Current Immunology Reviews (Discontinued) - Volume 6, Issue 4, 2010

This issue covers scientist-knowledge from different disciplines such as: immunology, neuroscience, endocrinology, pharmacology, psychiatry, biochemistry, oncology and infectology. Increasing research recognizes the importance of integrating and/or overlapping this borderline areas. Papers reflect advances in detailed immunological areas, like the impact of different variables on specific humoral, cellular and molecular events, that take place over the course of autoimmune, inflammatory, neural and endocrine responses and infection diseases. Also, manuscripts presented in this volume, indicate a clearly immunomodulatory role of thyroid hormones, gonadal hormones in addition to the glucocorticoids. The recognition of defects in cells of the innate system of aged individuals and the understanding of their consequences will help in the development of better therapeutic strategies for the elderly is analyzed. More emphasis is placed on the immunomodulatory role of neurotransmitter autoantibodies in immunophatological mechanisms. Furthermore, the molecular mechanism of action of sympathetic, parasimphatetic and histaminergic mediators are studied at increasing detailed levels, to gain understanding in the role that, second messengers, such as nitric oxide, prostaglandins, cGMP, cAMP and cytokines play in the transduction of their effects. The very innovative and interesting modulatory role of immune system in central cognitive processes (learning and memory), also has a place in this issue. Moreover, the range of diseases in which neural - immune mechanism are being studied has greatly expanded, from non traditional autoimmune diseases such as schizophrenia, depression and diabetes. Elucidation of immunological and inflammatory factors in the pathogenesis of this illnesses are in deep detailed in the present issue. In this context, recent evidence has shed light to an emerging role of protein-glycan interactions in the regulation of immune cell biology; and we integrate traditional and novel subsets of immune cells and will highlight the relevance of protein-glycan systems in modulating their physiology. Indeed, this issue represents a beginning of integration of immunology with other disciplines. Here, papers reflect studies of molecular mechanism, pharmacological and endocrine pathways to clinical relevant immune interaction, in health and diseases.

Schizophrenia affects 1% of the world's population, but its cause remains obscure. Numerous theories have been proposed regarding the etiology of schizophrenia, ranging from neurodegenerative, autoimmune processes, neurotransmitter abnormalities to inflammation. Here, we propose an integrative view of autoimmune processes and neurotransmitter dysregulation in schizophrenia. We focus on the role of serum autoantibodies against cerebral muscarinic cholinergic receptors (mAChR) as a neuroimmune factor in the etiology of schizophrenia. We describe the presence of circulating antibodies from patients with paranoid schizophrenia, that interact with mAChRs of cerebral frontal cortex neural and glial cells. The antibodies can inhibit irreversible binding of the specific mAChR radioligand. We have demonstrated with synthetic peptides that these autoantibodies react against the second extracellular loop of human neural M1 mAChR and glial M2 mAChR. Also, the corresponding affinity-purified anti-peptide antibody displays an agonisticlike activity that is associated with specific M1 and M2 receptor activation. We have established that anti-mAChR autoantibodies appear to interpose in crosstalk between neurons and glia, and therefore, could be involved in negative/positive symptoms or inflammatory abnormalities associated with schizophrenia. M1 or M2 mAChR activation by autoantibodies can give conflicting messages. Chronic autoantibody fixation on postsynaptic neuronal M1 mAChR results in receptor downregulation, uncoupled to Gq protein, which stabilizes phospholipase C activity, and interferes with cognitive function (including attention, learning and memory) and alters neuronal plasticity, which causes negative symptoms. On the contrary, the antibody fixation on. presynaptic glia M2 mAChR inhibits the agonist action determined that the glia loss the negative control on excitatory neurotransmitter release (dopamine and glutamate). Therefore, the antibodies could induce loss of glial physiological buffering function, which causes differential exposure to positive symptoms. Furthermore, the antibody with agonistic activity on glial M1 mAChR contributes to neuro-inflammatory activity, which triggers the production of NO (Nitric Oxide), PGE2 (Prostaglandin E2) and MMP-3 (Metalloproteinase-3) via induction of COX-1(Ciclooxygenase-1) and iNOS(inducible Nitric oxide syntase) gene expression and activity. We have evidence that supports the hypothesis that alteration of the immune system is involved in the pathogenesis of schizophrenia, and that muscarinic receptors could represent promising novel targets for the treatment of the disease.

