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We have previously demonstrated that treatment of female NOD mice with the histone deacetylase inhibitor Trichostatin A (TSA) bestowed irreversible protection against autoimmune diabetes. Herein we show that drug treatment diminished the infiltration of the pancreas with CD4+ and CD8+ T cells and Ly-6C+ monocytes. Significantly, TSA administration selectively repressed the expression of a set of genes exaggerated during diabetes and constitutively expressed primarily in the spleen and rarely in the pancreas. These genes encode lymphokines, macrophage-associated determinants, and transcription factors. Although the copy numbers of many histone deacetylases increased during diabetes in the spleen and pancreas, only those upregulated in the spleen were rendered sensitive to repression by TSA treatment. The T lymphocytes derived from drug-treated donors displayed diminished diabetogenic potential following transfer into immunodeficient NOD.scid mice. In the immunocompromised recipients, diabetes caused by the transfer of activated T lymphocytes from untreated diabetic mice was hampered by the co-transfer of highly purified splenic Ly-6C+ macrophages from drug-treated mice. However, the transfer of Ly-6C+ macrophages from drug-treated mice failed to block ongoing diabetes in wild-type NOD mice. These data demonstrate that the modified gene expression and functional alteration of T lymphocytes and macrophages collectively contribute to diabetes protection afforded by the histone modifier in female NOD mice.

Background Regardless of the agent, the inflammatory response is interconnected with infection. Mostly the initial response to infection is severe sepsis and characterized by a pro-inflammatory state, which then progresses to an anti-inflammatory state that develops and favors secondary infections (Florescu and Kalil, 2011) [1]. T-helper 1 (Th1) cells activated by microorganisms increase transcription of pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-γ (INF-γ), and interleukin-2 (IL-2) (Hotchkiss and Karl, 2003; Brown and Jones, 2004; Russell, 2006) [[2], [3], [4]]. Different cytokines, TNF-α, interleukins, lymphokines, monokines, IFN-γ, colony-stimulating factor (CSF) and transforming growth factors, released from endothelial cells and subsequently from macrophages can induce lymphocyte activation and infiltration at the sites of infection and will exert direct antiviral effects. Subsequently, with the shift toward an anti-inflammatory state, activated T-helper 2 (Th2) cells secrete interleukin-4 (IL-4) and interleukin-10 (IL-10) (Hotchkiss and Karl, 2003; Russell, 2006) [2,4]. Sometimes, T cells can become anergic and fail to proliferate as wells producing cytokines (Hotchkiss and Karl, 2003) [2]. Type I IFN has a potent anti-influenza virus activity, it induces transcription of several interferon-stimulated genes, which in turn restrict viral replication (Garcia-Sastre, 2011) [5]. However, the influenza virus developed several mechanisms to evade IFN response as NS1 protein, IFN-antagonist produced by the virus, PB1–F2 proteins that inhibit IFN induction, the viral polymerase inhibits IFN function, and M2 protein prevents toll-like receptor (TLR) induction (Garcia-Sastre, 2011) [5]. Influenza virus can also trigger the deregulation of the innate immune system with excessive cytokines release leading to potentially harmful consequences (Teijaro et al., 2011) [6]. Abnormal immune response to influenza can lead to endothelial damage through the remodeling of the cellular cytoskeleton, loss of intercellular junctional integrity, cellular apoptosis, deregulation of coagulation, the consequent alteration of microvascular permeability, tissue edema, and shock (Steinberg et al., 2012) [7]. This increase in permeability of the endothelium is mainly due to the intercellular pathways and to a lesser extent through the transcellular leak (Steinberg et al., 2012) [7]. Such vascular hyperpermeability and multi-organ failure with severe edema, shock, acute lung injury, and even acute encephalopathy have been described in severe influenza infections (Wang et al., 2010; Armstrong et al., 2013) [8,9]. Novel drugs and vaccines such as peramivir, baloxavir marboxil, and 4 egg-based quadrivalent inactivated influenza vaccines have been added recently [10]. These changes require better and more efficient diagnostic and therapeutic approaches to avoid a fatal progression. I would like to report a child patient with H1N1 influenza, who developed rapid fatal viral septicemia.

This chapter broadly describes the field of neuroendocrinimmunology (NEI). NEI encompasses a number of complementary subdisciplines that seek to elucidate the bidirectional regulatory relationships that exist between the nervous system, the endocrine system, and the immune system. Each component of this field focuses on the molecules of communication operating between these three systems that will maintain whole-body homeostasis and thus health. Examples are cytokines, lymphokines, and chemokines in the immune system; hormones of the hypothalamic–pituitary–peripheral gland axes; and neurotransmitters of the central and peripheral nervous systems. An understanding of these relationships facilitates a comprehension of stress responses and stress-related diseases. Subareas of interest include the actions of cytokines in the central nervous system; autonomic innervation and regulation of immune organs; neuroendocrine regulation of immune cells; immune cell production of neuroendocrine peptides and their functions; and the autoimmune mechanisms of neural destruction leading to conditions such as myasthenia gravis and multiple sclerosis.

The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention.

The major sex hormones that have been studied in immunity are estrogens, testosterone, progesterone, and vitamin D. Sex hormones bind to hormone receptors on the surface of immune cells or more classically, within the cytoplasm of the cell. Most immune cells express multiple sex hormone receptors that are involved in driving immune responses in sex-specific directions following antigen stimulation. Sex hormone regulation of innate antigen-presenting cells like dendritic cells, mast cells, and monocyte/macrophages is the key step in determining the type of adaptive immune response. Sex hormone receptors on adaptive T and B cells further distinguish sex differences in inflammation that characterize the immune response to infections and the development of chronic inflammatory diseases like autoimmune diseases. However, data are contradictory and further research is needed to better understand how sex hormone receptors regulate inflammation. This chapter describes current knowledge on how sex hormones alter the function of innate immune cells like dendritic cells, mast cells, macrophages, and adaptive immune cells like T cells, T regulatory cells, and B cells. Detailed descriptions of the downstream signaling pathways of major sex hormone receptors are also provided.

