Current Immunology Reviews (Discontinued) - Volume 8, Issue 1, 2012

As we have mentioned in previous editorials, Current Immunology Reviews has continued to focus on basic immunology and the interface with clinical immunology and immunopathology. The original research reviews published by CIR in recent years has been a great testament to the success of our efforts. However, in the past two years we also launched a more coordinated effort in this regard with the publishing of assembled reviews organized around timely Hot Topics in basic and clinical immunology. There have been several of these collections of articles around fascinating topics that could not easily be covered by single articles. The resulting Hot Topics collections are remarkable examples of how well a series of complementary articles around a single theme can provide multiple perspectives and a more comprehensive compilation of studies on the topic at hand. In my own case I would say that these collections have given me a much greater appreciation of the significance and complexity of these clinical immunology issues. In this respect, our Hot Topic initiative places CIR in an important role in the immunology literature. In this first issue of the year, we have two prime examples of how the Hot Topics collections have succeeded. Dr. Hiroto Kita has brought together a series of articles on dendritic cells in the liver, and their role from early development to immunemediated pathology and finally to potential immunotherapy. The liver is such a remarkably critical organ in the immune system despite not being commonly classified as one of the primary lymphoid tissues; it is a locus for early hematopoietic stem cell growth, and also is a site where incredibly potent immunoregulatory mechanisms operate. The articles in this collection give us interesting perspectives on this topic as well as provide an outlook for future studies. A second example is one of my favorite topics, Neural-Immune system interactions. Dr. Valter Lombardi has provided us with a series of articles that provide us with stories on ever more surprising connections between the immune system and nervous system functions. The articles here go well beyond the basic issues of immune system regulation of infection and inflammation in the nervous system. This issue is also fortunate to have an article on a very timely topic, the expanding role of rituximab therapy in the treatment of autoimmune disease. While rituximab gains more notice for its potential in several immune-mediated diseases, it also points to an expanding appreciation for the central role of B lymphocytes in immune effector functions and regulation. Perhaps we are beginning to pull back just a bit from the popular T cell-centric view of the immune system! In sum, I look forward to watching CIR move ahead in the coming year with even more interesting articles. As should be evident, I am impressed and excited by the diversity of fascinating articles submitted to CIR, especially the Hot Topics. As they used to say, keep the cards and letters coming!

The liver is rich in the diversity of its lymphocyte populations, with multiple phenotypes, cytotoxic activities, and cytokine secretion patterns found there. These intrahepatic lymphocytes are presumably selected and adopted for unique immunological functions. The hepatic immune system can respond to and eliminate pathogenic microorganisms, and toxins. Infection of the liver by pathogenic macroorganisms is identified and prompt immune response elicited to clear the infectious agents. At the same time, the liver is considered the least immunogenic among transplanted organs. Clearly, the immune response must be regulated locally within the liver in a unique way. Dendritic cells can capture and transfer information from the outside world to the cells of the adoptive immune system. They are critical for induction of primary immune responses and also important for the regulation of the cell-mediated immune responses as well as the induction of immunological tolerance. In this issue, the role of dendritic cells of the liver and liver disease is carefully reviewed by four experts from ontogenic development to cell-based immune therapy. Shu et al. have addressed the ontogenic development and population dynamics of hepatic dendritic cells. They stressed the importance of heterogeneity of DC subsets for better understanding of the diverse functions of these cells in the liver. HBV and HCV infection is a major cause of end-stage liver disease as well as hepatocellular carcinoma. Persisting hepatitis virus infection reflects unstable balance between tolerance and immunity to infected hepatocytes, due to an initially ineffective immune response to hepatocytes that express viral antigens. Kanto et al. have tried to overview many aspects of immunological response in HBV as well as HCV infection focusing on the role of hepatic dendritic cells. The exact role of dendritic cells in the pathogenesis of autoimmune liver disease is not completely clear, but these cells are involved in the initiation and progression of autoimmune processes. Abe et al. have tried to overview the role of dendritic cells on autoimmune liver disease, including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangisits, and IgG4 related sclerosing cholangisits. Although pathogenesis of these four diseases are still an enigma, potential therapeutic strategy are also discussed in this paper. Finally, Akbar et al. described recent advancement for therapeutic application of DCbased therapy. This field is one of the most attractive one because DC-based therapy potentially included the alteration of skewed immunological response in each liver disease. Although full understanding of DC immunology in the liver is still in progress, the use of DC-based immunotherapy shows great promise toward the resolution of chronic inflammatory response in the liver.