It is surprising that despite the prevalence of prostate disease, little is known about the immunobiology of the prostate and its contribution to disease. The prostate is the target of many diseases like infection of the prostate gland, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), benign hyperplasia and cancer. In this review we will focus on the relationship of the immune system with the prostate gland in two different scenarios: in the first one, the question of how prostate epithelial cells deal with inflammatory stimuli, like microorganisms, is addressed. Whereas the role of infiltrating innate immune cells like macrophages and neutrophils in prostate inflammation has been extensively studied, the particular contribution of prostate epithelial cells to an inflammatory setting has barely been investigated. Prostate epithelial cells can act as early sensors of infection, expressing Toll like receptors, the best well known innate immune receptors. Thus they become sentinels of the prostate gland, like the epithelial cells of other internal organs. The way these cells respond to infection up-regulating pro-inflammatory mediators is discussed. This topic is of particular interest since chronic inflammation has been postulated to be an important driving force to prostate carcinoma. In the second scenario, the situation in which the prostate gland becomes a target of an autoimmune response is analyzed. Chronic inflammatory prostate disease of noninfectious origin seems to be a good example of this situation, since at least 30% of the patients suffering from CP/CPPS exhibited IFN-γ-secreting, proliferating lymphocytes against prostate antigens such as prostatic acid phosphatase (PAP), prostate specific antigen (PSA), and other antigens present in prostate homogenates and seminal plasma. We have dissected the immunological mechanisms that are involved in these patients and in experimental models of autoimmune prostatitis as well as analyzed its consequences on the fertility of these patients.

More than three decades ago, screening for autoantibodies associated with immune mediated type 1A diabetes was limited to measuring antibodies to cytoplasmic antigens of islet cells (ICAs). After a period of identification and sequencing of the major autoantigens involved (insulin, glutamic acid decarboxylase and tyrosine phosphatase IA-2) the recombinant technology allowed the quasi-quantitative assessment of the respective specific autoantibodies (IAA, GADA and IA-2A). In addition, the beta-cell-specific zinc transporter isoform 8 (ZnT8) has recently emerged as another major autoantigenic target of type 1 diabetes. The first useful assay for measuring islet autoantibodies was an indirect immunofluorescence assay with frozen sections of human pancreas as substrate. Other methods for the determination of islet autoantibodies (markers) are the radioligand binding assay (RBA) and ELISA. The current fluid phase RBA utilizes low levels of tracers, usually labeled with 125I, 35S-methionine or 35S-cysteine. After a series of international workshops and proficiency programs starting in 1985, the first Diabetes Antibody Standardization Program (DASP) was run in 2000. The predictive value of markers assays was shown in several series of prospectively followed first-degree relatives of type 1 diabetes patients. On the other hand, islet autoimmunity is frequent in adult patients considered to have type 2 diabetes (Latent Autoimmune Diabetes of Adults, LADA). The presence of autoantibodies in such patients may forecast the need of insulin administration, thus sparing these patients from months of inadequate metabolic control. Signals above a cutoff value were usually employed as the criterion for marker positivity, whereas in other studies determination of titer, epitope specificity, and IgG subclass were included to improve diabetes prediction. Recently it was suggested that combining affinity and titer of specific antibodies significantly improves the sensitivity, specificity, and concordance of markers measurement between laboratories. These new contributions on stratification of type 1 diabetes risk on the basis of markers characteristics will be invaluable in the design, implementation and interpretation of multicenter intervention trials. Moreover, marker testing is likely to be increasingly used in clinical practice, and may need to be performed in nonspecialized laboratories.

Tuberculosis (TB) accounts for an increasing morbidity and mortality across the world. Approximately 8.8 million new TB cases emerge and 1.6 million people die of this disease every year. Host defense against microbial pathogens involves an inflammatory reaction in which innate and adaptive immune mechanisms play an active role in its development. When the pathogen cannot be contained by the initial response, as usually occurs in TB, a systemic response characterized by multiple metabolic and neuroendocrine changes develops. Essential functions like defensive responses and metabolism are regulated by a series of molecules with pleiotropic effects, like pro-inflammatory cytokines, adrenal steroids, and adipocytokines; which affect both the regulation and/or redirectioning of energy sources and immune activity. Patients with TB, frequently displaying a consumption state, and their highly exposed close-household contacts (HHC) constitute “natural models” for analyzing this type of immune-endocrine-metabolic relation. We have shown the existence of an immune-endocrine imbalance in TB patients characterized by increased circulating levels of IFN-γ, IL-6, prolactin, thyroid hormones, cortisol, and growth hormone, accompanied by decreased concentrations of leptin and DHEA, and without significant differences in insulin-like growth factor-1. In contrast HHC coursing a latent subclinical infection, showed a modest decrease of DHEA in presence of increased amounts of leptin. In vitro studies showed that culture supernatants from M. tuberculosis-stimulated PBMC of TB patients inhibited DHEA secretion by a human adrenal cell line. It was also found that the unbalanced immune-endocrine relation of TB patients was associated to the weight loss they presented, which in turn accounted for the impairment on their specific in vitro cellular immune responses. The host response during TB results in an altered immune-endocrine communication, affecting essential biological functions, like the development of protective responses, control of tissue damage and metabolism, implied in a poorer disease course.

