteristics of metazoans, and it develops in various forms, one of which is called 'microchimerism'. Furthermore, chimerism is a pivotal phenomenon, presenting complex biological and ecological expressions akin to a "double-edged sword", bypassing both innate and adaptive immune responses. Considering the proportionate contribution of chimeric partners and their spatial arrangements within chimeras, unveils six somatic states of chimerism (purged-chimerism, sectorial-chimerism, mosaic-chimerism, mixed-chimerism, microchimerism and multi-chimerism) and three states of germline chimerism (mixed-chimerism, male/female chimerism and parasitic germline chimerism). These diverse chimeric states are categorized into two distinct series of continua, namely 'somatic cell chimerism' and 'germline chimerism' scenarios where dynamic chimeric states transit into other states, and vice versa, within a specific continuum that relies on the concept of an endless 'Escherian stairwell' of chimerism states. Also, the same chimera may portray simultaneously, different chimeric states in various parts/organs. We further reviewed the evolutionary perspectives for chimerism, raising five commonly shared features of chimerism (multichimerism, ontogenic windows, reproductive chimerism, transmissible chimerism, germline hitchhiking) and 'costs' and 'benefits' accrued to chimerism, shared between invertebrates and vertebrates, including humans. We contest that 'microchimerism' lacks any quantitative definition, represents just a single facet in the multi-facet panorama of chimeric phenomena that demonstrate transitions over time into other states. All of the above carry evolutionary and clinical implications.

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.