Human immunodeficiency virus type 1 (HIV-1) gives rise to a chronic infection that progressively depletes CD4(+) T lymphocytes. CD4(+) T lymphocytes play a central coordinating role in adaptive cellular and humoral immune responses, and to do so they migrate and interact within lymphoid compartments and at effector sites to mount immune responses. While cell-free virus serves as an excellent prognostic indicator for patient survival, interactions of infected T cells or virus-scavenging immune cells with uninfected T cells can greatly enhance viral spread. HIV can induce interactions between infected and uninfected T cells that are triggered by cell surface expression of viral Env, which serves as a cell adhesion molecule that interacts with CD4 on the target cell, before it acts as the viral membrane fusion protein. These interactions are called virological synapses and promote replication in the face of selective pressure of humoral immune responses and antiretroviral therapy. Other infection-enhancing cell-cell interactions occur between virus-concentrating antigen-presenting cells and recipient T cells, called infectious synapses. The exact roles that these cell-cell interactions play in each stage of infection, from viral acquisition, systemic dissemination, to chronic persistence are still being determined. Infection-promoting immune cell interactions are likely to contribute to viral persistence and enhance the ability of HIV-1 to evade adaptive immune responses.

NF-κB (nuclear factor of κB site binding) proteins are an evolutionarily conserved family of inducible transcription factors that control the expression of a large number of genes with important developmental and effector functions in a variety of immune cells. Mice with genetic knockouts of individual genes encoding NF-κB proteins have distinct immune cell defects. Moreover, impaired regulation of NF-κB is found in many human immune diseases. For example, NF-κB is constitutively active in many chronic inflammatory diseases and leukemias/lymphomas, while depressed NF-κB activity is seen in some human immunodeficiencies. Thus, NF-κB is viewed as a therapeutic target for many immune cell diseases.

In the late 1960s, groups led by Henry Claman, Anthony Davis, and Jacque Miller demonstrated that thymus-dependent (T) lymphocytes help thymus-independent (B) lymphocytes synthesize and secrete antibody. This stimulated a search for other cellular interactions that regulate antibody synthesis and secretion. In 1972, Richard Gershon described a population of T lymphocytes that inhibited antibody production; he coined the term T suppressors (T S ). Subsequent studies characterized T S lymphocytes phenotypically and genetically. By 1980, elaborate schemes of cell interactions and soluble factors had been described to explain the function of these lymphocytes. Data presented in the mid-1980s, however, questioned the existence of these regulatory lymphocytes, and by 1990, T suppressor lymphocytes ceased to be a viable research topic. A second line of investigation initiated in the late 1960s by Yasuaki Nishizuka and Teruyo Sakakura revived the concept of T lymphocyte suppression. These investigators showed that thymectomy of 3-day-old mice enhanced the development of naturally occurring autoimmune diseases later in life. These investigations led to the description of a population of CD4 + T lymphocytes that regulate the production of autoantibodies and other autoimmune responses. These cells, termed T regulatory (T REG ) lymphocytes, not only prevent potential autoimmune responses, but they also are instrumental in regulating the response to pathogens and tumors. These lymphocytes possess a unique phenotype and mechanism of action, leading to efforts to manipulate them clinically in patients with tumors and autoimmune diseases.

Malignant transformation of cells produces radical changes in their metabolism and the soluble factors they produce. These changes support rapid cell proliferation and facilitate their invasion into surrounding tissues as well as distant metastatic spread. The type of soluble factors produced by tumors and their effect on the immune response can be divided into those that directly impair antitumor protective functions of T cells, and those that induce the production of high number of immature myeloid cells from the bone marrow that migrate to the tumor microenvironment (TME). Under normal conditions these cells are essential for tissue repair but in the TME they become chronic inflammatory cells that are potent inhibitors of T cells and NK cells. Multiple approaches are currently being tested in animal models and in patients to overcome these powerful mechanisms and allow the induction of a protective and therapeutic antitumor immune response.

Research in chickens has contributed significantly to our current understanding of the immune system. The existence of two distinct organs of lymphocyte development allowed elegant studies in bursectomized and thymectomized chickens leading to the discovery of bursa-derived (B) lymphocytes as antibody-producing cells and insights into the role of thymus-derived T cells as helper cells. Subsequent work showed that the avian immune system largely resembles that of mammals with some striking exceptions. These include the absence of lymph nodes, the presence of a unique organ of B cell development, the so called ‘minimal essential MHC,’ and a reduced repertoire of cytokines and chemokines. Sequencing of hundreds of avian genomes continues to provide new insights into the evolution of avian immune systems and facilitates the identification of thus far missing genes. In combination with recent advances in the generation of transgenic and gene knockout chickens, these efforts will accelerate progress in the understanding of the avian immune system and will provide the basis for the development of improved vaccines and immunomodulators.

B cells are a heterogeneous population of cells that can contribute to immune responses by producing antibody, presenting antigen to T cells, and via the provision of soluble factors including cytokines. Although one of the lesser known functions of B cells, it is well documented that B cells can produce a vast array of cytokines, including both pro-and anti-inflammatory cytokines such as IFNγ, IL-12, TNF, IL-6, IL-2, IL-4, and IL-13, and immune-regulatory cytokines such as IL-10 and TGFβ. Based on the production of these cytokines, B cells can be partitioned into distinct ‘effector’ and ‘regulatory’ subtypes. In this article, we will discuss the identification, induction, and function of both effector and regulatory B cells in mouse and human.

