Current Immunology Reviews (v.8, #1)

As we have mentioned in previous editorials, Current Immunology Reviews has continued to focus on basic immunology andthe interface with clinical immunology and immunopathology. The original research reviews published by CIR in recent yearshas been a great testament to the success of our efforts. However, in the past two years we also launched a more coordinatedeffort in this regard with the publishing of assembled reviews organized around timely Hot Topics in basic and clinicalimmunology. There have been several of these collections of articles around fascinating topics that could not easily be coveredby single articles. The resulting Hot Topics collections are remarkable examples of how well a series of complementary articlesaround 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 andcomplexity of these clinical immunology issues. In this respect, our Hot Topic initiative places CIR in an important role in theimmunology literature.In this first issue of the year, we have two prime examples of how the Hot Topics collections have succeeded. Dr. Hiroto Kitahas brought together a series of articles on dendritic cells in the liver, and their role from early development to immunemediatedpathology and finally to potential immunotherapy. The liver is such a remarkably critical organ in the immune systemdespite not being commonly classified as one of the primary lymphoid tissues; it is a locus for early hematopoietic stem cellgrowth, and also is a site where incredibly potent immunoregulatory mechanisms operate. The articles in this collection give usinteresting 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 witha series of articles that provide us with stories on ever more surprising connections between the immune system and nervoussystem functions. The articles here go well beyond the basic issues of immune system regulation of infection and inflammationin 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 ofautoimmune disease. While rituximab gains more notice for its potential in several immune-mediated diseases, it also points toan expanding appreciation for the central role of B lymphocytes in immune effector functions and regulation. Perhaps we arebeginning 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 beevident, I am impressed and excited by the diversity of fascinating articles submitted to CIR, especially the Hot Topics. As theyused 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 cytokinesecretion patterns found there. These intrahepatic lymphocytes are presumably selected and adopted for unique immunologicalfunctions. The hepatic immune system can respond to and eliminate pathogenic microorganisms, and toxins. Infection of theliver by pathogenic macroorganisms is identified and prompt immune response elicited to clear the infectious agents. At thesame time, the liver is considered the least immunogenic among transplanted organs. Clearly, the immune response must beregulated locally within the liver in a unique way. Dendritic cells can capture and transfer information from the outside world tothe cells of the adoptive immune system. They are critical for induction of primary immune responses and also important forthe 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 ontogenicdevelopment to cell-based immune therapy. Shu et al. have addressed the ontogenic development and population dynamics ofhepatic dendritic cells. They stressed the importance of heterogeneity of DC subsets for better understanding of the diversefunctions of these cells in the liver. HBV and HCV infection is a major cause of end-stage liver disease as well ashepatocellular carcinoma. Persisting hepatitis virus infection reflects unstable balance between tolerance and immunity toinfected 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 ofhepatic dendritic cells.The exact role of dendritic cells in the pathogenesis of autoimmune liver disease is not completely clear, but these cells areinvolved in the initiation and progression of autoimmune processes. Abe et al. have tried to overview the role of dendritic cellson autoimmune liver disease, including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangisits, andIgG4 related sclerosing cholangisits. Although pathogenesis of these four diseases are still an enigma, potential therapeuticstrategy are also discussed in this paper. Finally, Akbar et al. described recent advancement for therapeutic application of DCbasedtherapy. This field is one of the most attractive one because DC-based therapy potentially included the alteration ofskewed immunological response in each liver disease. Although full understanding of DC immunology in the liver is still inprogress, the use of DC-based immunotherapy shows great promise toward the resolution of chronic inflammatory response inthe liver.

