Gender Differences in Immune Responses Literature Review

Gender Differences in Immune Responses Literature Review ORDER NOW FOR CUSTOMIZED AND ORIGINAL ESSAY PAPERS ON Gender Differences in Immune Responses Literature Review I don’t understand this Biology question and need help to study. A review paper on immunology needs to be done based on these 5 papers. The topic is gender differences in immune responses so basically these are the 5 papers I’ve chosen and it also has to be a minimum of 2000 words. Gender Differences in Immune Responses Literature Review fd28e_ade8_4715_86f2_5f5f4c1adb0b.pdf a3_35ae_4007_b503_da2e44a24e72.pdf e50c5b04_1e1b_4a43_9e06_170635e0a7bd.pdf e22eb8_a185_4552_9eee_f48a12fd89cc.pdf b0783c2c_7e41_4e96_a6f3_d7f58f1c50d9.pdf Influence of Alcohol and Gender on Immune Response Elizabeth J. Kovacs, Ph.D., and Kelly A.N. Messingham, Ph.D. Decades of research have shown that women’s and men’s immune systems function differently. During the reproductive years, women have a stronger immune response than men. This gender difference is believed to be controlled by differences in the blood levels of gonadal steroid hormones—including the female hormone, estrogen, which stimulates immune responses, and the male hormone, testosterone, which is immunosuppressive. In both males and females, alcohol exposure suppresses immune responses; however, it is unclear whether there are significant gender differences in this suppression. Chronic exposure to alcohol alters the production of this same set of hormones (i.e., estrogen and testosterone), and hence alcohol’s effects on immunity could involve an indirect mechanism in which alcohol alters hormone levels and, in turn, the hormones regulate immune responses. This article discusses evidence that these hormonal changes play a role in the regulation of the immune response following alcohol exposure in males and females. In addition, the article considers the possible reasons why it takes less time and lower doses of alcohol exposure to cause liver damage in females than in males. K EY WORDS : immune response; gender differences; chronic AODE (alcohol and other drug effects); alcoholic beverage; hormones; estrogens; testosterone; cytokines; alcoholic liver disorder; literature review C linical and experimental research has demonstrated naturally occurring gender differences in immune response, but the reasons for these differences have yet to be determined. This article examines alcohol’s effects on the immune systems of both genders and the differential effects of alcohol on males’ and females’ immune responses. It then discusses whether alcohol-induced changes in stress hor­ mones and in gonadal steroid hormones such as estrogen and testosterone are suf­ ficient to trigger the observed defects in immune response and to explain gender differences in alcohol-induced immune suppression. Finally, the article considers the reasons why women are at higher risk than men of developing liver disease at any given level of alcohol intake. Vol. 26, No. 4, 2002 Alcohol and Immune Responses An overwhelming amount of evidence reveals that both acute and chronic alcohol exposure suppresses all branches of the immune system, including early responses to infection and the tumor surveillance system (for reviews, see Cook 1998; Diaz et al. 2002; Nelson and Kolls 2002; Messingham et al. 2002). For example, there is a decrease in the ability to recruit and activate germ-killing white blood cells (Deaciuc 1997; Szabo et al. 1999) and an increase in the incidence of breast cancer in peo­ ple who consume alcohol (WarnerSmith et al. 1998; Zhang et al. 1999). Some experts suspect that alcohol exerts an “all-or-none” effect on immune response—that is, the presence or absence of alcohol, rather than its amount, dictates the immune response (McGill et al. 1995; Messingham et al. 2002). Other researchers believe that low doses ELIZABETH J. KOVACS, PH.D., is director of the Alcohol Research Program and a professor in the Departments of Cell Biol­ ogy, Neurobiology and Anatomy, and Surgery, Loyola University Stritch School of Medicine, Maywood, Illinois. KELLY A.N. MESSINGHAM, PH.D., is a postdoctoral research fellow in the Department of Microbiology, University of Iowa, Iowa City, Iowa. This work was supported in part by the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism grants AA–12034 and AA–12034–S1, and the Illinois Excellence in Academic Medicine Grant. 