X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency characterized by hypogammaglobulinemia, fulminant infectious mononucleosis, and/or lymphoma associated to mutations of the SH2D1A gene, encoding SAP (signaling lymphocytic activation molecule-associated protein). The initial encounter with Epstein Barr virus (EBV) triggers a massive response that leads to a fatal outcome in around 50% of the XLP individuals. Most surviving patients develop hypogammaglobulinemia and eventually B cell lymphoma. B lymphocyte development seems to be normal, but there is a marked reduction of memory B cells (CD27+ B lymphocytes). In addition, Th1 cell mediated immune responses predominate over Th2 responses. Hypogammaglobulinemia and failure to develop a long term humoral immune response can be explained because both the germinal center (GC) reaction and GC formation in secondary lymphoid organs are greatly impaired both in human XLP and in experimental SAP deficiency. Non switched memory B cells (IgM+, IgD+, CD27+ B lymphocytes) persist in XLP patients, suggesting that in spite of the lack of a GC reaction, some subgroups of memory B lymphocytes can play a role in immune homeostasis in these patients. In addition, their persistence in the presence of EBV infection, could perhaps be associated to late occurrence of extranodal B-cell lymphoma, which is another pathological condition associated to the absence of SAP in humans.

Cumulative evidence indicates that aging exerts significant effects on the immune system, with a rise in the frequency and severity of infections, and a diminished protection occurring after vaccination. Age-related changes in the adaptive immune response have been well established but the alterations taking place in the innate immune response and its regulation by immune modulators are not well understood. This review examines the current knowledge about the way aging affects the function of several cells of the innate immune system. In particular, this review will focus on dendritic cells and macrophages and their contributions to the changes in the immune system during aging. Furthermore, this review will analyse how the response to Toll-like receptors is affected during aging. The recognition of defects in cells of the innate immune system of aged individuals and the understanding of their consequences will help in the development of better therapeutic strategies for the elderly.

The interaction between the immune and the neuroendocrine systems involves, in a bidirectional circuit, shared cellular receptors and their coupled signaling pathways. Disruptions of this circuit lead to pathological situations. Between the endocrine factors, thyroid hormones show to play a role in immunomodulation, maintaining immune system homeostasis in response to stress-mediated immunosuppression. Several experimental evidences showed that hypothyroidism leads to a depression of humoral and cell-mediated immune responses, effects that were reversed by restoration of the euthyroid state. By other hand, chronic stressful situations impair T-cell mediated immunity, affecting the intracellular signals involved in lymphocyte activation. Consequently, a reduction in both T-cell dependent antibody production and lymphocyte function were also described. Besides, a decrease in thyroid hormone serum levels was observed in these conditions. These stress-induced endocrine-immune alterations impact in tumor development, as an enhancement of tumor growth was described in animal models of chronic stress. Interestingly, hormone replacement treatment of chronic stressed animals, which restored the euthyroid status, reversed the observed reduction of T-cell responses improving the outcome of tumor bearing animals. These evidences strengthen the important role that thyroid hormones play in immunomodulation, with a special emphasis in their participation as neuroendocrine regulators of stress-mediated immune deficit.

The immune system has evolved as a highly effective and dynamic cellular network to signal the presence of invading pathogens and growing tumors and initiate a response that is specific for the danger signal; yet maintaining tolerance to self. In the recent years, data from genomics, proteomics and glycomics together with classical genetic approaches (knockout and transgenic experiments) and in vivo imaging technologies revealed a complexity of immune cells and molecules which is higher than anticipated. The diversity of effector and regulatory immune cells is entering a new era, in which their specialization might contribute to the development of novel therapeutic approaches in immunopathology. In this context, recent evidence has shed light to an emerging role of protein-glycan interactions in the regulation of immune cell biology. In this review we will integrate traditional and novel subsets of immune cells and will highlight the relevance of protein-glycan systems in modulating their physiology.

