True Cost of Mega-Retailers Essay Example for Free

True Cost of Mega-Retailers Essay The phenomenon of big box economics brings with several ethical concerns that taint its most favorable effect, that of bringing lower-priced goods to the American market. Whether manufacturers who produce these goods keep their factories on United States soil or abroad, many of the persons who work within them suffer under conditions that no American would be required to endure. On American soil, such workers (who are likely to be illegal immigrants) are often paid at the lowest rates possible, and along with this comes the lack of accompanying benefits, such as health or accident insurance (Mitchell, 36). Many manufacturers are often drawn to foreign soil because minimum wages are much lower in some countries, making the costs of production fall to a level that increases their profit margins significantly. Despite the fact that higher profit margins lead to greater overall taxes paid to the government, these practices do impact negatively on the American economy. One way in which this negative impact is felt is through the removal of jobs from the American arena into other countries. Many of these factories employ thousands of workers, and each of them represents one unemployed American that would otherwise be contributing to the overall national income (GDP) of the country. This negatively affects the unemployment rate within the country, and therefore counteracts the aforementioned positive benefits in the area of taxes by making it necessary for the government to pay out unemployment benefits. The employment of low-paid immigrants or the outsourcing of jobs also forces Americans to settle for lower wages, as any refusal to accept these would simply induce manufacturers to apply to the overabundance of these foreigners. This leads to a lower standard of living for Americans. One researcher has also shown that big-box retailers whose low-cost commodities put local retailers out of business also hurt the local banks, which traditionally have strong relationships with the small retailers (Mitchell, 42). In America’s banking crisis today, such retailers are likely to continue exacerbating the economic problem, making it that much more difficult for the economy to recover from recession. Reference Mitchell, S.. Big-box Swindle: The True Cost of Mega-Retailers and the Fight for America’s Independent Businesses. Boston: Beacon Press, 2006

The Perfect Couple in Woman in White Essay -- Wilkie Collins Woman in

The Perfect Couple  in Woman in White  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   In the Woman in White, the author gives the reader many opportunities to find their favorite romantic plot. The reader is left to wonder which characters are well suited for each other. We are given the choices of the gentlemanly Walter and the feminine Laura or Laura and the deceitful Sir Percival. It seems to this reader that the author gave us the answer to the puzzling perfect couple question; only, the perfect couple is really a perfect trio- Walter, Laura, and Marian. Walter did not have to make a choice between the two main female characters because they made it for him. It is obvious that Laura and Marian complete each other. We see that whatever qualities Laura lacks, Marian has, and vice versa. These two women combine to make the perfect woman. Let us first examine Laura. Walter seems to fall in love with Laura at first sight. She is the image of the perfect Victorian woman. She is beautiful, rich, and pliant. She is willing to do whatever it takes to make other people happy. She has a dee...