257 of alcohol—the amount equivalent to a glass of wine—can confer health benefits, including protection against damage to the cardiovascular (Holman et al. 1996) and immune systems (Mendenhall et al. 1997). Gender Differences in Immune Responses Literature Review Such benefits, if they are present, may be attributable to antioxi­ dants in alcoholic beverages such as red wine. In any case, health experts agree that the beneficial effects of antioxidants in some alcoholic beverages are lost if the level of alcohol consumption is elevated (Hanna et al. 1992). There are several mechanisms by which alcohol impedes immune func­ tion. First, alcohol impairs the ability of white blood cells known as neutrophils to migrate to sites of injury and infection, a process called chemotaxis (Bautista 2001). (See the sidebar for a general description of how the immune system works, pp. 261–262) In addition, removing germfighting white blood cells (macrophages) and proteins that act as messengers between immune cells (cytokines) from an animal that has not been given alcohol and culturing them in the presence of alcohol, or isolating these cells from humans or animals after administering alcohol, has been shown to alter produc­ tion of these macrophages and cytokines (Deaciuc 1997; Szabo 1998; Szabo 1999). Rodent studies also show that ani­ mals are more vulnerable to infection after chronic or acute exposure to alco­ hol (Deaciuc 1997; Cook 1998; Mess­ ingham et al. 2002). This increase in susceptibility is equally dramatic in human patients who sustain traumatic injury (Smith and Kraus 1988; Brezel et al. 1988). Those who have consumed alcohol prior to their injury are six times more likely to die than are alcoholfree patients with comparable injuries (McGill et al. 1995). The mechanisms responsible for this increased mortality are unknown, but it is thought that alcohol compromises the immune sys­ tem’s ability to quickly fight infection by unidentified invaders—a function of the innate immune system (Faunce et al. 1997; Cook 1998; Messingham et al. 2001). 258 Gender Differences in Immune Response Following Alcohol Exposure To date, only a handful of studies have directly examined gender differences in the effects of alcohol on inflammatory and immune responses (Grossman et al. 1993; Spitzer and Zhang 1996a,b; Lee and Rivier 1996; Li et al. 1998; Spitzer 1999; Spitzer and Spitzer 2000). These studies were conducted in rodents and employed different methods, including varying the quantity and duration of alcohol exposure. These reports show that in the absence of alcohol exposure, inflam­ matory and immune responses are stronger in females than in males (Grossman et al. 1993; Spitzer and Zhang 1996a,b; Spitzer 1999). However, the increased immunity in females is nullified by alcohol exposure. For example, in one study, proliferation of white blood cells was suppressed in alcohol-exposed female rats (Grossman et al. 1993); however, investigation also showed that alcohol induced an increase in antibody produc­ tion. In two other studies, female rats were less able to fight infection when intoxicated (Spitzer and Zhang 1996b; Li et al. 1998). The mechanisms driving these effects remain uncertain. One possibility is that gender differences in inflammatory and immune responses following alcohol exposure stem from alcohol-induced changes in the pro­ duction of gonadal steroid hormones, such as estrogen and testosterone. In general, estrogen stimulates immune responses and testosterone is immunosuppressive (Grossman 1989; Morell 1995; Cannon and St. Pierre 1997; Verthelyi 2001; Burger and Dayer 2002). Gender Differences in Immune Responses Literature Review During their reproductive years, females have more vigorous cellular and humoral immune responses than do males (see the sidebar for a description of these two types of immune response). This heightened immunity in females is evidenced by a more developed thymus,1 higher antibody concentrations, and a greater ability to reject tumors and transplanted tissues. Ironically, the enhanced immune function in women of repro­ ductive age is associated with a higher prevalence of autoimmune disorders than is found in postmenopausal women or in men.2 The effects of alcohol on production of the gonadal steroid hormones are well documented (Van Thiel et al. 1987; Gavaler and Van Thiel 1992; Gavaler et al. 1993; Gill 2000; Emanuele and Emanuele 2001). In women, chronic alcohol exposure causes an initial increase in estrogen levels, followed by a marked decrease (Gavaler and Van Thiel 1992; Gavaler et al. 1993). In men, chronic alcohol consumption causes a decrease in testosterone (Emanuele and Emanuele 2001). The alcohol-induced decrease in testosterone levels is significant enough to cause shrinkage (atrophy) of the testes, impotence, and loss of secondary sex characteristics (Van Thiel et al. 1987). Estrogen and Cytokines From the limited information available, it is thought that fluctuations in estrogen may alter immune cell func­ tion, in part, by increasing or decreas­ ing the production of cytokines (Olsen and Kovacs 1996; Cannon and St. Pierre 1997; Verthelyi 2001; Burger and Dayer 2002). There are several pieces of evidence for this idea. First, researchers found that removing the ovaries of adult rodents (eliminating the primary source of estrogen) low­ ered the level of cytokine production by certain types of white blood cells (Frazier-Jessen and Kovacs 1995; Chao et al. 1995; D’Agostino et al. 1999; Deshpande et al. 1997). This lower level of cytokine production was comparable to that of males and could be restored by administering estrogen (Gregory et al. 2000a). In other studies, drugs known as estrogen receptor antagonists inhibited the effect of estrogen on immune cells in animals (Gregory et al. 2000b; Wu et al. 1999). While receptor antagonists are bound to the same receptors that normally interact with estrogen, they block the binding of the hormone. 