金沢大学医薬保健研究域医学系, While B cells are generally considered to be positive regulators of humoral immune responses due to their ability to differentiate into plasmablasts/plasma cells and produce antibodies, B cells also modulate immune responses through antigen presentation and cytokine secretion. Moreover, " regulatory B cells" that suppress immune responses have been recognized as an important new component of the immune system. In mice, the function of regulatory B cells is almost exclusively dependent on IL-10. The cell-surface phenotype of murine IL-10-producing regulatory B cells is reported to be CD1dhiCD5+ or CD1dhiCD21hiCD23+IgMhi, and thus their phenotype overlaps with that of CD5+ B-1a cells, CD1dhiCD21hiCD23loIgMhi marginal zone (MZ) B cells, and CD1dhiCD21hiCD23hiIgMhi T2-MZ precursor B cells. Contrary to earlier work that suggested a minor role for B cells in contact hypersensitivity, regulatory B cells are now known to have a critical inhibitory functions in this type of immune response. Furthermore, studies using murine disease models have demonstrated that regulatory B cells play a significant role in autoimmune connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as organ-specific autoimmune diseases including experimental autoimmune encephalomyelitis and inflammatory bowel disease. In comparison to mouse regulatory B cells, little is known regarding their human counterparts. One recent study demonstrates that human CD19+CD24hiCD38hi B cells possess regulatory capacity. Clarifying the molecular mechanisms by which regulatory B cells suppress immune responses will be of great benefit in the development of new B cell-targeted therapeutic strategies. © 2010 Japanese Society for Investigative Dermatology.

The immune response in drug hypersensitivity is normally explained by the hapten hypothesis. It postulates that drugs with a molecular weight of less than 1000 D are too small to cause an immune response per se. However, if a chemically reactive drug or drug metabolite binds covalently to a protein and thus forms a so-called hapten-carrier complex, this modified protein can induce an immune response. This concept has recently been supplemented by the p-i concept (or pharmacological interaction with immune receptors), which postulates that some drugs that lack hapten characteristics can bind directly and reversibly (noncovalently) to immune receptors and thereby stimulate the cells. For example, a certain drug may bind to a particular T-cell receptor, and this binding suffices to stimulate the T cell to secrete cytokines, to proliferate, and to exert cytotoxicity. The p-i concept has major implications for our understanding of drug interaction with the specific immune system and for drug hypersensitivity reactions. It is based on extensive investigations of T-cell clones reacting with the drug and recently of hybridoma cells transfected with the drug-specific T-cell receptor for antigen (TCR). It is a highly specific interaction dependent on the expression of a TCR into which the drug can bind with sufficient affinity to cause signaling. Small modification of the drug structure may already abrogate reactivity. Stimulation of T cells occurs within minutes as revealed by rapid Ca++ influx after drug addition to drug-specific T-cell clones or hybridoma cells, thus, before metabolism and processing can occur. As the immune system can only react in an immunologic way, the symptoms arising after drug stimulation of immune receptors imitate an immune response after recognition of a peptide antigen, although it is actually a pharmacological stimulation of some T cells via their TCRs. Clinically, the p-i concept could explain the sometimes rapid appearance of symptoms without previous sensitizations and the sometimes chaotic immune reaction of drug hypersensitivity with participation of different immune mechanisms while normal immune reactions to antigens are highly coordinated. Nevertheless, because the reactions lead to expansion of drug-reactive cells, many features such as skin test reactivity and stronger reactivity upon reexposure are identical to real immune reactions. Keywords: p-i concept, drug hypersensitivity, hapten, prohapten, T-cell receptor, T cells

The immune system has been described as a function of our body’s defense and as a major communication system between tissues, organs, and organic systems. Cytokines form essential messengers for both functions. In order to understand cytokines’ modes of action and their importance for the immune system, the latter has been described stepwise. The chapter defines immunity by giving an overview of the divisions of immunity. Inborn immunity (innate) represents the immunity that has been found with a similar function and repertoire of recognition in all individuals of a species. The chapter also gives description of the specialized set of lymphocytes (T and B) that has been called adaptive immunity. The T and B cells give rise to a unique set of immune cells for each individual of a species. These make an individually specific repertoire for molecular recognition by which the immune system can detect microbes. Whereas B cells recognize three-dimensional molecular structures, T cells can recognize linear molecular structures embedded in the specialized set of self-molecules called major histocompatibility antigens (HLA in humans). The development of T and B cells (and their recognition repertoires) has been described with implications for their functions in the adult tissues of the body.

The cells of the adaptive immune system upon activation make various types of responses that are basically directed against microbiological intruders. The types of T helper effector cells have been widely used as prototypes for immune responses. Thus we have a proinflammatory Th1 type, Th17 type, and pro-allergic Th2 type of the response. In addition, Th9 and Th22 types have been recently described. The Th3, Tr1, and Treg type of responses have been seen as a downregulation of the previously mentioned Th1, Th17, or Th2 types. Their anticipated roles are being described. The cytokines play an essential role in the development of these types of immune response, and furthermore, they are the effector molecules in many of them. Especially important are the regulatory and overlapping functions of cytokines in these responses, and many of them are still not discovered.

Interleukins form by name a group of cytokines that are of essential importance for the function of the immune system—both innate and adaptive. Their biologic role exceeds the anticipated one in communication between the cells of the immune system. Among cytokines, which, in general, are harbingers of physiologic homeostasis of the body of each individual, interleukins’ share is the key element. The complex interaction between hematopoietic cells themselves, and tissues they travel or reside in highlight the interleukins’ influence on immunity. This chapter describes interleukins from IL-1 until IL-38. Apart from their aliases, structure, source, and function, including their receptors and signaling, interleukins’ roles in immunologic reactions, associations with various diseases and therapeutic potentials, are in the focus of this chapter.

B lymphocytes have a unique capacity to produce antibodies and are important antigen-presenting cells. In addition to these primary functions, they can secrete cytokines and subsequently influence immunity in a non-antigen-restricted manner. Through these activities, B cells can act as drivers and regulators of immune responses. B cell-mediated regulatory activities primarily involve their production of antiinflammatory cytokines such as interleukin (IL)-10 and IL-35. Through production of these factors, B cells can protect from autoimmune disease and limit host resistance to pathogens. Here, we review current data on the suppressive activities of B cells, using several examples of autoimmune or inflammatory disorders, and infectious diseases in mice. We also discuss available data on the phenotype and function of human IL-10-producing B cells. Finally, we detail throughout the text the recently identified relationship between IL-10-producing B cells and antibody-secreting cells, which demonstrates that plasmablasts/plasma cells can have antibody-independent functions.