Dendritic cells (DCs) are rare, bone marrow-derived antigen-presenting cells (APCs) characterized by a unique capacity to stimulate naïve T cells and initiate primary immune responses. The special immunological microenvironment in the liver is associated with the induction of tolerance to dietary food antigens, and yet, it maintains the capacity to sustain effective responses against pathogens. Recent studies have provided data to elucidate the critical roles that DCs play in the induction of central and peripheral immunological tolerance, in regulating the types of T cell immune responses, and functioning as sentinels in innate immunity against microbes in the liver. The diverse functions of hepatic DCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here, we review recent progress in our understanding of the ontogenic development, the population dynamics, and the functional plasticity of DCs in the liver.

Hepatitis B or C virus (HBV or HCV) causes chronic liver diseases that eventually progress to liver cancer. Both viruses are armed with multiple machineries for modulating immune responses in infected hosts. Mild and pervasive immune cell dysfunction, but not fully compromised, is a hallmark of chronic HBV or HCV infection, of which fundamental mechanisms are yet to be clarified. Dendritic cells (DC) as immune sentinels sense virus via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I) and evoke a cascade of immune reactions by secreting cytokines or by interacting other lymphocytes. Reduced and disabled DC potentially give negative impact on adjacent cells, such as NK cells, NKT cells and T cells. However, lack of evidence for active viral replication in DC or blood cells imply the presence of undisclosed contrivances that are independent of infection. Successful treatment of chronically infected patients with anti-viral agents is accompanied with numerical and/or functional restoration of DC, suggesting that DC could serve as potential therapeutic targets. Further studies are warranted for the establishment of therapeutic DC vaccine in order to gain more vigorous and sustained virus-specific immune responses. Cross talk between DC and lymphocytes are thus critical in shaping innate and subsequent adaptive immune responses against hepatitis virus, either spontaneously or therapeutically.

Dendritic cells (DC) are professional antigen presenting cells that maintain immune tolerance to self-antigens by controlling the pathogenicity of autoreactive T cells, and a lack of immune tolerance against self-antigens results in autoimmune diseases. Therefore, DCs play an essential role in the induction and/or maintenance of autoimmunity. In the present review, we focus on the role of DCs in the pathogenesis of autoimmune liver diseases. In addition, recent developments in DC-based immunotherapy using regulatory (tolerogenic) DCs in autoimmune diseases will be discussed.

The field of immune therapy is currently undergoing a shift in focus, from non antigen-specific immune modulator-based immune therapy to antigen-based vaccine therapy to more sophisticated cell-based vaccine applications. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to capture, process and present antigens to T cells. By culturing DCs with viral antigens or tumor-associated antigens or different cellular products, immunogenic or tolerogenic DCs can be produced. When antigen-pulsed DCs are administered, an increase in the functional capacities of cells of innate immune system is observed. Also, patients administered with antigen-loaded DCs exhibit an augmentation of helper T cells, cytotoxic T cells, and plasma cells activities. Patients with liver diseases exhibit distorted immune responses to invading pathogens or cancer cells or autoantigens. On the other hand, recovery from liver diseases is usually associated with restoration of host immunity. In this review, we would discuss about rationale and strategies of immune therapy including DC-based therapy in liver diseases.