Fantasy Books

What if you discovered a magic spring that would keep you forever as young and vital as the day you drank from it- would you partake it? Fantasy represents that which is impossible and outside the parameters of our known reality. Although some people believe that fantasy books, movies and TV shows are corrupting the minds of teens nevertheless fantasy books should be read because they teach the difference between good and bad. Fantasy books often tend to be very appealing to teenagers and help develop their personality, which is why a lot of teenagers who previously never used to read books started reading books.Reading fantasy books such as Harry Potter and twilight instills love for reading books in young teens. These adolescents can partially relate to some of these stories, as most of the characters of the novels are the same age as the readers. Hence, teenagers undergo a similar experience, though they are restricted by realities of life. These books tend to be a temporary escap e from daily life. This is evident from the fact that before Harry Potter it was usually unheard of kids queuing in front of book shops to buy books (CITATION . Teens are interested in reading books that let them explore the world beyond their immediate surroundings. It helped them think out of the box. This allowed them to dream much bigger than they could ever before. It also develops critical reading skills of the teenagers which later helps in their academics. For example reading lengthy books such as Harry Potter, not only increases the reading speed of these children but also helps them read effectively when in class, as it helps them save time.Therefore it is beneficial not detrimental for teenagers to read fantasy books as it instills in them the habit of reading from an early age which later helps them in life. Fantasy books and movies increase the imagination and creativity of teens. When a teenager reads fantasy books and watches fantasy movies, the thought provoking natu re of his/her mind is triggered. It makes the reader intrigued by what is happening in the plot, and what will happen? They will want to speculate the story and be surprised by what they read.This increases the sensible predicting capacity of an individual. According to UK’s fantasy book reviews, fantasy books such as Earthsea Saga (CITATION5) Fantasies allow readers to consider and speculate painful realistic themes sometimes in a way that is more acceptable than in reality. This enables them Therefore teenagers are interested in reading books that let them explore the world beyond their immediate surroundings. It helps them think outside the box. This allows them to dream bigger than they could ever before.These books and movies allow teenagers to see how different situations instigate different emotions in people and how can they be overcome. Although critics argue that reading fantasy corrupts young minds, however Fantasy books and television shows can often be productive . This is because fantasy books help develop the young minds, rather than corrupt them. They help individuals think outside the box, and go beyond what they see in their daily lives. They . They develop values, and desire and passion for excellence. For example, inFantasy books and movies often portray being part of the good team as a norm that is supported by society and almost always results in a good outcome, whereas evil leads one astray and leads to eventual defeat and shamefulness*. This is evident from fantasy movies such as Spiderman and Batman. For example in Batman, Firstly, it is believed by certain sections of society that reading fantasy books and seeing television shows do not develop but rather corrupt young minds. This view is often supported through examples such as Twilight and the need

The Violence Prevention Alliance - 981 Words

Resistance The Violence Prevention Alliance, an initiative by the WHO, defines interpersonal violence as violence against an individual or a community. It further subdivides this definition into two categories; family and community violence. The first, family violence is described as an act of violence against an intimate partner, children or elders while the latter refers to violence against acquaintances and strangers including property crimes and vandalism (Mitchell and M.D., pg. 64-68). In nature, interpersonal violence can be physical, sexual or psychological in nature. Such forms of violence may be fueled by factors such as neglect, greed, jealousy, desire or other such motives. Interpersonal violence can be classified into many forms including, but not restricted to domestic violence, child abuse, kidnapping, harassment and rape. Most victims of interpersonal violence often are weak targets who either do not resist, or are not trained or equipped to resist against their attacker. Moreover, most might fear that if their resistance doesnt bear fruit, it will only provoke their attacker further and they might end up being harmed more than originally planned hence they often give in to the criminals demands. It is said that in most cases, the victim often