Addictive drugs and their relationship with infectious diseases

The use of drugs of abuse, both recreationally and medicinally, may be related to serious public health concerns. There is a relationship between addictive drugs of abuse such as alcohol and nicotine in cigarette smoke, as well as illegal drugs such as opiates, cocaine and marijuana, and increased susceptibility to infections. The nature and mechanisms of immunomodulation induced by such drugs of abuse are described in this review. The effects of opiates and marijuana, using animal models as well as in vitro studies with immune cells from experimental animals and humans, have shown that immunomodulation induced by these drugs is mainly receptor-mediated, either directly by interaction with specific receptors on immune cells or indirectly by reaction with similar receptors on cells of the nervous system. Similar studies also show that cocaine and nicotine have marked immunomodulatory effects, which are mainly receptor-mediated. Both cocaine, an illegal drug, and nicotine, a widely used legal addictive component of cigarettes, are markedly immunomodulatory and increase susceptibility to infection. The nature and mechanism of immunomodulation induced by alcohol, the most widely used addictive substance of abuse, are similar but immunomodulatory effects, although not receptor-mediated. The many research studies on the effects of these drugs on immunity and increased susceptibility to infectious diseases, including AIDS, are providing a better understanding of the complex interactions between immunity, infections and substance abuse.     

Disturbance of human immunohomeostasis by environmental pollution and alcohol consumption

Environmental pollution and consumption of alcohol evoke various immunomodulations promoting the progress of different pathologies. The purpose of this study was to evaluate the influence of alcohol consumption intensity on the immune system functions of humans living in ecologically different regions, i.e. in a district polluted with industrial siftings (Trakai, n = 270) and in a relatively clean district (Sirvintos, n = 250). In the Trakai cohort 96% and in Sirvintos group 89% of persons consumed alcohol. With regard to alcohol consumption habits the immunohaematological indices were investigated in the following four groups: abstinents, light alcohol users, moderate alcohol users and alcohol abusers. We determined the compensatory mechanisms of immune system functions of moderate alcohol users and alcohol abusers in comparison with abstinents in the relatively clean Sirvintos district. In the Trakai district polluted with industrial siftings such compensatory reactions where not found. Thus, damage to the immune system functions is not only an endogenous risk factor for many diseases, but also an indicator of organism injury. This investigation stated, that immunity disturbance in humans depends on alcohol consumption intensity and place of residence.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway

A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol‐related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll‐like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila‐specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster.     

Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis

Ethanol consumption is known to cause significant acute liver damage resulting in hepatic fibrosis and eventual cirrhosis when consumed chronically. The mechanism(s) by which ethanol exerts its damaging effects on the liver are not well understood; however, recent scientific investigation has begun to delineate the earliest events in alcoholic liver disease. From these studies, it is apparent that components of the innate immune system and, in particular, Kupffer cells, play a significant role in this process. It is also becoming clear that other parts of the immune system including T cells may also be responsible for mediating the devastating effects of chronic alcohol consumption on the liver. This review will highlight recent experiments demonstrating a role for the innate immune response in the initiation and progression of alcohol-induced liver hepatitis and subsequent organ damage.     

Immunological responses to semen in the female genital tract

When spermatozoa, seminal plasma and semen extender reach the uterus and interact with local leukocytes and endometrial cells, several immune mechanisms are initiated which have immediate, mid-term and long-term effects on ovulation, sperm cell selection, fertilization and pregnancy success by assuring the acceptance of fetal tissues. This report gives an overview on relevant key immune mechanisms following roughly the time axis after insemination. Detailed knowledge regarding these mechanisms will aid maximizing reproductive efficiency in livestock production. In the future, the many species involved will require a more comparative approach, since evidence is growing that endometrial physiology and the response to varying amounts and compositions of seminal plasma, various semen extenders, and variable numbers of spermatozoa also provoke different immune responses.     

Reduced Contextual Discrimination following Alcohol Consumption or MDMA Administration in Mice

The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.     