Adaptive immunity evolved to deal with the cornucopia of pathogenic microbes that are present in the environment. Randomization of immune receptors and division of labor among highly specialized immune cell subsets were both key steps in the development of an immune system that could distinguish each unique microbial threat in a sea of potential threats. B cells recognize microbial pathogens through a randomly rearranged antigen receptor and begin to produce soluble antibodies that may affect the removal of microbes from the host. B cells can differentiate into long-lived cells that continuously produce antibodies that protect the host from future microbial threats and are capable of tailoring their activity to a specific threat by modifying the type or quality of antibody they produce. In a similar manner, specialized subsets of T cells developed that could seek out and destroy intracellular pathogens that were hidden from antibodies, while yet other subsets of helper cells produce specific cytokines to modulate the humoral and cell-mediated immune responses of the host. This specialization permits the immune system to stock a limited number of sentinel cells that can sense infection and differentiate into a variety of distinct cell lineages individually suited to perform the necessary antimicrobial tasks.

CD4 + T cells are derived from the thymus and activated in the periphery when their T-cell receptors encounter cognate ligands. In response to specific cytokine milieu during T-cell activation, naive CD4 + T cells differentiate into distinct T helper (Th) subsets that secrete unique sets of cytokines. Through cytokine production, activated Th cells orchestrate adaptive immune responses to infectious pathogens, noninfectious environmental agents, and self-antigens. Specific cytokines and transcription factors play critical roles in the development, activation, fate determination, plasticity, and memory generation of heterogeneous Th cell subsets. Abnormality during these processes often leads to immune-related human diseases.

The human immune system is arguably the most complex system in the human body. It is comprised of dozens of completely distinct cell types, each with its own set of signaling molecules, antigen-recognition mechanisms and effector functions. This complexity allows the immune system to respond to the potentially millions of distinct foreign antigens that it might encounter, from bacteria, viruses and other microscopic pathogens, to the body’s own cells when they go awry in diseases such as cancer. This chapter provides an overview of the central cellular architecture of the immune system and describes the ways in which its cells are regulated during the immune response. We are now entering an era in which we have a sufficiently deep understanding of these fundamental regulatory mechanisms that they can be harnessed to provide a highly selective therapeutic strategy for targeting cancer cells.

Once alerted by the innate immune system to the presence of a pathogen or a cellular abnormality, the adaptive immune system responds by activating and expanding antigen-specific B and T lymphocytes. This chapter focuses specifically on the activation and activities of T lymphocytes, which coordinate the adaptive immune response. We open with a description of where and how naive T cells first encounter antigen. We then examine what factors influence the differentiation of helper CD4+ T lymphocytes into one of several effector subsets, each of which secretes a distinct subset of cytokines. We follow with a discussion of the origin and function of cytotoxic CD8+ T cells, the lymphocyte with the capacity to directly kill tumor cells. We close with a brief summary of the unique challenges that face the adaptive immune system when it tried to mount a response to a tumor.

Vitamin A (also called retinol), absorbed in the intestine and stored mainly in the liver and fat, is normally maintained at significant concentrations in the human blood plasma. Vitamin A is constitutively metabolized at high levels in certain tissues such as the small intestine and eyes. Retinoic acid (RA) produced at high levels in the intestine plays important roles in mucosal immunity and immune tolerance. RA at basal levels is required for immune cell survival and activation. During immune responses, enzymes metabolizing vitamin A are induced in certain types of immune cells such as dendritic cells (DCs) and tissue cells for induced production of RA. As a result, induced gradients of RA are formed during immune responses in the body. RA regulates gene expression, differentiation, and function of diverse immune cells. The cells under the influence of RA in terms of differentiation include myeloid cells such as neutrophils, macrophages, and DCs. Also included are lymphoid cells such as effector T cells, regulatory T cells, and B cells. Our current understanding of the function of RA in regulation of these immune cells is reviewed in this chapter.

The immune system responds to cues in the microenvironment to make acute and chronic adaptations in response to inflammation and injury. Locally produced purine nucleotides and adenosine provide receptor-mediated signaling to all bone-marrow derived cells of the immune system to modulate their responses. This review summarizes recent advances in our understanding of the effects of adenosine signaling through G protein-coupled adenosine receptors on cells of the immune system. Adenosine A(2A) receptors (A(2A)Rs) have a generally suppressive effect on the activation of immune cells. Moreover, their transcription is strongly induced by signals that activate macrophages or dendritic cells through toll-like receptors, or T cells through T cell receptors. A(2A)R induction is responsible for producing a gradual dissipation of inflammatory responses. A(2A)R activation is particularly effective in limiting the activation of invariant NKT (iNKT) cells that play a central role in acute reperfusion injury. A(2A) agonists have clinical promise for the treatment of vaso-occlusive tissue injury. Blockade of A(2A) receptors may be useful to enhance immune-mediated killing of cancer cells. A(2B)R expression also is transcriptionally regulated by hypoxia, cytokines, and oxygen radicals. Acute A(2B)R activation attenuates the production of proinflammatory cytokines from macrophages, but sustained activation facilitates macrophage and dendritic cell remodeling and the production of acute phase proteins and angiogenic factors that may participate in evoking insulin resistance and tissue fibrosis. A(2B)R activation also influences macrophage and neutrophil function by influencing expression of the anti-inflammatory netrin receptor, UNC5B. The therapeutic significance of adenosine-mediated effects on the immune system is discussed.

The gastrointestinal immune system is in constant contact with gut luminal antigens and commensal bacteria. It has two major seemingly contradictory missions: (1) protect the intestine from pathogens but (2) induce immune tolerance to commensal bacteria and food antigens. The barrier function provided by epithelial cells and their products such as mucus secretion and antibacterial peptides serves as the first line of defense to prevent infection. The intestinal tract has highly organized lymphoid tissues such as Peyer’s patches and the mesenteric lymph node to surveillance pathogens in the intestine. The intestinal immune system develops immune tolerance to harmless antigens by producing suppressive cytokines and regulatory metabolites, which induce regulatory cells to suppress immune responses. The gut immune system recognizes pathogens with specialized receptors for pathogen-associated molecular patterns. Upon detection of pathogens, the intestinal immune system chooses to mount effective immune responses by activating immune effector cells such as innate immune cells, macrophages, eosinophils, mast cells, T cells, and B cells. Intestinal T and B cells express gut-homing receptors to migrate into the intestine. These lymphocytes fight pathogens through antigen-specific immune responses. Uncontrolled immune responses to harmless gut antigens can cause inflammatory bowel disease and food allergy. Vitamin A metabolites and short-chain fatty acids provide gut tissue-specific signals important for regulation of both immunity and tolerance.