is aware of the criminals identity yet chooses not to report the crime to the authorities. This happens because of a variety of factors; the victim might not be able to prove that the crime happened leaving theShow MoreRelatedEssay about Effective After-school Programs596 Words   |  3 Pagesdrugs and alcohol. There are many programs that bring awareness and prevention to alcohol and drugs. The South Carolina Afterschool Alliance program provides groups and organizations with an effective after-school program plan. The after-school programs are essential in promoting awareness and prevention of drugs, alcohol, tobacco, abstinence, and violence to young children or adolescents. The South Carolina Afterschool Alliance program strives to reach the community and explain the importance ofRead MorePrevention of Suicide in Adolescents Essay1317 Words   |  6 Pagescrucial for suicide prevention in adolescents. By having the community involved, it allows a more effective prevention plan, along with measures on how to properly handle the situation more efficiently. The U.S. Department of Health and Human Services (HHS) Office of the Surgeon General and National Action Alliance for Suicide, revised the National Strategy for Suicide Prevention (NSSP) in 2012. In which, they classified suicide prevention interventions into two categories: prevention targeted at theRead MoreEssay about Alone Without a Home: Homeless and Runaway Youth 1624 Words   |  7 Pageshousing. The fact is that regardless of how the child became homeless they are inadequate to survive on their own on the streets. There are many dangers and challenges that can arise and cause more problems for them. They are at significant risk of violence, crime, drugs, prostitution, HIV and other STDs, and other health problems (Pergamit Ernst, 2010). Instead of finding the refuge they seek, once on the street they are further exposed to a multitude of risks including rape, sexual victimizationRead MoreSchool Safety Is Not The Most Heinous Act Of School Violence1735 Words   |  7 Pagesclassmates and wounded eleven in Jonesboro, Arkansas. Just one year after that, Eric Harris and Dylan Kleibold committed the most heinous act of school violence in United States history in Littleton, Colorado. There, in Columbine High School, Harris and Kleibold killed twelve students, a teacher and later took their own lives. Random acts of school violence seemed to spread across the nation undetected, and protecting no one. School safety is not an issue to be taken lightly, for in order to ensure studentRead MoreRape Crisis Centers For Women1704 Words   |  7 Pagesothers do no. Whichever the case, with such a high number of survivors, the help must remain readily available. Rape and sexual abuse is a horrible act of violence, yet, it remains a taboo and the voices of those survivors aren’t heard by everyone. Statistics from the Center for Disease Control and Prevention show that one in five women will be raped at some point in their lives (Center for Disease Control, 2012). 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In order to maintain a peaceful environment for all, we must address and inform our schools, children, and parents as well as the neighboring communities about the issue of school violence. As David W. Johnson, the author of Reducing School Violence states, â€Å"To eliminateRead MoreChild Abuse Prevention and Treatment Act Essay713 Words   |  3 Pages(2005), â€Å"We find an incidence rate for child abuse and neglect that is about ten times as high as the incidence rate for all forms of cancer†¦There is a multi-billion-dollar research base reliably renewed on an annual basis for cancer treatment and prevention. Nothing remotely similar to this exists for child abuse and neglect† (p. 1). The 2001 federal fiscal year budget was $3.74 billion for the National Cancer Institution. Between all of CAPTA’s grants combined, the total of monetary governmentalRead MoreMental Health And Its Effects On Society972 Words   |  4 Pagesproblem Mental health is often overlooked in today’s society. Some people don’t understand the seriousness of mental health towards a person’s and other peoples well being. Mental health can affect many different people. According to the National Alliance of Mental Illness, â€Å"Approximately 1 in 5 adults in the U.S.—43.8 million, or 18.5%—experience mental illness in a given year.† (NAMI)Mental health is not acted upon as seriously as it should be, and should be treated like any other illness in theRead Moreâ€Å"Dying Before Their Time: The Startling Trends in Adolescent Suicide†1217 Words   |  5 Pageshave increased by more than 100 percent (NCSL, 2005). In this paper, I seek to address the reasons why adolescents kill themselves, the methods adolescents use to commit suicide, and the prevention and treatment methods that are used to slow this rapidly increasing trend down. First of all, Thio, National Alliance on Mental Illness (NAMI), and the AACAP all suggest that Adolescent Suicide is often influenced by a child’s experience of societal pressures, change in family dynamics, and difficulty getting

