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Periodontitis, a major inflammatory disease of the oral mucosa, is epidemiologically associated with other chronic inflammation-driven disorders, including cardio-metabolic, neurodegenerative and autoimmune diseases and cancer. Emerging evidence from interventional studies indicates that local treatment of periodontitis ameliorates surrogate markers of comorbid conditions. The potential causal link between periodontitis and its comorbidities is further strengthened by recent experimental animal studies establishing biologically plausible and clinically consistent mechanisms whereby periodontitis could initiate or aggravate a comorbid condition. This multi-faceted ‘mechanistic causality’ aspect of the link between periodontitis and comorbidities is the focus of this Review. Understanding how certain extra-oral pathologies are affected by disseminated periodontal pathogens and periodontitis-associated systemic inflammation, including adaptation of bone marrow haematopoietic progenitors, may provide new therapeutic options to reduce the risk of periodontitis-associated comorbidities.Periodontitis has been causally linked to the development of other chronic inflammatory diseases outside the oral mucosa. In this Review, George Hajishengallis and Triantafyllos Chavakis consider the molecular basis of these links.

Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn’s disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and the cytokine IL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.This Review explains how cytokines contribute to the pathogenesis of inflammatory bowel disease (IBD). The author highlights the cytokine-targeting drugs that are already being successfully used in the clinic and discusses the potential of other cytokine-modulating drugs in IBD.

Mucosal vaccines offer the potential to trigger robust protective immune responses at the predominant sites of pathogen infection. In principle, the induction of adaptive immunity at mucosal sites, involving secretory antibody responses and tissue-resident T cells, has the capacity to prevent an infection from becoming established in the first place, rather than only curtailing infection and protecting against the development of disease symptoms. Although numerous effective mucosal vaccines are in use, the major advances seen with injectable vaccines (including adjuvanted subunit antigens, RNA and DNA vaccines) have not yet been translated into licensed mucosal vaccines, which currently comprise solely live attenuated and inactivated whole-cell preparations. The identification of safe and effective mucosal adjuvants allied to innovative antigen discovery and delivery strategies is key to advancing mucosal vaccines. Significant progress has been made in resolving the mechanisms that regulate innate and adaptive mucosal immunity and in understanding the crosstalk between mucosal sites, and this provides valuable pointers to inform mucosal adjuvant design. In particular, increased knowledge on mucosal antigen-presenting cells, innate lymphoid cell populations and resident memory cells at mucosal sites highlights attractive targets for vaccine design. Exploiting these insights will allow new vaccine technologies to be leveraged to facilitate rational mucosal vaccine design for pathogens including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and for cancer.Here, Ed Lavelle and Ross Ward discuss the unique aspects of mucosal immunity that must be considered when developing effective mucosal vaccines. The authors highlight the key immune cell populations that are targeted by mucosal vaccination strategies and explain how innovative adjuvant and delivery approaches should lead to new vaccines for infectious diseases and cancers.

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. A defective gut barrier and microbial dysbiosis induce such accumulation and local activation of immune cells, which results in a pro-inflammatory cytokine loop that overrides anti-inflammatory signals and causes chronic intestinal inflammation. This Review discusses pathogenic cytokine responses of immune cells as well as immune cell trafficking as a rational basis for new translational therapies in IBD. Underlying inflammatory bowel disease is a complex web of activated immune cells. In this Review, Neurath delineates the cells, pathways and signals that contribute to the pathology of inflammatory bowel disease and the potential for therapeutic intervention.

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.

Accumulating evidence implicates metabolites produced by gut microbes as crucial mediators of diet-induced host-microbial cross-talk. Here, we review emerging data suggesting that microbial tryptophan catabolites resulting from proteolysis are influencing host health. These metabolites are suggested to activate the immune system through binding to the aryl hydrocarbon receptor (AHR), enhance the intestinal epithelial barrier, stimulate gastrointestinal motility, as well as secretion of gut hormones, exert anti-inflammatory, anti-oxidative or toxic effects in systemic circulation, and putatively modulate gut microbial composition. Tryptophan catabolites thus affect various physiological processes and may contribute to intestinal and systemic homeostasis in health and disease. Gut microbial metabolites are known to impact many physiological processes of the host and play a critical role in immune-homeostasis. Here the authors review our current understanding and appreciation of the importance of microbially derived tryptophan catabolites during both health and disease.