T cells contribute to defense against ocular pathogens by recognizing pathogen proteins processed into peptides and presented by the major histocompatibility complex on the cell surface. CD8+ T cells are primarily lytic effectors, whereas CD4+ T cells primarily prod0uce cytokines, which orchestrate immune responses by inducing immunoglobulin heavy chain class switching in B cells, and by activating innate immune cells to promote inflammation. Immunosuppressive molecules within the eye normally attenuate T-cell responses to prevent tissue damage caused by inflammation. However, certain ocular pathogens induce T-cell responses that break this ocular immune privilege causing blinding immunopathology.

The past 30 years have witnessed enormous insights into the cellular and molecular mechanisms that contribute to immune privilege in the eye. Among these is the generation of dynamic immunoregulatory processes that downregulate immune-mediated inflammation in the eye. These processes uniformly employ T regulatory cells that prevent the induction and expression of immune responses that inflict antigen-nonspecific injury to ocular tissues while preserving immune processes that do not adversely affect innocent bystander cells. Although much is known about the inductive phase of ocular T regulatory cells, much remains to be learned about the mechanisms that these cells use to suppress immune-mediated inflammation.

Type I interferon (IFN), as its name implies, ‘interferes’ with virus replication by activating numerous genes. Further, virus-induced type I IFN regulates the magnitude and functions of cells directing the host immune system. Importantly, recent exploration into how type I IFN operates following virus infection has advanced our understanding of its role with respect to modulation of host innate and adaptive immune responses. Such activities include the activation of antigen-presenting dendritic cells and the localization, expansion or differentiation of virus-specific T lymphocytes and antibody-producing B lymphocytes. However, type I IFN not only benefits the host but can also induce unnecessary or extremely pathogenic immune responses. This review focuses on such interactions and the manner in which type I IFN induces dynamic changes in the host immune network, particularly adaptive immune responses to viral invasion. Manipulating the type I IFN-mediated host immune response during virus infections could provide new immunotherapeutic interventions to remedy viral diseases and implement more effective and sustainable type I IFN therapy.

Publisher Summary First messengers are natural extracellular ligands that bind and activate receptors, which are subdivided as hormones, neurotransmitters, cytokines, lymphokines, growth factors, chemoattractants, etc. Each of these terms attempts to define a class of agents that take effect in a particular setting. Hormones are commonly released in small amounts at sites remote from the organs they target. On entering the circulation, they are diluted enormously and are subject to enzymes that break them down. Many of them circulate as complexes with specific binding proteins, reducing their free concentration still further. The result of all this is that their level in the vicinity of a target cell is likely to be extremely low and accordingly, the cell receptors must possess high affinity. Also, unlike hormones, the effects of growth factors are short range, generally influencing the growth and function of neighboring cells. Neurotransmitters are also first messengers, but their release and detection at chemical synapses contrast strongly with that of endocrine signals. This chapter highlights the fact that in addition to the transcriptional actions of hydrophobic messengers, there is increasing evidence for non-transcriptional effects, which take place rapidly and involve interactions with cell surface receptors. They include cAMP, Ca2+, diacylglycerol, and the 3-phosphorylated inositol lipids. The binding of ligands, measurement of their binding affinity, and heterogeneity of binding have also been discussed later in this chapter.

Cell-mediated immunity, which encompasses T-cell responses, plays a principal role bringing viral infections under control. T cells accomplish this by elaborating effector functions, such as the production of chemokines and cytokines, which can have direct as well as indirect antiviral effects, and also assist in regulating the overall immune response. Certain effector T cells can kill virus-infected cells through cell-to-cell contact and in this way provide an important means of destroying the host's cells which serve as the production sites of progeny virus. Cell-mediated immune responses are not only effective during acute phase of viral infections but also establish long-lived immunological memory. These memory T cells become rapidly activated if they re-encounter virally infected cells and therefore function to protect against secondary exposures to the original viral pathogen. Although many viral infections are cleared from the host, certain viruses can persist indefinitely following infection. In these instances T-cell responses often bring about some level of initial containment of the infection and operate to control the infection at a steady-state level over time. Cell-mediated immune responses during viral infections are not always beneficial as they can cause damage to host tissues which manifests as immunopathology.

Publisher Summary This chapter provides a framework for understanding how the immune response is altered in favor of forming a suppressive network in the tumor microenvironment, integrating different immune cell types and molecules. To induce tumor immunity, sufficient numbers of functional antigen-presenting cells (APCs) are required in situ, and they must be able to capture, process, and present the tumor-associated antigens (TAAs). APCs are also required to migrate to secondary lymphoid organs, and then stimulate the TAA-specific T cells. The TAA-specific T cells must then dwell to the tumor, recognize TAA on the tumor cells, and eradicate the tumor cells. The tumor microenvironment presents an arsenal of active immune imbalances, including an imbalance of the mature versus immature dendritic cells (DCs), stimulatory versus inhibitory B7 family molecules, and regulatory versus conventional T cells. The pathological interaction between the tumor and host immune system results in formation of a “tolerance network” through establishing these irregular immune balances in the tumor environment.

This chapter describes the molecular and cellular components involved in the specific immune response. It starts with explaining the evolutionary aspects, especially the “common roots” of many structural elements that underlay both the nervous system and the immune system. After describing the immunoglobulin superfamily members and their duplication in the evolution, the work addresses the issue of the milieu of the immune response and the nature of the immunogens, especially the wide-ranging spectrum of epitopes. The work portrays the primary antibody response, involvement of B and T cells, antigen processing, antigen presentation, activation of T cells, formation of B cell–T cell conjugates, and the clonal expansion of B cells. Details of the antibody response (including the repertoires of antibody) are given, and special attention is paid to isotype switch and affinity maturation. Thereupon the secondary immune response and formation of memory is explained, and also the processes of induction and maintenance of tolerance, anergy, and apoptosis are given. Besides the T-dependent responses, also responses not requiring T cell help, specific cytotoxic responses as well as involvement of regulatory T cells (Tregs) are portrayed. This chapter does not address the innate immune response (nor the field of Toll-like receptor family) that is left to another chapter(s) of this volume.