Effects of extremely high-frequency electromagnetic radiation on the immune system and systemic regulation of homeostasis

Low-intensity of electromagnetic radiation of extremely high frequencies (EHF EMR) is effectively used in medical practice for diagnostics, prevention and treatment of a broad spectrum of diseases of different etiology. However, in spite of existence of many hypotheses about mechanisms of EHF EMR effects on the molecular and cellular levels of organization of living systems, there is not conception that could explain all diversity of the EHF-therapy effects from unified approach. In our opinion, the problem of determination of mechanisms of EHF EMR effects on living organism is divided into two basic tasks: first, determining subcellular structures which can receive radiation, and, second, studying physiological reactions of the organism which are caused by radiation. It is obviously, that investigation of functions of single cells and subcellular elements can not entirely explain therapeutic effects and mechanisms of EHF EMR influence on multicellular organism on the whole. Plenty of functional relationships between organs and systems of organs should be taken into account. In the present review, a realization of the EHF-therapy effects due to the influence on immune system functions and start of system mechanisms of maintenance of the homeostasis on the organism level is hypothesized. Potential targets for EHF EMR acception on the level of different systems of the organism are analysed. The material is formed so that functional relations between immune system and other regulatory systems (nervous and endocrine systems) are traced.     

Lactational alcohol exposure elicits long-term immune deficits and increased noradrenergic synaptic transmission in lymphoid organs

Increasing evidence suggests that the sympathetic nervous system plays an important role in immunomodulation. While chronic alcohol consumption has been associated with immune deficits, the effects of exposure to alcohol during early postnatal life on subsequent immunocompetence and activity of sympathetic neurons in lymphoid organs are not known. This study examined the long-term effects of lactational alcohol consumption on cellular immune responses and noradrenergic synaptic transmission in lymphoid and other organs of the young adult C57BL/6 mouse. The data show that exposure to alcohol via the mother's milk was associated with long-term deficits in cellular immunity, including suppression of the local graft vs host and contact hypersensitivity responses. The animals also displayed enhanced noradrenergic synaptic transmission and decreased beta-adrenoceptor density selectively in lymphoid organs. These neuroimmune changes are particularly striking since body weight-gain of the suckling pups was normal and their blood alcohol concentration was considerably lower than that of the alcohol-consuming dam. This suggests an increased sensitivity of the nascent immune and nervous systems during the critical period of early postnatal development.     

MFG-E8 and HMGB1 Are Involved in the Mechanism Underlying Alcohol-Induced Impairment of Macrophage Efferocytosis

Efferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.     

The mechanisms for the effects of dietary lipid modification on autoimmune diseases: the role of membrane lipid composition in antigen presenting cells.

Several mechanisms have been proposed to explain the effects of dietary lipid modification on autoimmune diseases. One of these being the modification of cell membranes which affects immune functions. In order to further define this mechanism, the author proposes that dietary lipid modification could affect antigen presentation, an immune function responsible for initiating cell-mediated immune responses in body defense or autoimmune diseases, through membrane lipid composition modification.     

Electromagnetic field effects on cells of the immune system: the role of calcium signaling.

During the past decade considerable evidence has accumulated demonstrating that nonthermal exposures of cells of the immune system to extremely low-frequency (ELF) electromagnetic fields (< 300 Hz) can elicit cellular changes that might be relevant to in vivo immune activity. A similar responsiveness to nonionizing electromagnetic energy in this frequency range has also been documented for tissues of the neuroendocrine and musculoskeletal system. However, knowledge about the underlying biological mechanisms by which such fields can induce cellular changes is still very limited. It is generally believed that the cell membrane and Ca(2+)-regulated activity is involved in bioactive ELF field coupling to living systems. This article begins with a short review of the current state of knowledge concerning the effects of nonthermal levels of ELF electromagnetic fields on the biochemistry and activity of immune cells and then closely examines new results that suggest a role for Ca2+ in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca2+ signaling processes are involved in the mediation of field effects on the immune system.     

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

Dimethyl fumarate (DMF) is an important oral treatment option for various autoimmune diseases, such as multiple sclerosis (MS) and psoriasis. DMF and its dynamic metabolite, monomethyl fumarate (MMF) are the major compounds that exert therapeutic effects on several pathologic conditions in part, through downregulation of immune responses. The exact mechanism of DMF is yet to be fully understood even though its beneficial effects on the immune system are extensively studied. It has been shown that DMF/MMF can affect various immune cells, which can get involved in both the naive and adaptive immune systems, such as T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells. It is suggested that DMF/MMF may exert their effect on immune cells through inhibition of nuclear factor-κB translocation, upregulation of nuclear factor erythroid-derived 2(E2)-related factor antioxidant pathway, and activation of hydroxyl carboxylic acid receptor 2. In this review, the mechanisms underlying the modulatory functions of DMF or MMF on the main immune cell populations involved in the immunopathogenesis of MS are discussed.     