What Drives Adult Personality Development - 1542 Words

Question #1 According to Specht, Bleidorn, Dennisen, Henneck, Huteman, Kandler, Luhmann, Orth, Reitz and Zimmerman’s article (2014) What Drives Adult Personality Development? A Comparison of Theoretical Perspectives and Empirical Evidence In terms of adult personality development, the most prominent perspectives utilize genetic and environmental factors into their models. Some examples of these theories consist of the five factor theory of personality and neo-social analytic theory (Specht et al., 2014). McCray and Costa’s five factor theory focuses on biological maturation and not life experiences (Specht et al., 2014). Meaning that innate biological processes may parallel physical fluctuations experienced in puberty. Many organisms go through stages of crucial development and reproduction events that include sexual and physical maturation (Specht et al., 2014). In turn, McCray and Costa hypothesized that higher levels of Openness to experience and Extraversion are detrimental to finding a mating partner while Conscientiousness and Agreeableness facilitate raising a family (Specht et al., 2014). One of the limitations associated with this theory is that individual differences appear around the age of 30 based on the empirical evidence (Specht et al., 2014). Thus, the empirical data suggest that more changes occur and this theory doesn’t encompass all those changes. This perspective also fails to acknowledge normal ranging common life experiences (Specht et al., 2014).S how MoreRelatedEssay on Freud V Erickson1371 Words   |  6 Pagestheories of development relied heavily on the belief that infantile sexuality must be seen as an integral part of a broader developmental theory of human personality. 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Sigmund Freud s psychoanalytic theory of personality argues that human behavior is the result of the interactions among three component parts of the mind: theRead MoreWhat Can Psychology Teach Us About Human Development?1558 Words   |  7 PagesPSYCHOLOGY ESSAY WHAT CAN PSYCHOLOGY TEACH US ABOUT HUMAN DEVELOPMENT? WORDCOUNT 1532 INTRODUCTION Psychology evolved out of both philosophy and biology. Discussions on the two subjects date as far back as the early Greek thinkers such as Aristotle and Socrates. The word psychology is derived from the Greek word ‘psyche’ meaning ‘soul’ or ‘mind’. Psychology is both an applied and academic field, that is the scientific study Of behaviour and experience. Research into psychology helps us toRead MorePsychological Aspects Of Criminal Behavior1565 Words   |  7 Pagespatterns and trends unique to each criminal offender’s past. Intelligence, learning, and personality all play into the likelihood for someone to exhibit any kind of criminal behavior. In order to understand the root causes of criminal behavior and deviance of an offender, one must identify the particular parts of the human personality that play into the psychodynamics and psychosexual stages of development during childhood. From there mental disorders and other antisocial behavior may become apparentRead MoreA Study On Twins, Twins Separated At Birth Through Adoption1275 Words   |  6 Pagesenvironment in which they grew up in and their genes. Schulsinger (1972) carried out the first adoption study in Denmark. His theory was to compare adopted adults, some adults had been diagnosed as psychopaths and others hadn’t. There was a lot of criticism regarding his theory because Schulsinger used his own criteria to diagnose particular adults with psychopathic behaviour. Another criminologist who developed a theory around adoption was Crowe, he studied those that came from families with criminalRead MoreEssay about Explanations of Personality Development701 Words   |  3 PagesExplanations of Personality Development According to Sigmund Freud, what we do and why we do it, who we are and how we became this way are all related to our sexual drive. Differences in personalities originate in differences in childhood sexual experiences. In the Freudian psychoanalytical model, child personality development is discussed in terms of psychosexual stages. In his Three Essays on Sexuality (1915), Freud outlined five stages of manifestations of theRead MorePsy/405 Klein vs. Erikson Debate Essay960 Words   |  4 PagesErikson’s Post-Freudian Theory in regards to their describing of individual personality characteristics along with interpersonal relations. 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He always considered himself a scientist firstRead MorePsychodynamic Theory1497 Words   |  6 Pagestheories and t hose of his followers. Freud’s psychoanalysis is both a theory and a therapy. His theory had the main focus that: * Children pass thru a series of age-dependent stages during development * Each stage has a designated â€Å"pleasure zone† and â€Å"primary activity† ,human motivation is guided by the drive to seek pleasure * Each stage requires resolution of a particular conflict/task * Failure to successfully navigate a stage’s particular conflict/ task is known as Fixation * LeavingRead MoreThe Importance Of Extracurricular Activities1265 Words   |  6 PagesMany people in school, no matter what age or grade one may be in, are involved in some type of extracurricular. Many people also don’t get to choose what extracurricular they begin to partake in due to their parents or guardians deciding what they would like their child to participate in, more often than not at a very young age. Whether it be attached to the school they attend or not, many people aren’t aware of the many positive effects that it may have on their own self, or their child. While