Publisher Summary Iron—dithiocarbamates are a class of compounds that scavenge NO in vitro and in vivo. Iron—dithiocarbamates appear to have unique attributes as well: besides scavenging NO they were found to have anti-inflammatory and immunosuppressant properties. This chapter reviews the experimental evidence for the role of NO in cardiac allograft rejection with special emphasis on the protective action of iron—dithiocarbamates. The expression of inducible nitric oxide synthase (iNOS) has been implicated in graft rejection. Despite caveats of certain experimental designs, the role of iNOS in cardiac rejection has been investigated by a broad range of pharmacological and gene deletion strategies. The pharmacological strategies concentrate on either inhibition of NOS enzyme activity or on scavenging and neutralizing nitric oxide (NO). Acute rejection of solid organ grafts involves a complex array of inflammatory mediators. Among leading candidates for these mediators are lymphokines, cytokines, and NO derived from iNOS.

Natural killer (NK) cells are CD56+CD3- large granular lymphocytes that constitute a key component of the human innate immune response. In addition to their potent cytolytic activity, NK cells elaborate a host of immunoregulatory cytokines and chemokines that play a crucial role in pathogen clearance. Furthermore, interactions between NK and other immune cells are implicated in triggering the adaptive, or antigen-specific, immune response. Interleukin-2 (IL-2) and IL-15 are two distinct cytokines with partially overlapping properties that are implicated in the development, homeostasis, and function of NK cells. This review examines the pervasive effects of IL-2 and IL-15 on NK cell biology, with an emphasis on recent discoveries and lingering challenges in the field.

Publisher Summary The immune system has developed to be highly specialized and effective in eradicating a wide variety of pathogens with minimum immunopathology. The adaptive arm of the immune response, consisting of antigen-specific T and B cells, interacts with cells of the innate immune system to mediate an effective response to infectious pathogens. Heterogeneity of T cell responses to pathogens can determine the resistance or susceptibility of a host to such infectious agents. T helper 1 cells have been also implicated in animal models of organ-specific autoimmune diseases, such as multiple sclerosis and insulin-dependent diabetes, as well as chronic inflammatory diseases, including inflammatory bowel disease.

Several lines of evidence from recent years support the existence of cancer immunosurveillance, especially studies of natural killer (NK) cells and the IFN-gamma pathway. However, immune suppression is clearly observed in cancer patients and tumor-bearing animals as well. The fact is that although cancers often elicit a vigorous immune response during the early part of their growth, the immune response is soon down-regulated, permitting progressive tumor growth. Apparently, the intrinsic plasticity of tumors allows the immune system to sculpt the immunogenic phenotypes of tumors to escape efficient immune destruction. But most evidently, several mechanisms have now been found to contribute to the failure of immune control of tumor growth. Tumor cells have a very low level of MHC class II, costimulatory molecules, and weak antigens. They also produce immune suppressive factors (VEGF, IL-10, PGE(2)) that exert systemic effects on immune cell function. In particular, disabled dendritic cell differentiation, maturation, migration, and function are fundamental to this defect, as they are the most potent antigen-presenting cells (APCs) of the immune system, interacting with T and B lymphocyte as well as NK cells to induce and modulate immune responses. In addition, tumors also alter host hematopoiesis and produce large numbers of immature dendritic cells, and evidence shows that these cells are directly immune suppressive. Harnessing the immune system for effective cancer therapy has remained a great challenge. DC-based vaccines, or DC-based vaccines in combination with treatments designed to improve the host immune environment, may offer hope for more effective cancer immunotherapy. Tumor-host interactions are an important determinant of tumor behavior and response to therapy. How tumors interact with their hosts is thus a very broad and complex topic. In this chapter, we will focus on tumor-host immune interactions and the roles of dendritic cell dysfunction in tumor avoidance of host immune responses. We will survey recent findings regarding tumor immune surveillance, antitumor host immune responses, and how the immune system also functions to promote or select tumor variants with reduced immunogenicity. We will then discuss immune suppression caused by tumors, which is clearly observed in tumor-bearing animals and cancer patients. Finally, we will discuss altered dendritic cell function and differentiation in some detail, as it is likely to be one of the most fundamental mechanisms by which tumors escape immune responses.

This chapter discusses about cytokines and chemokines. Cytokines are soluble proteins or glycoproteins produced by leukocytes or other types of cells. They serve as chemical communicators from one cell to another. Cytokines include monokines, synthesized by macrophages and lymphokines produced by activated T cells and natural killer cells. Chemokines are molecules that recruit and activate leukocytes and other cells at the sites of inflammation. They comprise a family of pro-inflammatory activation-inducible cytokines, previously referred to as members of SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, platelet factor-4 superfamily, or intercrines. There are two groups of chemokines: those that mainly activate neutrophils are the α-chemokines (C-X-C chemokines); and those that activate monocytes, lymphocytes, basophils, and eosinophils are designated β-chemokines (C-C chemokines). The biological activities of chemokines are mediated by specific receptors and also by receptors with overlapping ligand specificities that bind several of these proteins, belonging either to the CC chemokines or the group of CXC chemokines. Other functions of cytokines are to regulate the expression of matrix metalloproteinases (MMP), including activating medically important enzymes such as angiotensin-converting enzyme, enkephalinase, and collagenase.