Ontogenic Development and Population Dynamics of Hepatic Dendritic Cells by Shang-an Shu, Hong-Di Ma, Zhe-Xiong Lian (3-11).
Dendritic cells (DCs) are rare, bone marrow-derived antigen-presenting cells (APCs) characterized by a uniquecapacity to stimulate naïve T cells and initiate primary immune responses. The special immunological microenvironmentin the liver is associated with the induction of tolerance to dietary food antigens, and yet, it maintains the capacity tosustain effective responses against pathogens. Recent studies have provided data to elucidate the critical roles that DCsplay in the induction of central and peripheral immunological tolerance, in regulating the types of T cell immuneresponses, and functioning as sentinels in innate immunity against microbes in the liver. The diverse functions of hepaticDCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here, we reviewrecent progress in our understanding of the ontogenic development, the population dynamics, and the functional plasticityof 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 pervasiveimmune cell dysfunction, but not fully compromised, is a hallmark of chronic HBV or HCV infection, of whichfundamental mechanisms are yet to be clarified. Dendritic cells (DC) as immune sentinels sense virus via toll-likereceptors (TLR) or retinoic acid inducible gene-I (RIG-I) and evoke a cascade of immune reactions by secreting cytokinesor by interacting other lymphocytes. Reduced and disabled DC potentially give negative impact on adjacent cells, such asNK cells, NKT cells and T cells. However, lack of evidence for active viral replication in DC or blood cells imply thepresence of undisclosed contrivances that are independent of infection. Successful treatment of chronically infectedpatients with anti-viral agents is accompanied with numerical and/or functional restoration of DC, suggesting that DCcould serve as potential therapeutic targets. Further studies are warranted for the establishment of therapeutic DC vaccinein order to gain more vigorous and sustained virus-specific immune responses. Cross talk between DC and lymphocytesare thus critical in shaping innate and subsequent adaptive immune responses against hepatitis virus, either spontaneouslyor therapeutically.

Dendritic Cells in Autoimmune Liver Diseases by Masanori Abe, Yoichi Hiasa, Morikazu Onji (23-27).
Dendritic cells (DC) are professional antigen presenting cells that maintain immune tolerance to self-antigensby controlling the pathogenicity of autoreactive T cells, and a lack of immune tolerance against self-antigens results inautoimmune diseases. Therefore, DCs play an essential role in the induction and/or maintenance of autoimmunity. In thepresent review, we focus on the role of DCs in the pathogenesis of autoimmune liver diseases. In addition, recentdevelopments in DC-based immunotherapy using regulatory (tolerogenic) DCs in autoimmune diseases will be discussed.

Dendritic Cell-Based Immune Therapy in Liver Diseases by Sheikh Mohammad Fazle Akbar, Yoichi Hiasa, Mamun Al-Mahtab, Morikazu Onji (28-36).
The field of immune therapy is currently undergoing a shift in focus, from non antigen-specific immunemodulator-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 antigensto T cells. By culturing DCs with viral antigens or tumor-associated antigens or different cellular products, immunogenicor tolerogenic DCs can be produced. When antigen-pulsed DCs are administered, an increase in the functional capacitiesof cells of innate immune system is observed. Also, patients administered with antigen-loaded DCs exhibit anaugmentation of helper T cells, cytotoxic T cells, and plasma cells activities. Patients with liver diseases exhibit distortedimmune responses to invading pathogens or cancer cells or autoantigens. On the other hand, recovery from liver diseasesis usually associated with restoration of host immunity. In this review, we would discuss about rationale and strategies ofimmune 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 dataincreasingly implicate insomnia as a predictor of cardiovascular and non-cardiovascular disease mortality, particularly in agedpeople. It is already accepted that persons deprived of sleep are more susceptible to infections, and that infectious porcessesseem to increase somnolence. In the review by Dr. Cardinali, the reciprocal influences of sleep and the immune system havebeen evaluated. Specifically, this review addresses whether the immune system causes changes in sleep, and whether sleepmight have a role in the modulation of the immune system with possible consequences for disease risk. Finally, the multipleorgan dysfunction syndrome (MODS) in which disordered sleep and disordered immune function co-occur has beenconsidered, providing strong evidences for a role of sleep in the regulation of the immune system and possibly in mediatingincreases 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 andimmune components and an anti-inflammatory and/or immunotherapeutic approach might be considered. Although it hasbecome increasingly recognized that inflammation may be important in the neuropathological damage that occurs in AD, unlikeMS the inflammation in AD seems to arise from inside the central nervous system (CNS) with little or no involvement oflymphocytes 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 asecondary response to early accumulation of Amyloid beta (A