The high prevalence of insomnia represents a large economical burden to society giving rise to reduced productivity, accidents, behavioural and cognitive consequences, and possibly association with increased disease risk. Epidemiological data increasingly implicate insomnia as a predictor of cardiovascular and non-cardiovascular disease mortality, particularly in aged people. It is already accepted that persons deprived of sleep are more susceptible to infections, and that infectious porcesses seem to increase somnolence. In the review by Dr. Cardinali, the reciprocal influences of sleep and the immune system have been evaluated. Specifically, this review addresses whether the immune system causes changes in sleep, and whether sleep might have a role in the modulation of the immune system with possible consequences for disease risk. Finally, the multiple organ dysfunction syndrome (MODS) in which disordered sleep and disordered immune function co-occur has been considered, providing strong evidences for a role of sleep in the regulation of the immune system and possibly in mediating increases in the risk infectious disease and inflammatory disorders in these populations. Different diseases such as Alzheimer's disease (AD), multiple sclerosis (MS) and stroke have important inflammatory and immune components and an anti-inflammatory and/or immunotherapeutic approach might be considered. Although it has become increasingly recognized that inflammation may be important in the neuropathological damage that occurs in AD, unlike MS the inflammation in AD seems to arise from inside the central nervous system (CNS) with little or no involvement of lymphocytes or monocytes beyond their normal surveillance of the brain. The inflammatory cytopathology (microgliosis, astrocytosis, complement activation, increased cytokine expression and acute phase response), is thought to represent a secondary response to early accumulation of Amyloid beta (Aβ) in the brain. Dr. Cacabelos in his review shows that histamine, a pleiotropic factor, plays a main role in neuroimmune regulation. This biogenic amine shows age- and sex-dependent changes in the CNS, and is significantly altered, together with interleukin 1beta (IL-1β) and tumor necrosis factor alfa (TNF-α), in AD and other neurodegenerative disorders in which neuroinflammation appears to be an aggravating phenotype. Dr. Leszek suggests that a long-term activation of the innate immune system in AD patients might trigger an inflammatory cascade that converges in cytoskeletal alterations like intracellular aggregation of the microtubule-associated protein tau into filamentous inclusions. Because appearance of tau-aggregate bearing lesions correlates with both cognitive decline and neurodegeneration, in this review it has been suggested that novel therapeutic approaches must rely on regulation of endogenous inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies. MS is an inflammatory disease of the CNS characterized by perivascular cuffs of mononuclear cells that include both lymphocytes and macrophages. This infiltration leads to damage of the myelin sheath and the underlying axon. In the initial stages of the disease, inflammation is the prominent process, causing relapsing-remitting MS (RRMS), the most common form of the disease. Dr. Fernandez-Novoa points out the importance of studying the genetic risk for developing MS. In the conclusions she points out that the HLA-DRB1*15 gene appears to be the most important genetic marker for disease susceptibility. Damage to the CNS usually has a much more profound effect on the individual, since brain and spinal cord repair is limited, and persistent functional deficits still remain following disease and injury. Dr. Lombardi analyzes recent strategies used in brain damage repair and tries to answer some basic answers: are stem cells for neurons and glia present in the human CNS? If so, cane they migrate from germinal centres to the sites of injury? Will growth-factor therapy prove to be effective and well tolerated as a means of protecting cells from injury? Can adult CNS be made amenable to axon regeneration? Will the implantation of neurons and glia restore the structure and function of the adult human CNS? Stroke is a major cause of death and disability throughout the world. Its pathophysiology is complex and includes excitotoxicity, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis and other cell death mechanisms, angiogenesis, and neuroprotection. Inflammation plays an important role in the development of atherosclerosis and is increasingly believed to contribute to reperfusion injury and delayed ischemia in the brain after stroke. Evidence is now beginning to emerge that lymphocytes may have a greater and earlier involvement during stroke, opening the door for novel and highly specific targets for diagnosing, management, treatment, and prevention strategies for both stroke and vascular disease. Dr. Jordan has summarized the role of adhesive molecules and inflammatory mediators in different experimental models of cerebral ischemia, their approaches and effects in therapy and neuroprotection, and has critically reviewed recent treatment strategies in the management of acute ischemic stroke. During ageing both neuroendocrine and immune systems are affected and the altered homeostasis contributes to an increase in morbidity and mortality. Dr. De la Fuente suggests that several immune functions can be used as markers of biological age and predictors of longevity. This hypothesis has been confirmed in several murine models of premature aging of neuroimmunomodulation such as poor response to stress, anxiety, depression or loss of estrogens. In this review special attention has been paid on obesity and immune system and it has been suggested that obese individuals compared to normal subjects of the same chronological age, are prematurely aged, supporting the hypothesis that obesity can be considered a model of premature senescence. The review by Dr. Maletic discusses the role of aberrant neuroimmune functioning in chronic pain disorders. Pain activates a complex adaptive response that includes endocrine, autonomic and immune components. When appropriate, this response reestablishes homeostasis. However, in the context of chronic pain dysregulated immune, autonomic and endocrine responses contribute to peripheral and central sensitization, a phenomena emblematic of chronic pain. Excessive neuroimmune interactions in the vicinity are associated with increased immune/inflammatory signalling in the dorsal horn and supraspinal pain-process circuitry, the so-called “pain-matrix”. The role of immune system as a meta-homeostatic entity that coordinates interactions of emotion- and stress-modulating brain circuitry with endocrine and autonomic systems is also discussed. As we learn more about how central nervous and endocrine systems influence immunologically based disorders and how immune system affects CNS functioning, there may be a need to redefine the nature of some diseases, and, thus, develop novel strategies for therapeutic and personalized interventions.

Stroke is a major cause of death and disability throughout the world. Its pathophysiology is complex and includes excitotoxity, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis and other cell death mechanisms, angiogenesis, and neuroprotection. The ultimate result of the complex ischemic cascade is neuronal death with irreversible loss of neuronal functions. New developments in stroke pathophysiology have induced significant advances in acute stroke management. Among the extracellular signals, inflammation, microglia and cytokines as major consequences of hypoxia may be targets for future therapies. Among the intracellular signals, calcium-induced cell death and oxidative stress as most important factors of ischemic cell death and for dysfunctions of the blood-brain barrier are important goals for neuroprotective agents. Third messengers, like p53, peroxisome proliferator-activated receptors and nuclear factor kappa-B (NF-kB) also play important roles in the pathogenesis of ischemic cell death, and may be further important targets of modern neuroprotective agents. The final stage of ischemic cell death via apopotosis and other cell death cascades, mainly influenced by energy deficiency and mitochondrial dysfunction may be influenced by antiapoptotic and other strategies as potential new targets for designing newer and more successful therapeutic modalities of acute ischemic stroke.