This chapter provides an overview of cytokines, which evolved from four originally independent sources. The first source is immunology and, more specifically, the field of lymphokine research. The second source of cytokine research derives from the study of the interferons. The third source of cytokine research is the field of hematopoietic growth factors: colony-stimulating factors. In addition to promoting the growth and differentiation of hematopoietic stem cells, colony stimulating factors have shown to regulate some functions of fully differentiated hematopoietic cells, thus blurring the dividing line between these agents and lymphokines / monokines, and the fourth source of cytokine research derives from the study of growth factors acting on nonhematopoietic cells. The beginnings of lymphokine research are usually traced to the demonstration that migration of normal macrophages is inhibited by material released from sensitized lymphocytes upon exposure to antigen. The putative factor responsible for this action was termed macrophage migration inhibitory factor (MIF). Among the lymphokines a central role in the regulation of T cell growth and function is played by interleukin- 2 (IL-2). The first monocyte/macrophage-derived cytokine described were tumor necrosis factor (TNF), and lymphocyte activation factor (LAF), now known as interleukin-1 (IL- 1). Many proteins that can stimulate the growth of non-hematopoietic cells have been identified. Best known among these are epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factors (FGF), and vascular endothelial growth factors (VEGF).

This chapter discusses interleukin (IL)-7, which is an important lymphopoietin that plays a critical role in both B- and T-cell development. IL-7 promotes expansion of T lymphocytes exhibiting antigen-specific reactivity. IL-7 may be implemented to promote strong and effective immune responses against tumor cells, or directed against microbial or viral infections. It may also be useful in reconstituting an effective, and functional immune system after bone marrow transplantation, or helping to design novel strategies for immune reconstitution in patients with cancer or with HIV infection. IL-7 serves as the major growth and differentiation factor for both thymic and extrathymic development of γ∂ + T lymphocytes. IL-7 promotes immune effector functions in T lymphocytes, natural killer (NK) cells and mono-cytesmacrophages, and modulates the quantity and quality of immune responses in vitro and in vivo .

Publisher Summary Both T cells and B cells express the β 2 -adrenergic receptor (AR) and bind norepinephrine that is released within lymphoid organs. Norepinephrine plays a role in modulating the activity of CD 4 + T cells and B cells participating in an immune response against antigen. This role of norepinephrine in regulating T and B cell activity needs to be fully understood because antibodies preserve well-being by defending against bacteria, viruses, and allergens and cytokines provide help to B cells, allowing the B cell to differentiate and thus secrete antibodies of particular isotypes. Given the importance to the host of having T cells and B cells that function optimally, it is likely that the mechanisms regulating and modulating these functions are varied and interrelated. For example, it is necessary to understand how products released from the hypothalamic-pituitary-adrenal axis, at the same time norepinephrine is released by sympathetic nerve terminals within lymphoid organs, affect immune cell function. An understanding of the mechanism by which the sympathetic nervous system (SNS) modulates the level of cytokines and antibody produced enables the development of therapeutic approaches for treating and preventing changes in the immunocompetent state of persons experiencing any disease that involves an alteration in either the nervous or the immune system function.

A remarkable immune property of the hormone/cytokine prolactin (PRL) is its ability to modulate the cytotoxic activity of natural killer (NK) cells. This effect is observed with purified CD56+ cell populations stimulated by PRL or with peripheral blood mononuclear cells (PBMC) stimulated by PRL plus suboptimal concentrations of IL-2. The effect of PRL on NK cells can be referred to: i) increased proliferation of the γ/δ TCR positive NK subpopulation (CD16+CD3+), ii) increased release of IFN-γ, which acts as a potent autocrine maturation factor for lymphokine activated killers (LAK) and iii) activation of IRF-1, which regulates transcription of perforin, one of the effectors molecules of cell-mediated cytotoxicity. Modulation of MHC-restricted cytotoxic T lymphocytes (CTL) by PRL has recently been described. Acquisition of antigen presenting capabilities by monocytes is increased by physiological PRL in conjunction with GM-CSF, which results in increased IFN-γ response of T lymphocytes to alloantigen. IFN-γ release and cytotoxicity of CTL-sensitized in vitro against the tumor associated carcinoembrionic antigen (CEA) are also potentiated by the same concentrations of PRL. As a general trend, both NK cell mediated and MHC-restricted cytotoxicities are inhibited by high concentrations of PRL, so is Th1 cytokines production. CEA positive tumors produce PRL, which does not seem to be necessary for autocrine growth stimulation. It is tempting to speculate that by producing excess PRL the tumor hampers the local host tumor defense, thus creating a microenvironment favourable to its undisturbed growth.

Publisher Summary The pulmonary immune system is constantly exposed to pathogens within the inhaled air; therefore, it becomes essential for the system to determine whether an antigenic molecule represents a hazard or not. Under normal conditions, most infectious agents or foreign antigenic materials do not signal to the host and are processed without requiring an inflammatory response. It is only when infectious burden becomes dangerous that the pulmonary accessory cells process and expose the antigen to T lymphocytes so that the required action is taken. This chapter reviews current concepts on the recruitment, homing, and activity of lymphocytes in the lower respiratory tract. The chapter highlights the activity pattern shown by lung T cells in response to immunological challenges in addition to explaining relevant abnormalities detected in B, T, and natural killer cells in asthma and chronic obstructive pulmonary disease (COPD). Antigen-specific lung lymphocytes have evolved a number of effector mechanisms to respond to foreign antigens, ranging from direct cytotoxicity mechanisms to the secretion of lymphokines that have the ability to activate themselves or other pulmonary immunocompetent cells.

The functional interaction between the immune and neuroendocrine system is mediated by humoral mediators, cytokines, neurotransmitters, and hormones. Indeed, the immune response is accompanied by homeostatic changes in the neuroendocrine system. The neuroendocrine changes produced by T-cell independent antigens are very different from those produced by T-cell dependent antigens. Several lines of evidence indicate that prolactin (PRL) and thyrotrophin releasing hormone (TRH) play important roles in T-cell dependent immune responses. This review focuses on the immunoregulatory functions of PRL, which is required for the induction of T-cell dependent immune response.

