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This seventh edition of Medical Immunology, now in a full-color presentation, continues to provide a succinct clinical review of the human response to infection while being firmly grounded in science. The authors, distinguished and experienced educators, have been able to anticipate readers' conceptual challenges and use illustrations, diagrams, and algorithms throughout to simplify complex concepts. With an emphasis on clinical applications, methodological advances, immunological diseases, and innovative interventions, this tried and true guide navigates readers through state-of-the-sciences technologies and demonstrates their implementation in the day-to-day clinical practice of immunology.

Key Points The atypical serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. A complex formed between the immunosuppressive drug rapamycin and the immunophilin FK506-binding protein 1A, 12 kDA (FKBP12) inhibits mTOR kinase activity. mTOR functions in at least two multi-protein complexes: mTOR complex 1 (mTORC1) and mTORC2. mTOR in mTORC1 is highly sensitive to inhibition by rapamycin, whereas mTOR in mTORC2 is resistant to rapamycin. mTORC1 regulates cell growth downstream of phosphoinositide 3-kinase–AKT signalling, in which active mTORC1 phosphorylates S6 kinase (S6K1) and the eukaryotic translation initiation factor-binding protein 1 (EIF4EBP1). Both of these activities promote mRNA translation and cell growth. Rapamycin exerts many effects on the differentiation and function of professional antigen-presenting cells (APCs). mTOR inhibition by rapamycin impedes antigen uptake and can modulate antigen presentation by dendritic cells (DCs); its differential effects on cytokine production and chemokine receptor expression by DCs regulate interactions between innate and adaptive immune cells. Recent findings have shed light on previously unappreciated effects of mTOR inhibition on T cells. Rapamycin induces thymic involution, whereas the ontogeny of naturally occurring regulatory T (T Reg ) cells seems to be less affected. During conventional T cell activation, rapamycin-mediated mTOR inhibition blocks cell cycle progression and can sequester activated T cells in secondary lymphoid tissues. By contrast, rapamycin causes an increase in the frequency of FOXP3 (forkhead box P3) + T cells, reflecting both the ability of T Reg cells to proliferate in the presence of rapamycin and the promotion of FOXP3 expression in peripheral T cells that are then converted into modulators of immune reactivity. mTOR inhibition is a promising therapeutic strategy to prevent rejection in transplantation and for autoimmune disease. Differential effects of rapamycin on T cells and T Reg cells (both naturally occurring and inducible) favour its ability to promote tolerance in tolerance-enhancing protocols. In addition, adoptively transferred rapamycin-conditioned APCs inhibit organ allograft rejection and graft-versus-host disease following haematopoietic cell transplantation. Ongoing and future areas of enquiry, which could prove fruitful, include distinguishing the role of mTORC1 and mTORC2 in the regulation of immune responses and tolerance, investigating the role of the mTOR–survivin–aurora B complex in T cell activation and ascertaining the mechanisms that determine T Reg cell resistance to rapamycin and mTOR-mediated regulation of FOXP3 expression, as well as their relevance to therapy. Angus Thomson and colleagues describe the consequences of mammalian target of rapamycin (mTOR) inhibition by rapamycin on dendritic cells, effector T cells and regulatory T cells. These effects make mTOR inhibition a promising immunosuppressive, but tolerance-promoting, therapeutic strategy. The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and has important roles in the activation of effector T cells and the function and proliferation of regulatory T cells. In this Review, we discuss our current understanding of the mTOR pathway and the consequences of mTOR inhibition, both in DCs and T cells, including new data on the regulation of forkhead box P3 expression.

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer’s disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Many proliferative, invasive, and immune tolerance mechanisms that support normal human pregnancy are also exploited by malignancies to establish a nutrient supply and evade or edit the host immune response. In addition to the shared capacity for invading through normal tissues, both cancer cells and cells of the developing placenta create a microenvironment supportive of both immunologic privilege and angiogenesis. Systemic alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarization evident in advanced cancers and midtrimester pregnancy. This review summarizes the similarities between growth and immune privilege in cancer and pregnancy and identifies areas for further investigation. Our PubMed search strategy included combinations of terms such as immune tolerance, pregnancy, cancer, cytokines, angiogenesis, and invasion. We did not place any restrictions on publication dates. The knowledge gained from analyzing similarities and differences between the physiologic state of pregnancy and the pathologic state of cancer could lead to identification of new potential targets for cancer therapeutic agents.

The Compatibility Gene takes readers on a global journey of discovery spanning 60 years, involving scores of scientists, and encompassing the history of transplants and immunology. That journey has revealed astonishing links between who we are as individuals and our never-ceasing struggle to survive disease. Most of the 25,000 genes we possess are the same for all of us. Compatibility genes are those that vary most from person to person and give each of us a unique molecular signature. These genes determine both the extent to which we are susceptible to a vast range of illnesses and the different ways each of us fights disease. In The Compatibility Gene, distinguished immunologist Daniel Davis draws on new research to suggest a number of even more fascinating-and controversial-conclusions about compatibility genes: that we find others more or less sexy according to their compatibility genes (dating services are starting to match people in this way); that the wiring between some neurons is kept or broken according to the activity of compatibility genes; and that compatibility genes influence the chances of a couple having a successful pregnancy. Profoundly personal, life-forming and life-changing decisions appear to be governed by the actions of a few inherited genes. Most importantly, Davis proposes that because we each respond slightly differently to any particular disease, in the not-too-distant future vaccines and other medications may be tailored to match our compatibility genes, a revolutionary breakthrough in the fight against disease. Including vivid portraits of the scientists who worked tirelessly to unlock the secrets of compatibility genes, as well as patients who survived disease due to lucky genetic inheritances, The Compatibility Gene explains an aspect of human biology that will undoubtedly have profound impacts on medical practice in the 21st Century.

