Immunological Reviews最新文献

Multiple sclerosis (MS) affects more than 2.8 million people worldwide but the distribution is not even. Although over 200 gene variants have been associated with susceptibility, studies of genetically identical monozygotic twin pairs suggest that the genetic make-up is responsible for only about 20%–30% of the risk to develop disease, while the rest is contributed by milieu factors. Recently, a new, unexpected player has entered the ranks of MS-triggering or facilitating elements: the human gut microbiota. In this review, we summarize the present knowledge of microbial effects on formation of a pathogenic autoreactive immune response targeting the distant central nervous system and delineate the approaches, both in people with MS and in MS animal models, which have led to this concept. Finally, we propose that a tight combination of investigations of human patients with studies of suitable animal models is the best strategy to functionally characterize disease-associated microbiota and thereby contribute to deciphering pathogenesis of a complex human disease.

Type 1 diabetes (T1D) is a chronic autoimmune disease targeting insulin-producing pancreatic beta cells. T1D is a multifactorial disease incorporating genetic and environmental factors. In recent years, the advances in high-throughput sequencing have allowed researchers to elucidate the changes in the gut microbiota taxonomy and functional capacity that accompany T1D development. An increasing number of studies have shown a role of the gut microbiota in mediating immune responses in health and disease, including autoimmunity. Fecal microbiota transplantations (FMT) have been largely used in murine models to prove a causal role of the gut microbiome in disease progression and have been shown to be a safe and effective treatment in inflammatory human diseases. In this review, we summarize and discuss recent research regarding the gut microbiota–host interactions in T1D, the current advancement in therapies for T1D, and the usefulness of FMT studies to explore microbiota–host immunity encounters in murine models and to shape the course of human type 1 diabetes.

Fat is stored in distinct depots with unique features in both mice and humans and B cells reside in all adipose depots. We have shown that B cells modulate cardiometabolic disease through activities in two of these key adipose depots: visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT). VAT refers to the adipose tissue surrounding organs, within the abdomen and thorax, and is comprised predominantly of white adipocytes. This depot has been implicated in mediating obesity-related dysmetabolism. PVAT refers to adipose tissue surrounding major arteries. It had long been thought to exist to provide protection and insulation for the vessel, yet recent work demonstrates an important role for PVAT in harboring immune cells, promoting their function and regulating the biology of the underlying vessel. The role of B-2 cells and adaptive immunity in adipose tissue biology has been nicely reviewed elsewhere. Given that, the predominance of B-1 cells in adipose tissue at homeostasis, and the emerging role of B-1 cells in a variety of disease states, we will focus this review on how B-1 cells function in VAT and PVAT depots to promote homeostasis and limit inflammation linked to cardiometabolic disease and factors that regulate this function.