Publisher Summary The role of chemokines in hematopoiesis was first recognized with the discovery of a factor produced by macrophages that inhibited in vivo colony-forming unit-spleen (CFU-S) and in vitro CFU-A colony formation. Production and differentiation of hemato-lymphopoietic cells and the organization of these cells into a functional immune system depend critically on the anatomy of bone marrow, thymus, and secondary lymphoid tissues. The chemokine system is being recognized as an essential element in recruiting and retaining cells within the anatomic compartments, where the cellular interactions occur that are necessary for immune cell development and for mounting an effective immune response. Also, the positioning of cells in response to chemokines can serve as the event that initiates lymphoid organ formation. The roles of chemokines in cell migration have also been discussed in this chapter. It is also possible that chemokines serve directly to enhance cell–cell adhesion and activation that is important for immune cell differentiation and/or function. Increasing attention is now being paid to how multiple components co-operate at the level of the immune system and the organism as a whole to provide for host defense. The chemokine system serves not only to orchestrate the effector responses during inflammation, but also to support immune cell production and organize the structures on which the immune response depends.

Publisher Summary Cytokines are extracellular signaling proteins, produced by different cell types and involved in cell-to-cell interactions. They affect closely adjacent cells and function mainly in paracrine fashion. Lymphokines form the most important class of cytokines involved in immunological mechanisms. Particular subsets of CD4 T cells may be induced preferentially, secreting defined patterns of cytokines and resulting in the initiation and propagation of distinct immune effector mechanisms. Other classes of cytokines include chemokines and growth factors. The effects of cytokines are mediated by binding to cell-surface high affinity receptors, which can be upregulated with cell activation. The receptors for many cytokines are grouped into superfamilies based on the presence of common homology regions. An analysis of cytokines in asthma and chronic obstructive pulmonary disease (COPD) from the separate studies available reveals different profiles, pathophysiologies, and initiating mechanisms for these two conditions. However, recent observations indicate an overlap of some of cytokines contributing equally in these conditions.

Publisher Summary Epidemiologic data convincingly demonstrate risk for atherosclerotic disease associated with bacterial infection and endotoxin; however, the independent contributions to disease and pathogenic mechanisms of endotoxin remained elusive. Further investigation into this relation tested the correlation between endotoxin and neopterin, and indicated that neopterin functions as effect modifying factor on the effects of endotoxin. Until now, interferon-y could not be associated with atherosclerosis risk. Since neopterin is the typical product of immune-activated macrophages, with interferon-y as principal stimulatory agent, it may well be that this lymphokine gives rise to the array of effects that chronic infections impart in atherogenesis. Synergistic effects of interferon-y and endotoxin on atherosclerosis- related hemostasis have been observed by many scientists.

Publisher Summary This chapter discusses the central and peripheral tolerance in the T-cell population and self-tolerance in the B-cell population. The understanding of tolerance induction in lymphocyte subpopulations is exponentially advanced in the generation of T- and B-cell receptor transgenic mice. Initial contradictions that seem to appear as different transgenic models are published and have given way to overall consensus; at least as far as central tolerance induction in the thymus is concerned. The first direct demonstration for the elimination of potentially autoreactive cells in the thymus came from studies of the T-cell repertoire to endogenous superantigens. T cells bearing Vβ segments that conferred binding to endogenous mouse mammary tumor viruses (Mtv) were absent from mice carrying these superantigens in their genome. One mechanism of deletion is terminal differentiation to short-lived effector cells that may die by apoptosis because of lymphokine depletion. The latter mechanism could be prominent for CD8 T cells. The activation of T cells requires at least two signals: a signal through the T-cell receptor and a second signal presumed to involve a co-stimulatory molecule(s) on an antigen-presenting cell.

Studies of the biology of the IL-2 receptor have played a major part in establishing several of the fundamental principles that govern our current understanding of immunology. Chief among these is the contribution made by lymphokines to regulation of the interactions among vast numbers of lymphocytes, comprising a number of functionally distinct lineages. These soluble mediators likely act locally, within the context of the microanatomic organization of the primary and secondary lymphoid organs, where, in combination with signals generated by direct membrane-membrane interactions, a wide spectrum of cell fate decisions is influenced. The properties of IL-2 as a T-cell growth factor spawned the view that IL-2 worked in vivo to promote clonal T-cell expansion during immune responses. Over time, this singular view has suffered from increasing appreciation that the biologic effects of IL-2R signals are much more complex than simply mediating T-cell growth: depending on the set of conditions, IL-2R signals may also promote cell survival, effector function, and apoptosis. These sometimes contradictory effects underscore the fact that a diversity of intracellular signaling pathways are potentially activated by IL-2R. Furthermore, cell fate decisions are based on the integration of multiple signals received by a lymphocyte from the environment; IL-2R signals can thus be regarded as one input to this integration process. In part because IL-2 was first identified as a T-cell growth factor, the major focus of investigation in IL-R2 signaling has been on the mechanism of mitogenic effects in cultured cell lines. Three critical events have been identified in the generation of the IL-2R signal for cell cycle progression, including heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These proximal events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. One intriguing outcome of the IL-2R signaling studies performed in cell lines is the apparent functional redundancy of the A and H regions of IL-2R beta, and their corresponding downstream pathways, with respect to the proliferative response. Why should the receptor complex induce cell proliferation through more than one mechanism or pathway? One possibility is that this redundancy is an unusual property of cultured cell lines and that primary lymphocytes require signals from both the A and the H regions of IL-2R beta for optimal proliferative responses in vivo. An alternative possibility is that the A and H regions of IL-2R beta are only redundant with respect to proliferation and that each region plays a unique and essential role in regulating other aspects of lymphocyte physiology. As examples, the A or H region could prove to be important for regulating the sensitivity of lymphocytes to AICD or for promoting the development of NK cells. These issues may be resolved by reconstituting IL-2R beta-/-mice with A-and H-deleted forms of the receptor chain and analyzing the effect on lymphocyte development and function in vivo. In addition to the redundant nature of the A and H regions, there remains a large number of biochemical activities mediated by the IL-2R for which no clear physiological role has been identified. Therefore, the circumstances are ripe for discovering new connections between molecular signaling events activated by the IL-2R and the regulation of immune physiology. Translating biochemical studies of Il-2R function into an understanding of how these signals regulate the immune system has been facilitated by the identification of natural mutations in IL-2R components in humans with immunodeficiency and by the generation of mice with targeted mutations in these gen