1 The thymus is a gland located in the upper chest that is involved in the maturation of immune cells. 2 Although estrogen is present in males, its concentration is too low to affect immune response. Alcohol Research & Health Alcohol, Gender, and Immune Response Thus, it is possible to alter immune responses by blocking estrogen at one of its sites of action in white blood cells. Further evidence that estrogen affects immune cell function, in part, by alter­ ing production of cytokines comes from cell-culture studies in which estrogen was added to a culture of white blood cells (Burger and Dayer 2002). The effects of estrogen on cytokine produc­ tion by immune target cells may involve direct interaction (binding) of the hor­ mone and hormone receptors within those cells (Hall et al. 2001). The idea of direct effects of estrogen on target cells is supported by the existence of estrogen receptors not only in reproductive tissues, including the uterus, ovaries, and testes, where one would expect the hor­ mone’s actions to occur, but also in white blood cells (Weusten et al. 1986; Gul­ shan et al. 1990; Benten et al. 2001). Alcohol, Stress Responses, and Immunity Like other stressors, alcohol stimulates a neuroendocrine network known as the hypothalamic–pituitary–adrenal (HPA) axis, resulting in a dampening of the immune response (Eskandari and Sternberg 2002) (see figure 1). This pro­ cess begins with activation of the hypothalamus (near the base of the brain), which produces a molecule called corti­ cotropin-releasing hormone (CRH). Gender Differences in Immune Responses Literature Review This triggers the pituitary gland (below the hypothalamus) to secrete adrenal corti­ cotropic hormone (ACTH). Finally, ACTH stimulates the adrenal glands (above the kidneys) to release glucocorti­ coids (cortisol in humans and corticos­ terone in rodents). These steroid hor­ mones, which direct the activity of many cell types, are transmitted throughout the body in the blood. At high levels, they suppress inflammatory and immune responses (Guyre and Goulding 1993; Da Silva 2002). Several studies have docu­ mented that under resting (baseline) con­ ditions and in response to stress, females have higher levels of glucocorticoids than do men (Kant et al. 1983; Chasari et al. 1995). Furthermore, estrogen stimulates glucocorticoid production in females (Burgess and Handa 1992; Carey et al. 1995), whereas testosterone suppresses its production in both male and female sub­ jects (Carlstrom and Stege 1990; De Weerdt and Gooren 1992; Handa et al. 1994). Alcohol exposure stimulates gluco­ corticoid production in both males and females (Ogilvie et al. 1998; Eskandari and Sternberg 2002). Thus, there are two possible pathways by which alcoholinduced changes in steroid hormones could suppress immune responses in females, whereas there is only one such potential pathway in males (as shown in figure 2). Further study will be required to determine if and how the two pathways interact to mediate alcohol-induced effects on immune function in females. Gender, Alcohol, and Liver Damage Epidemiologic evidence clearly indicates that the adverse consequences of alcohol consumption, including severe liver dis­ ease, such as alcoholic cirrhosis, develop more quickly and require lower levels of alcohol exposure for females than for males (Ashley et al. 1977; Loft et al. Figure 1 Involvement of the hypothalamic–pituitary–adrenal axis in alcohol-induced immune suppression. Alcohol exposure stimulates the hypothalamus to produce corticotropin-releasing hormone (CRH). This triggers the pituitary gland to secrete adrenal corticotropic hormone (ACTH), which in turn stimulates the adrenal glands to release glucocorticoids. At high levels, glucocorticoids signal white blood cells to alter cytokine production, suppressing inflammatory and immune responses. (Yellow arrows indicate increased or decreased production or activity.) Vol. 26, No. 4, 2002 259 Figure 2 Hormone-dependent pathways by which alcohol could suppress immune responses. As the figure illustrates, there is only one potential pathway in males, but there are two in females, which could result in an additive effect. 1987; Schenker 1997; for reviews, see Thurman 2000; Diehl 2002). At any given level of alcohol intake, women are at higher risk than men of developing liver disease (Ashley et al. 1977; Loft et al. 1987; Dawson 1994; Schenker 1997). It has been shown that a daily alcohol ingestion of as low as two drinks per day increases the risk of developing cirrhosis in women, although at least four drinks per day are required to increase this risk in men (Ashley et al. 1977; Loft et al. 1987; Thomasson 1995; Frezza et al. 1990; Taylor et al. 1996). These obser­ vations were made taking into account differences in body weight, fat distribu­ tion, body water, and other potentially confounding variables. The mechanisms responsible for the gender difference in alcohol-related liver injury are currently under intense inves­ tigation and have been better described in animal studies (Kono et al. 2000; Nanji et al. 2001). Performing studies in animals allows the investigator to include experiments involving hormone