From a physiological perspective the sleep-wake cycle can be envisioned as a sequence of three physiological states, identified by a particular homeostatic patent: wakefulness, non-rapid eye movement (NREM) or slow sleep, and REM sleep. These three physiological states are defined by a particular neuroendocrine-immune profile that regulates the immune system response. This review discusses the physiological basis of such a control of the immune system at different sleep stages, as well as the manner in which humoral signals (cytokines) produced by immunocompetent cells modify the mechanisms of sleep.

With aging the neuroendocrine-immune communication suffers an impairment, which explains the altered homeostasis and the resulting increase of morbidity and mortality. Since the aging process is very heterogeneous, the biological age determines the level of aging experienced by each individual and therefore his/her life expectancy. We have proposed several immune functions as markers of biological age and predictors of longevity, as well as the key involvement of the immune system in the rate of aging modulating oxi-inflamm-aging. This has been confirmed in several murine models of premature aging of neuroimmunomodulation such as poor response to stress, anxiety, depression or loss of estrogens. In the present article we summarize knowledge of the obesity and immune system and suggest that obese subjects, compared to non-obese of the same chronological age, are prematurely aged. Thus, we show some data supporting the hypothesis that obesity is a model of premature immunosenescence.

This review discusses the role of aberrant neuroimmune functioning in chronic pain disorders. Like other negatively-valenced emotions, pain activates a complex adaptive response that includes endocrine, autonomic and immune components. When appropriate, this response re-establishes homeostasis. However, in the context of chronic pain dysregulated immune, autonomic and endocrine responses contribute to peripheral and central sensitization, a phenomena emblematic of chronic pain. Excessive neuroimmune interactions in the vicinity of nociceptors and in dorsal root ganglia augment peripheral pain-related transmission. These amplified peripheral signals are associated with increased immune/inflammatory signaling in the dorsal horn and supraspinal pain-processing circuitry, the so-called “pain maitrix”. We focus on the neuron-glia-immune cell junction as the principal processing unit of pain signals in the CNS. Neuroimmune disturbances not only have functional consequences, such as amplified pain signaling, but also contribute to structural alterations in pain-processing brain areas. Lastly, aberrant immune activation also participates in dysfunctional descending pain regulation. The role of the immune system as a meta-homeostatic entity that coordinates interactions of emotion- and stress-modulating brain circuitry with endocrine and autonomic systems is discussed in some detail. We emphasize the importance of neuroimmune mechanisms not only in the genesis but also in treatment of chronic pain.

The Central Nervous System (CNS) is the organ with the least capacity for repair in mammals. Diseases of the CNS may follow developmental deficits, inappropriate environmental factors and acquired damages after maturation. The latter damages may consist of neuronal cell death, like Alzheimer's disease and/or to a lesion of the axon, like in the paraplegic patients. Hopes of obtaining a functional recovery after trauma or neurodegeneration, are very low and clinicians have very low possibilities for therapeutic interventions. The causes of the regenerative block in the adult CNS are only partially attributable to the neural component. Direct or indirect interactions with glial cells, the resident CNS immune cells, and with the extracellular matrix play a crucial role in determining the relative inability of adult CNS connections to be modified: adult neurites find themselves within an environment rich in molecules strongly inhibitory for regrowth and sprouting. A further complication arises from the fact that regenerative processes are always accompanied by an inflammatory reaction with the consequent activation of astrocytes and microglia; this activation alters the properties of the extracellular milieu. Thus, research on post lesional plasticity must not only study the molecular mechanisms active in neurons but also consider the role of glial cells and the extracellular environment.

In recent years, advances in our understanding of the regulation of the immune system have enabled the identification of cellular and molecular targets that could affect the pathogenesis of many autoimmune diseases. B-cells play pivotal role in autoantigen presentation and in autoantibody production. Thus, rituximab (RTX), a chimeric monoclonal antibody specific for human CD20, which targets B lymphocytes, could be a potential new biological treatment for autoimmune diseases. The aim of this mini review is to discuss the potential use of RTX in the management of autoimmune disorders. Results from early phase clinical trials indicates that RTX therapy may provide clinical benefit in systemic lupus erythematosus, Sjogren' syndrome, thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis and myasthenia gravis. So, it is concluded that RTX therapy alone/or in combinations with corticosteroids, is likely to provide an important new treatment option for a number of difficult to treat autoimmune diseases.