Since histamine discovery in 1910, it has been recognized as a major mediator in gastric acid secretion and inflammation that is a main pathophysiological characteristic of allergy. For many years, drug development and therapeutic application of histamine antagonists were mainly focused on the allergic and gastrointestinal diseases. At present, it is one of the monoamines (2-(imidazol-4-yl)ethylamine) with the broadest spectrum of activities in various physiological and pathological situations. Thus, it has been shown to be involved in aminergic neurotransmission and numerous brain functions including learning, memory, sleep/wakefulness, locomotor activity, nociception, food intake, secretion of pituitary hormones, and regulation of gastrointestinal and circulatory functions, as well as modulation of immunity and hematopoiesis. A significant body of research has contributed to the elucidation of the functional capacities of histamine in tumor cell growth and development. Evidences for multiple cellular sources of histamine, the discovery of a novel histamine receptor (H4R) and the demonstration of a histamine-cytokine cross-talk have modified the perspective which suggests new potential therapeutic uses of histamine and its receptor ligands. The involvement of histamine in cancer immunotherapy has been a subject of interest for more than a decade. Histamine dihydrochloride is being safely used in clinical trials as an adjuvant for the potential treatment of different cancers, improving efficacy by increasing survival benefit and exhibiting no unexpected or irreversible side effects. Interleukin-2 and interferon-alpha have been used as therapeutic options for the treatment of certain malignancies such as metastatic malignant melanoma, myelogenous leukemia, renal cell carcinoma and chronic hepatitis C. Combination therapy with histamine has two key advantages over cytokine therapy alone, namely improved cytotoxicity against a greater range of cancer types, and improved quality-of-life as a consequence of lower dose administration of the cytokines. Furthermore, radiation therapy is a well recognized treatment modality for cancer. Although effective, adverse effects due to radiotherapy are unavoidable, even with localized delivery techniques. Regardless of many years of research, there are surprisingly few radiation protectors in use today, whose clinical use is limited due to their toxicity; thus, the development of effective and nontoxic agents is yet a challenge for oncologists and radiobiologists. We have recently reported that histamine significantly protects two of the most radiosensitive tissues, small intestine and bone marrow, from high doses of radiation. In addition, histamine has the ability to prevent functional and histological alterations of salivary glands exerted by ionizing radiation. These features make histamine a suitable candidate for its use as an adjuvant for cancer immunotherapy and also as a selective radioprotector for patients undergoing radiotherapy. In the present review we aimed to briefly summarize some general notions on histamine functions before focusing on some recent evidence supporting the novel role of histamine in the immune function and the potential application as an adjuvant to tumor immunotherapy and radiotherapy.

Glucocorticoid (GCs) hormones have pleiotropic activities in the body playing important roles in metabolism and modulating/regulating the stress and immune responses. Upon stimuli that trigger immune or inflammatory responses there is a concomitant activation of the hypothalamus-pituitary-adrenal axis ultimately manifested by an increase in the synthesis and release of GCs to the systemic circulation. GCs play a pivotal role in the interface between the neuroendocrine and immune systems by modulating the final outcome of the immune response. The successful resolution of an immune response depends on the fine tune interplay between GCs and cytokines. The interaction between intracellular signals elicited by cytokines and the activated glucocorticoid receptor (GR) results in the induction or repression of gene transcription coordinating an effective immune response, and then its resolution avoiding excessive deleterious reactions. Herein, we describe recent knowledge regarding basic research in the complex interaction between GCs and components of the immune system at cellular and molecular levels, as well as their clinical implications for health and disease. The benefits of therapeutic GCs controlling immune disorders as well as their misconduct are also discussed in terms of considering the benefits and adverse effects to control disease and inflammation.

The definition of Natural Killer (NK) cells has undergone dramatic modification with the advance of immunological research tools. NK cells can no longer be classified only as indiscriminate killer innate immune cells. NK cells are now known to form functional relationships with accessory cells to shape and promote the adaptive immune response. Recently, antigen specific and cytokine induced memory NK cells have been demonstrated to exhibit the characteristic phases of an adaptive immune cell, including extended persistence and robust function in response to reexposure. New findings in basic NK immunobiology indicate that the role of NK cells is underappreciated and these cells may potentially be manipulated for the development of anti-viral therapies.