Capturing Real Life in Jane Austens Emma Essay - 2772 Words

Capturing Real Life in Emma Jane Austen deliberately confined herself to the realistic portrayal of a segment of contemporary English life-upper middle-class society. The heroine, Emma Woodhouse, lives on her fathers estate at Hartfield which is in effect an adjunct of the village of Highbury in spite of its separate lawns and shrubberies. Mr. Westons estate of Randals is in the parish of Highbury, and Mr. Knightleys Donwell Abbey is situated in the neighbouring parish, within comfortable walking distance. Here life is concentrated within itself and separated from London which although only sixteen miles away was much beyond...daily reach. Significantly, Emma has never visited London, never been to the seaside, never visited†¦show more content†¦Coles carriage horses returning from exercise, or a stray letter-boy on an obstinate mule, were the liveliest objects she could presume to expect; and when her eyes fell only on the butcher with his tray, a tiny old woman travelling homewards from the shop with her full basket, two curs quarrelling over a dirty bone, and a string of dawdling children round the bakers little bow-window eyeing the gingerbread, she knew she had no reason to complain, and was amused enough; quite enough still to stand at the door. In such a narrow society gossip helps to relieve the tedium. This gossip may be harmless - Mr. Frank Churchills coming to visit his father and stepmother; speculation about Mr. Eltons fiancee, Miss Augusta Hawkins of Bristol; excited accounts (becoming more and more exaggerated with each telling) of Harriets gallant rescue from the gypsies by Frank Churchill. However, gossip can also be malicious, as we shall see when Emma confides in Frank Churchill her unfounded suspicion that Jane Fairfaxs pianoforte is a gift from a secret admirer, Mr. Dixon, husband of Janes dearest friend Miss Campbell. Highbury society can also be unbearably claustrophobic. This is symbolically highlighted when Emma is trapped alone with Mr. Elton in her carriage on the journey home from the Christmas Eve dinner-party at Randals. After she has rejected the vicars proposal of marriage out of hand, they have no choice but to continue theShow MoreRelatedComparing Clueless and Emma Essay1816 Words   |  8 PagesCLUELESS VS. EMMA Adaptations of Jane Austen’s, Emma, are usually period pieces diligent in capturing and replicating the manners, dress, language and values of the original text. Clueless, written and directed by Amy Heckerling, deviates drastically from the norm, as the film is not a period piece. While Emma is set in the early nineteenth century in the country village of Highbury, sixteen miles out of London, England, Clueless is set in Bronson Alcott High School almost two hundred years laterRead MoreGoal Movie Review10720 Words   |  43 Pagesmust prove that he’s got the grit and the game to win a contract with one of the most prestigious football clubs in the world. Muddy fields, cold winds and crunching blows from teammates—not to mention personal woes, injuries, and the temptations of life in the fast lane—are just a few of the obstacles Santiago must overcome to triumph in the heady, heart-pounding world of international football. 1 Directed by Danny Cannon, â€Å"Goal! The Dream Begins† stars up and coming Latino actor Kuno Becker. SomeRead MoreLogical Reasoning189930 Words   |  760 Pagesproblem without bringing in the most relevant information. This first chapter explains what it means to be logical—to reason logically. It demonstrates the usefulness of logical reasoning as a means to making more effective decisions about your own life—decisions about what to believe and decisions about what to do. The chapter begins a systematic program of study of all the major topics regarding logical reasoning. Along the way, the book focuses on developing the following five skills: (1) writing