Key Points The immunology of pregnancy has been considered as a host–graft response characterized by immune suppression and consequently a period of increased risk of bacterial and viral infection. However, accumulating evidence suggests that pregnancy is a more complex immunological condition, and thus a reassessment of many the immunological processes evaluated during pregnancy is required. Whereas a successful organ transplant requires constant immunosuppression, a successful pregnancy requires a robust, dynamic and responsive immune system. Embryo implantation and trophoblast invasion require a local inflammatory environment that promotes cell clearance, angiogenesis, cell growth and tolerance. Pregnancy complications, such as preterm birth, are often polymicrobial in nature and can involve viral infections that sensitize the pregnant mother to subsequent bacterial infections. Interferon-β is a crucial immune modulator during pregnancy; it protects the fetus against viral infections and contributes to the process of immune regulation at the maternal–fetal interface. The immune response associated with placental viral infections can affect maternal and fetal survival. Maternal inflammation due to viral or bacterial infections has detrimental consequences for fetal development. Although healthy pregnancies were traditionally considered to require an anti-inflammatory state, emerging evidence suggests that inflammation is important for a healthy pregnancy. Here, the authors discuss how the immune response varies throughout the main stages of pregnancy, and they consider how bacterial and viral infections can affect immune responses at the maternal–fetal interface. The comparison of the immunological state of pregnancy to an immunosuppressed host–graft model continues to lead research and clinical practice to ill-defined approaches. This Review discusses recent evidence that supports the idea that immunological responses at the receptive maternal–fetal interface are not simply suppressed but are instead highly dynamic. We discuss the crucial role of trophoblast cells in shaping not only the way in which immune cells respond to the invading blastocyst but also how they collectively react to external stimuli. We also discuss the role of the microbiota in promoting a tolerogenic maternal immune system and highlight how subclinical viral infections can disrupt this status quo, leading to pregnancy complications.

Innate lymphoid cells (ILCs) are important for tissue homeostasis and for the initiation of immune responses. Based on their transcriptional regulation and cytokine profiles, ILCs can be categorized into five subsets with defined phenotypes and functional profiles, but they also have the ability to adapt to local environmental cues by changing these profiles. This plasticity raises the question of the extent to which the cytokine production profiles of ILCs are pre-programmed or are a reflection of the tissue microenvironment. Here, we review recent advances in research on ILCs, with a focus on the plasticity of these cells. We highlight the ability of ILCs to communicate with the surrounding microenvironment and discuss the possible consequences of ILC plasticity for our understanding of the biological roles of these cells. Finally, we discuss how we might use this knowledge of ILC plasticity to develop or improve options for the treatment of inflammatory diseases.Innate lymphoid cell (ILC) subsets with defined phenotypes can adapt to local environmental cues through transdifferentiation. Studies of such plasticity have improved our understanding of the biological roles of ILCs and offer promise for new strategies to treat inflammatory diseases and cancer.

The revolution in microbiota research over the past decade has provided invaluable knowledge about the function of the microbial species that inhabit the human body. It has become widely accepted that these microorganisms, collectively called ‘the microbiota’, engage in networks of interactions with each other and with the host that aim to benefit both the microbial members and the mammalian members of this unique ecosystem. The lungs, previously thought to be sterile, are now known to harbor a unique microbiota and, additionally, to be influenced by microbial signals from distal body sites, such as the intestine. Here we review the role of the lung and gut microbiotas in respiratory health and disease and highlight the main pathways of communication that underlie the gut–lung axis. Marsland and colleagues review the role of the lung and gut microbiotas in respiratory health and disease.

In mice, commensal bacteria are shown to provide critical signals that limit bacterial trafficking to the mesenteric lymph nodes by immune cells, thus preventing the induction of mucosal immune responses. 'Good' gut microbes send right signals A critical question in the field of intestinal immunology is how the immune system can mount protective immune responses against pathogens while avoiding such responses against useful or commensal organisms. Gretchen Diehl et al . show that commensal bacteria provide critical signals that limit the trafficking of CX 3 CR1 hi phagocytic or dendritic lamina propria cells to the mesenteric lymph nodes, thus inhibiting the induction of mucosal immune responses. Therapeutic modulation of these cells may attenuate intestinal inflammation or enhance priming for mucosal vaccines. The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents 1 , 2 , 3 , 4 , 5 , 6 . Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis 7 . We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX 3 CR1 hi mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory 8 . These findings define a central role for commensals in regulating the migration to the MLNs of CX 3 CR1 hi mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.