Modulation of Apoptosis in Acute Ischemic Stroke as Treatment Challenges by Joaquin Jordan, Laura Moreno-Parrado, David Anton-Martinez, Kurt A. Jellinger, Maria F. Galindo (39-49).
Stroke is a major cause of death and disability throughout the world. Its pathophysiology is complex andincludes excitotoxity, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis and other cell deathmechanisms, angiogenesis, and neuroprotection. The ultimate result of the complex ischemic cascade is neuronal deathwith irreversible loss of neuronal functions. New developments in stroke pathophysiology have induced significantadvances in acute stroke management. Among the extracellular signals, inflammation, microglia and cytokines as majorconsequences of hypoxia may be targets for future therapies. Among the intracellular signals, calcium-induced cell deathand oxidative stress as most important factors of ischemic cell death and for dysfunctions of the blood-brain barrier areimportant goals for neuroprotective agents. Third messengers, like p53, peroxisome proliferator-activated receptors andnuclear factor kappa-B (NF-kB) also play important roles in the pathogenesis of ischemic cell death, and may be furtherimportant targets of modern neuroprotective agents. The final stage of ischemic cell death via apopotosis and other celldeath cascades, mainly influenced by energy deficiency and mitochondrial dysfunction may be influenced byantiapoptotic and other strategies as potential new targets for designing newer and more successful therapeutic modalitiesof acute ischemic stroke.

Sleep and the Immune System by Daniel P. Cardinali, Ana I. Esquifino (50-62).
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 systemresponse. This review discusses the physiological basis of such a control of the immune system at different sleep stages, as wellas the manner in which humoral signals (cytokines) produced by immunocompetent cells modify the mechanisms of sleep.

Obesity as a Model of Premature Immunosenescence by Monica De La Fuente, Nuria M. De Castro (63-75).
With aging the neuroendocrine-immune communication suffers an impairment, which explains the alteredhomeostasis and the resulting increase of morbidity and mortality. Since the aging process is very heterogeneous, thebiological age determines the level of aging experienced by each individual and therefore his/her life expectancy. We haveproposed several immune functions as markers of biological age and predictors of longevity, as well as the keyinvolvement of the immune system in the rate of aging modulating oxi-inflamm-aging. This has been confirmed in severalmurine models of premature aging of neuroimmunomodulation such as poor response to stress, anxiety, depression or lossof estrogens. In the present article we summarize knowledge of the obesity and immune system and suggest that obesesubjects, compared to non-obese of the same chronological age, are prematurely aged. Thus, we show some datasupporting the hypothesis that obesity is a model of premature immunosenescence.

Immune Disturbances in Chronic Pain: Cause, Consequence or Both? by Vladimir Maletic, Charles L. Raison (76-86).
This review discusses the role of aberrant neuroimmune functioning in chronic pain disorders. Like othernegatively-valenced emotions, pain activates a complex adaptive response that includes endocrine, autonomic andimmune components. When appropriate, this response re-establishes homeostasis. However, in the context of chronic paindysregulated immune, autonomic and endocrine responses contribute to peripheral and central sensitization, a phenomenaemblematic of chronic pain. Excessive neuroimmune interactions in the vicinity of nociceptors and in dorsal root gangliaaugment peripheral pain-related transmission. These amplified peripheral signals are associated with increasedimmune/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 contributeto structural alterations in pain-processing brain areas. Lastly, aberrant immune activation also participates indysfunctional descending pain regulation. The role of the immune system as a meta-homeostatic entity that coordinatesinteractions of emotion- and stress-modulating brain circuitry with endocrine and autonomic systems is discussed in somedetail. We emphasize the importance of neuroimmune mechanisms not only in the genesis but also in treatment of chronicpain.

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

Rituximab Therapy and Autoimmune Disease by Asha Ram Yadav, Nirmala Deo (94-100).
In recent years, advances in our understanding of the regulation of the immune system have enabled theidentification of cellular and molecular targets that could affect the pathogenesis of many autoimmune diseases. B-cellsplay pivotal role in autoantigen presentation and in autoantibody production. Thus, rituximab (RTX), a chimericmonoclonal antibody specific for human CD20, which targets B lymphocytes, could be a potential new biologicaltreatment for autoimmune diseases. The aim of this mini review is to discuss the potential use of RTX in the managementof autoimmune disorders. Results from early phase clinical trials indicates that RTX therapy may provide clinical benefitin systemic lupus erythematosus, Sjogren’ syndrome, thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritisand myasthenia gravis. So, it is concluded that RTX therapy alone/or in combinations with corticosteroids, is likely toprovide an important new treatment option for a number of difficult to treat autoimmune diseases.