Neuroimmune mechanisms in fetal alcohol spectrum disorder

Fetal alcohol spectrum disorder (FASD) is a major health concern worldwide and results from maternal consumption of alcohol during pregnancy. It produces tremendous individual, social, and economic losses. This review will first summarize the structural, functional, and behavior changes seen in FASD. The development of the neuroimmune system will be then be described with particular emphasis on the role of microglial cells in the normal regulation of homeostatic function in the central nervous system (CNS) including synaptic transmission. The impact of alcohol on the neuroimmune system in the developing CNS will be discussed in the context of several key immune molecules and signaling pathways involved in neuroimmune mechanisms that contribute to FASD. This review concludes with a summary of the development of early therapeutic approaches utilizing immunosuppressive drugs to target alcohol-induced pathologies. The significant role played by neuroimmune mechanisms in alcohol addiction and pathology provides a focus for future research aimed at understanding and treating the consequences of FASD. ? 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.     

Patients, pathogens, and protective immunity: the relevance of virus-induced alloreactivity in transplantation

Successful transplantation requires the establishment of an ongoing state in which there is simultaneous inhibition of the undesired T cell-dependent rejection response and yet retention of the ability to develop effective cell-mediated primary and memory responses to pathogens. The complexity of attaining such a precarious state is underscored by the growing body of evidence that alloreactivity can be profoundly influenced by infections that occur before, concurrent with, or subsequent to an organ transplant. In this review, we explore the growing list of mechanisms that have been identified by which pathogen-host interactions might influence rejection, including the degeneracy of TCR recognition leading to cross-reactive immune responses, the effects of pathogens on innate immune mechanisms, and the potential impact of virally induced lymphopenia.     

Fetal alcohol syndrome: an assessment of the field

Fetal exposure to alcohol is the major known cause of mental retardation in the Western world. For more than half of the 20th century, the placenta was widely believed to be an effective barrier against environmental agents. The discovery that offspring of pregnant women who were exposed to German measles or administered thalidomide were often malformed raised awareness that teratogens could be any environmental agent, including viruses and drugs, that caused abnormal development. Alcohol was not identified as a teratogen until the 1970s. Fetal exposure to alcohol can cause fetal alcohol syndrome (FAS), which is characterized by specific physical traits and central nervous system dysfunctions. The development of animal model systems has facilitated our study of the effects of fetal alcohol exposure and the elucidation of the mechanisms involved in alcohol-induced abnormal development. Despite our current understanding of the effects of fetal alcohol exposure, the occurrence of FAS and associated fetal alcohol spectrum disorders is still widespread and the associated health-care costs are staggering. This symposium provides an up-to-date analysis of fetal exposure to alcohol and FAS. It is directed not only to investigators working in the field but to a diverse group of scientists working in the biological and biomedical fields to stimulate cross-disciplinary awareness, interest, and collaboration.     

Drinking Songs: Alcohol Effects on Learned Song of Zebra Finches

Speech impairment is one of the most intriguing and least understood effects of alcohol on cognitive function, largely due to the lack of data on alcohol effects on vocalizations in the context of an appropriate experimental model organism. Zebra finches, a representative songbird and a premier model for understanding the neurobiology of vocal production and learning, learn song in a manner analogous to how humans learn speech. Here we show that when allowed access, finches readily drink alcohol, increase their blood ethanol concentrations (BEC) significantly, and sing a song with altered acoustic structure. The most pronounced effects were decreased amplitude and increased entropy, the latter likely reflecting a disruption in the birds’ ability to maintain the spectral structure of song under alcohol. Furthermore, specific syllables, which have distinct acoustic structures, were differentially influenced by alcohol, likely reflecting a diversity in the neural mechanisms required for their production. Remarkably, these effects on vocalizations occurred without overt effects on general behavioral measures, and importantly, they occurred within a range of BEC that can be considered risky for humans. Our results suggest that the variable effects of alcohol on finch song reflect differential alcohol sensitivity of the brain circuitry elements that control different aspects of song production. They also point to finches as an informative model for understanding how alcohol affects the neuronal circuits that control the production of learned motor behaviors.