manip­ ulations that would not be feasible in human experimentation. These experi­ ments could include removing ovaries (the primary site of estrogen production) or giving a hormone receptor antagonist (i.e., a molecule that blocks the hormone from binding to its receptor). Gender Differences in Immune Responses Literature Review It is possible that gender differences in alcohol-related liver disease could be explained by gender differences in: • The breakdown and elimination of alcohol and its byproducts, includ­ 260 ing the resulting differences in acetaldehyde levels within the liver (Thomasson 1995; Li et al. 2000). • The level of activation of inflamma­ tory and immune cells within the liver in response to alcohol ingestion, including Kupffer cells (Adachi et al. 1994; Kono et al. 2000; Nanji et al. 2001; McClain et al. 2002).3 Upon stimulation, these cells produce free oxygen radicals and cytokines, which damage and destroy liver cells (Adachi et al. 1994). • The amount of alcohol that is metab­ olized in the stomach (first-pass met­ abolism). Some research has indi­ cated that women break down less alcohol in the stomach than men do, leading to higher blood alcohol lev­ els—and hence greater risk to the liver—for a given dose of alcohol (Poz­ zato et al. 1995; Baraona et al. 2001). Summary Taken together, these studies show clearly that there are dramatic suppres­ sive effects of both acute and chronic alcohol exposure on inflammation and 3 Kupffer cells are star-shaped immune cells that reside in the microscopic blood vessels of the liver. They are phagocytic, meaning that they are capable of ingesting other cells and foreign particles. Alcohol exposure can cause leakiness of the digestive tract, which can result in the release of endotoxins (bacterial cell wall products) from the gut into the blood. These endotoxins travel through the blood to the liver, where they can activate Kupffer cells. immunity, regardless of gender. This results in decreased ability of the immune system to fight infections and tumors. The decrease in immunity after consumption of larger quantities of alcohol is in marked contrast to the effects of very low levels of some alco­ holic beverages (such as a single glass of red wine), which contain immunopro­ tective antioxidants. By depressing estrogen levels, chronic or acute alcohol exposure may cause females to lose the important boost to the immune system that estrogen normally provides. This could act additively or synergistically with an elevation in immunosuppres­ sive glucocorticoids (through activation of the HPA axis) to attenuate immune response, thus leading to a weakened ability to fight infections and tumors. Finally, although chronic alcohol exposure causes liver damage in both males and females, it takes less alcohol and shorter periods of consumption to raise the risk of liver damage for females than for males. Like the observed gender dif­ ferences in alcohol-induced immune suppression, this effect may involve the combined effect of stimulating gluco­ corticoid production and inhibiting estrogen production (see figure 2). Further studies will be required to determine whether the alcohol-induced changes in gonadal steroid hormone production are sufficient to explain the observed gender differences in immune function. Gender Differences in Immune Responses Literature Review These will require using a similar model system in which both males and females are given alcohol at doses designed to raise blood alcohol levels to the same extent, after which immune responses can be examined. Because of the complexity of studying these parameters in humans, it may be necessary to conduct these studies in animal models of alcohol exposure. By using animal models, it will also be possible to manipulate the levels of estrogen, testosterone, and glucocorti­ coids by removing organs (ovaries, testes, and adrenal glands, respectively) and administering hormones and hor­ mone antagonists to determine the role of those hormones in regulating inflammatory and immune responses after alcohol exposure. ? Alcohol Research & Health Alcohol, Gender, and Immune Response How the Immune System Works The immune system is designed to provide protection from invading organisms, including bacteria and viruses, tumor cells, dirt, pollen, and other foreign material. Normally, barriers—including the skin and the lining of the lungs and gastrointestinal and reproductive tracts— protect the underlying delicate tissues from the outside environment. However, when there is a breakdown in that protective lining, germs and other irritants can enter the body. The immune system’s function is to conquer these foreign molecules by engulfing them or by destroy­ ing them with enzymes or other detoxifying means. In addition to fighting off these foreign invaders, the immune system has evolved to destroy abnormal cells (such as tumor cells) but occasionally reacts against the body’s own normal tissues (autoimmunity). Innate and Acquired Immunity There are two principal types of immune response, innate and adaptive (or acquired) immunity, which are distin­ guished from one another by … Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10