The emerging field of immunometabolism has substantially progressed over the last years and provided pivotal insights into distinct metabolic regulators and reprogramming pathways of immune cell populations in various immunological settings. However, insights into immunometabolic reprogramming in the context of reproduction are still enigmatic. During pregnancy, the maternal immune system needs to actively adapt to the presence of the fetal antigens, i.e., by functional modifications of distinct innate immune cell subsets, the generation of regulatory T cells, and the suppression of an anti-fetal effector T cell response. Considering that metabolic pathways have been shown to affect the functional role of such immune cells in a number of settings, we here review the potential role of immunometabolism with regard to the molecular and cellular mechanisms necessary for successful reproduction. Since immunometabolism holds the potential for a therapeutic approach to alter the course of immune diseases, we further highlight how a targeted metabolic reprogramming of immune cells may be triggered by maternal anthropometric or nutritional aspects.

Dendrobium huoshanense is a valuable and versatile Chinese herbal medicine with the anecdotal claims of cancer prevention and anti-inflammation. However, its immunological activities are limited to in vitro studies on a few cytokines and immune cell functions. First, we investigated the effects of polysaccharides isolated from DH (DH-PS) on inducing a panel of cytokines/chemokines in mice in vivo and human in vitro. We found that DH polysaccharides (DH-PS) induced TH1, TH2, inflammatory cytokines and chemokines in mouse in vivo and human cells in vitro. Secondly, we demonstrated that DH-PS expanded mouse splenocytes in vivo including CD4(+) T cells, CD8(+) T cells, B cells, NK cells, NKT cells, monocytes/macrophages, granulocytes and regulatory T cells. Notably, DH-PS induced an anti-inflammatory molecule, IL-1ra, in mouse and human immune cells, especially monocytes. The serum level of IL-1ra elicited by the injection of DH-PS was over 10 folds of IL-1β, suggesting that DH-PS-induced anti-inflammatory activities might over-ride the inflammatory ones mediated by IL-1β. The signaling pathways of DH-PS-induced IL-1ra production was shown to involve ERK/ELK, p38 MAPK, PI3K and NFκB. Finally, we observed that IL-1ra level induced by DH-PS was significantly higher than that by F3, a polysaccharide extract isolated from another popular Chinese herbal medicine, Ganoderma lucidum. These results indicated that DH-PS might have potential applications for ameliorating IL-1-induced pathogenic conditions.

Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab')(2) fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-1β mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7(+) T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation.

Natural selection favors individuals that respond with effective and appropriate immune responses to macro or microparasites. Animals living in populations close to ecological carrying capacity experience increased intraspecific competition, and as a result are often in poor nutritional condition. Nutritional condition, in turn, affects the amount of endogenous resources that are available for investment in immune function. Our objective was to understand the relationship between immune function and density dependence mediated by trade-offs between immune function, nutritional condition, and reproduction. To determine how immune function relates to density-dependent processes, we quantified bacteria killing ability, hemolytic-complement activity, and nutritional condition of North American elk (Cervus elaphus) from populations maintained at experimentally high- and low-population densities. When compared with elk from the low-density population, those from the high-density population had higher bacteria killing ability and hemolytic-complement activity despite their lower nutritional condition. Similarly, when compared with adults, yearlings had higher bacteria killing ability, higher hemolytic-complement activity, and lower nutritional condition. Pregnancy status and lactational status did not change either measure of constitutive immunity. Density-dependent processes affected both nutritional condition and investment in constitutive immune function. Although the mechanism for how density affects immunity is ambiguous, we hypothesize two possibilities: (i) individuals in higher population densities and in poorer nutritional condition invested more into constitutive immune defenses, or (ii) had higher parasite loads causing higher induced immune responses. Those explanations are not mutually exclusive, and might be synergistic, but overall our results provide stronger support for the hypothesis that animals in poorer nutritional condition invest more in constitutive immune defenses then animals in better nutritional condition. This intriguing hypothesis should be investigated further within the larger framework of the cost and benefit structure of immune responses.

The devastating impact of smoking on health is well known. Here the authors warn of the complex and multiple adverse effects of cigarette smoke on the immune system, which increase susceptibility to respiratory infections, lung pathologies and cancer. A complex and multilayered immune defence system protects the host against harmful agents and maintains tissue homeostasis. Cigarette smoke ex posure markedly impacts the immune system, compromising the host's ability to mount appropriate immune and inflammatory responses and contributing to smoking-related pathologies. These adverse effects on the immune system not only occur in active smokers, but also in those exposed to smoke passively in contaminated environments, and may persist for decades after exposure has ended.