Medical Immunology Free Essays

MEDICAL IMMUNOLOGY SEROLOGY Terence L. Eday, RMT, MT(ASCPi), MPH College of Medical Technology / Medical Laboratory Science University of Perpetual Help System DALTA Historical Perspective †¢ 1773, Voltaire reported on an ancient Chinese custom where dried and powdered small pox scabs were inhaled †¢ 1798, Edward Anthony Jenner, Smallpox vaccination †¢ 1862, Ernst Haekel, Recognition of phagocytosis 1877, Paul Erlich, recognition of mast cells Historical Perspective †¢ 1879, Louis Pasteur, Attennuated chicken cholera vaccine development †¢ 1883, Ellie Metchnikoff developed the cellular theory of immunity through phagocytosis; phagocytic theory; cellular theory of vaccination †¢ 1885, Pasteur discovered therapeutic vaccination; first report of live â€Å"attenuated† vaccine for rabies Historical Perspective 1888, Pierre Roux Alexander Yersin, Bacterial toxins (Yersinia pestis) †¢ 1888, George Nuttall, Bactericidal action of blood †¢ 189 0, Emil von Behring and Kitasata introduced passive immunization into modern medicine; humoral theory of immunity †¢ 1891, Robert Koch demonstrated the cutaneous (delayed-type) hypersensitivity †¢ 1894, Richard Pfeiffer, Bacteriolysis Historical Perspective (1 of 6 ) 1895, Jules Bordet, Complement and antibody activity in bacteriolysis †¢ 1900, Paul Ehrlich, responsible for the antibody formation theory †¢ 1901, Karl Landsteiner, A, B, and O †¢ 1901-8, Carl Jensen Leo Loeb, Transplantable tumors †¢ 1902, Paul Portier Charles Richet, Anaphylaxis Historical Perspective (1 of 6 ) †¢ 1903, Nicolas Maurice Arthus, discovered the Arthus reaction of intermediate hypersensitivity †¢ 1903, Almroth Wright and Stewart Douglas observed the humoral component, opsonin †¢ 1906, Clemens von Pirquet, coined the word allergy †¢ 1907, Svante Arrhenius, coined the term immunochemistry Historical Perspective †¢ 1910, Emil von Dungern, Ludwik Hirszfeld, Inheritance of ABO blood groups †¢ 1910, Peyton Rous, Viral immunology theory †¢ 1914, Clarence Little, Genetics theory of tumor transplantation †¢ 1915-20, Leonll Strong Clarence Little, Inbred mouse strains Historical Perspective †¢ 1917, Karl Landsteiner, Haptens †¢ 1921, Carl Prausnitz Heinz Kustner, Cutaneous reactions †¢ 1924, L. Aschoff, Reticuloendothelial system †¢ 1926, Loyd Felton GH Bailey, Isolation of pure antibody preparation †¢ 1938, John Marrack, Antigen-antibody binding hypothesis Historical Perspective 1936, Peter Gorer, Identification of the H2 antigen in mice †¢ 1940, Karl Landsteiner Alexander Weiner, Identification of the Rh Antigens †¢ 1941, Albert Coons, Immunofluorescence technique †¢ 1942, Jules Freund Katherine McDermott, Adjuvants †¢ 1942, Karl Landsteiner Merill Chase, Cellular transfer of sensitivity in guinea pigs (anaphylaxis) Historical Perspective †¢ 1944, Peter Medwar, Immunological hypothesis of allograft rejection †¢ 1948, Astrid Fagraeus, Demonstration of antibody production in plasma B cells †¢ 1948, George Snell, Congenic mouse lines †¢ 1949, Macfarlane Burnet Frank Fenner, Immunological tolerance hypothesis Historical Perspective †¢ 1950, Richard Gershon and K Kondo, Discovery of supressor T cells †¢ 1952, Ogden and Bruton, discovery of agammaglobulinemia (antibody immunodeficiency) †¢ 1953, Morton Simonsen and WJ Dempster, Graft-versus-host reaction †¢ 1953, James Riley Geoffrey West, Discovery of histamine in mast cells Historical Perspective †¢ 1953, Rupert Billingham, Leslie Brent, Peter Medwar, Milan Hasek, Immunological tolerance hypothesis †¢ 1955-1959, Niels Jerne, David Talmage, Macfarlane Burnet, Clonal Selection Theory †¢ 1957, Ernest Witebsky et all. We will write a custom essay sample on Medical Immunology or any similar topic only for you Order Now Induction of autoimmunity in animals †¢ 1957, Alik Isaacs Jean Lindemann, Discovery of interferon (cytokine) Historical Perspective †¢ 1958-62, Jean Dausset et al. , Human leukocyte antigens †¢ 1959-62, Rodney Porter et al. , Discovery of antibody structure †¢ 1959, James Gowans, Lympocyte circulation †¢ 1961-62, Jaques Miller et al. , Discovery of thymus involvement in cellular immunity †¢ 1961-62, Noel Warner et al. , Disctinction of cellular and humoral immune response Historical Perspective †¢ 1963, Jacques Oudin et al. Antibody isotypes †¢ 1964-68, Anthony Davis et al. , T and B cell cooperation in immune response †¢ 1965, Thomas Tomasi et al. , Secretory immunoglobulin antibodies †¢ 1967, Kimishige Ishizaka et al. , Identification of IgE as the reaginic antibody Historical