Well known functions of adipose tissue include energy storage, regulation of thermogenesis, and glucose homeostasis—each of which are associated with the metabolic functions of fat. However, adipose tissues also have important immune functions. In this issue of Immunological Reviews, we present a series of articles that highlight the immune functions of adipose tissue, including the roles of specialized adipose-resident immune cells and fat-associated lymphoid structures. Importantly, immune cell functions in adipose tissues are often linked to the metabolic functions of adipocytes and vice versa. These reciprocal interactions and how they influence both immune and metabolic functions will be discussed in each article. In the first article, Wang et al.,¹¹ discuss adipose-associated macrophages and how obesity and metabolism impact their phenotype and function. Several articles in this issue discuss T cells as either contributors to, or regulators of, inflammatory responses in adipose tissues. Valentine and Nikolajczyk¹² provide insights into the role of T cells in obesity-associated inflammation and their contribution to metabolic dysfunction, whereas an article from Kallies and Vasanthakumar¹³ and another from Elkins and Li¹⁴ describe adipose-associated Tregs and how they help prevent inflammation and maintain metabolic homeostasis. Articles from Okabe³⁵ as well as from Daley and Benezech¹⁵ discuss the structure and function of fat-associated lymphoid clusters (FALCs) that are prevalent in some adipose tissues and support local immune responses to pathogens, gut-derived microbes and fat-associated antigens. Finally, an article from Meher and McNamara¹⁶ describes how innate-like B1 cells in adipose tissues regulate cardiometabolic disease. Importantly, these articles highlight the physical and functional attributes of adipose tissues that are different between mice and humans, the metabolic and immune differences between various adipose depots in the body and the differences in immune cells, adipose tissues and metabolic functions between the sexes. At the end of this preface, we highlight how these differences are critically important for our understanding of anti-tumor immunity to cancers that metastasize to a specific example of visceral adipose tissue, the omentum. Together, these articles identify some unanswered mechanistic questions that will be important to address for a better understanding of immunity in adipose tissues.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, affecting nearly 2 million people worldwide. The etiology of MS is multifactorial: Approximately 30% of the MS risk is genetic, which implies that the remaining ~70% is environmental, with a number of factors proposed. One recently implicated risk factor for MS is the composition of the gut microbiome. Numerous case–control studies have identified changes in gut microbiota composition of people with MS (pwMS) compared with healthy control individuals, and more recent studies in animal models have begun to identify the causative microbes and underlying mechanisms. Here, we review some of these mechanisms, with a specific focus on the role of host genetic variation, dietary inputs, and gut microbial metabolism, with a particular emphasis on short-chain fatty acid and tryptophan metabolism. We put forward a model where, in an individual genetically susceptible to MS, the gut microbiota and diet can synergize as potent environmental modifiers of disease risk and possibly progression, with diet-dependent gut microbial metabolites serving as a key mechanism. We also propose that specific microbial taxa may have divergent effects in individuals carrying distinct variants of MS risk alleles or other polymorphisms, as a consequence of host gene-by-gut microbiota interactions. Finally, we also propose that the effects of specific microbial taxa, especially those that exert their effects through metabolites, are highly dependent on the host dietary intake. What emerges is a complex multifaceted interaction that has been challenging to disentangle in human studies, contributing to the divergence of findings across heterogeneous cohorts with differing geography, dietary preferences, and genetics. Nonetheless, this provides a complex and individualized, yet tractable, model of how the gut microbiota regulate susceptibility to MS, and potentially progression of this disease. Thus, we conclude that prophylactic or therapeutic modulation of the gut microbiome to prevent or treat MS will require a careful and personalized consideration of host genetics, baseline gut microbiota composition, and dietary inputs.

Commensal microbes have the capacity to affect development and severity of autoimmune diseases. Germ-free (GF) animals have proven to be a fine tool to obtain definitive answers to the queries about the microbial role in these diseases. Moreover, GF and gnotobiotic animals can be used to dissect the complex symptoms and determine which are regulated (enhanced or attenuated) by microbes. These include disease manifestations that are sex biased. Here, we review comparative analyses conducted between GF and Specific-Pathogen Free (SPF) mouse models of autoimmunity. We present data from the B6;NZM-Sle1^NZM2410/AegSle2^NZM2410/AegSle3^{NZM2410/Aeg−}/LmoJ (B6.NZM) mouse model of systemic lupus erythematosus (SLE) characterized by multiple measurable features. We compared the severity and sex bias of SPF, GF, and ex-GF mice and found variability in the severity and sex bias of some manifestations. Colonization of GF mice with the microbiotas taken from B6.NZM mice housed in two independent institutions variably affected severity and sexual dimorphism of different parameters. Thus, microbes regulate both the severity and sexual dimorphism of select SLE traits. The sensitivity of particular trait to microbial influence can be used to further dissect the mechanisms driving the disease. Our results demonstrate the complexity of the problem and open avenues for further investigations.

It is now widely understood that visceral adipose tissue (VAT) is a highly active and dynamic organ, with many functions beyond lipid accumulation and storage. In this review, we discuss the immunological role of this tissue, underpinned by the presence of fat-associated lymphoid clusters (FALCs). FALC's distinctive structure and stromal cell composition support a very different immune cell mix to that found in classical secondary lymphoid organs, which underlies their unique functions of filtration, surveillance, innate-like immune responses, and adaptive immunity within the serous cavities. FALCs are important B cell hubs providing B1 cell-mediated frontline protection against infection and supporting B2 cell-adaptative immune responses. Beyond these beneficial immune responses orchestrated by FALCs, immune cells within VAT play important homeostatic role. Dysregulation of immune cells during obesity and aging leads to chronic pathological “metabolic inflammation”, which contributes to the development of cardiometabolic diseases. Here, we examine the emerging and complex functions of B cells in VAT homeostasis and the metabolic complications of obesity, highlighting the potential role that FALCs play and emphasize the areas where further research is needed.