Perspective †¢ 1971, Donald Bailey, Recombinant inbred mouse strains †¢ 1972, Gerald M. Edelman Rodney Porter, Identification of antibody molecul e †¢ 1974, Rolf Zinkernagel Peter Doherty, MHC restriction †¢ 1975, Kohler and Milstein, First monoclonal antibodies used in genetic analysis Historical Perspective †¢ 1984, Robert Good, Failed treatment of severe combined immunodeficiency (SCID, David the bubble boy) by bone marrow grafting †¢ 1985, Tonegawa, Hood et al. , Identification of immunoglobulin genes †¢ 1985-1987, Leroy Hood et al. , Identification of genes for the T cell receptor †¢ 1986, Monoclonal hepatitis B vaccine Historical Perspective †¢ 1986, Mosmann, Th1 versus Th2 model of T-helper-cell function †¢ 1990, Yamamoto et al. Molecular differences between the genes for blood groups O and A and between those for A and B †¢ 1990, NIH team, Gene therapy for SCID using cultured T cells †¢ 1993, NIH team, Treatment of SCID using genetically altered umbilical cord cells Historical Perspective †¢ 1996-1998, Identification of toll-like receptors †¢ 2001, FOXP3, the gene directing regulatory-T-cell development †¢ 2005, Frazer, Development of human papilloma-virus vaccine The IMMUNE SYTEM What is Immunology? â⠂¬ ¢ Study of the molecules, cells, organs, and systems responsible for the recognition and disposal of foreign (nonself) material †¢ †¦ ow body components respond and interact †¢ †¦desirable and undesirable consequences of immune interactions †¢ †¦ways in which the immune system can be advantageously manipulated to protect against or treat disease What is Immunity? †¢ Latin word â€Å"immunitas†, freedom from †¢ It refers to all mechanisms used by the body as protection against environmental agents that are foreign to the body. †¢ Can be either natural (innate or inborn) or acquired (adaptive) Function of the Immune System †¢ Recognize â€Å"self† from â€Å"nonself† †¢ Defend the body against nonself Physiologic function is to prevent infection and to eradicate established infections (sterilizing immunity) Key Characteristics of the Immune System †¢ Innate immunity †¢ Primary response †¢ Sec ondary response and immunologic memory †¢ Immune response is highly specific †¢ Immune system is tolerant of self-antigens †¢ Immune responses against self-antigens can result in autoimmune diseases †¢ Immune responses against infectious agents do not always lead to elimination of the pathogen (HIV/AIDS) Major Principles of Immunity (immune response): Elimination of many microbial agents through the nonspecific protective mechanisms of the innate immune system. †¢ Cues from the innate immune system inform the cells of the adaptive immune system as to whether it is appropriate to make a response and what type of response to make. Major Principles of Immunity (immune response): †¢ Cells of the adaptive immune system display exquisitely specific recognition of foreign antigens and mobilize potent mechanisms for elimination of microbes bearing such antigens. The immune system displays memory of its previous responses. †¢ Tolerance of self-antigens. Cel ls of the Immune System †¢ Lymphocytes – occupy the central stage; determines the specificity of immunity †¢ Dendritic cells (DCs) Langerhan cells †¢ Monocyte/macrophages †¢ Natural killer (NK) cells †¢ Neutrophils †¢ Mast cells Basophils †¢ Eosinophils †¢ Epithelial and stromal cells – provides anatomic environment (secretion of critical factors that regulate migration, growth and homeostasis) Lymphoid Tissues and Organs Primary Lymphoid Organs Sites where pre-B and pre-T lymphocytes mature into naive T and B cells in the absence of foreign antigen; †¢ Fetal Liver, Adult bone marrow, and thymus The INNATE IMMUNE SYTEM INNATE IMMUNE SYSTEM †¢ relies on germ line-encoded receptors to detect a limited set of microbial structures that are uniquely associated with microbial infection †¢ not a function of a single defined physiologic system; rather, it is a product of multiple and diverse defense mechanisms Modules of the Innate Immune System †¢ Surface epithelium The phagocyte system – critical for the defense against both intracellular and extracellular bacteria as well as fungal pathogens; aided by opsonins †¢ Acute phase response and complement – variety of secreted proteins that function in the circulation and in tissue fluids; secreted by the hepatocytes in response to the inflammatory cytokines IL1 and IL-6 Modules of the Innate Immune System †¢ Natural killer (NK) cells are specialized in the elimination of infected host cells and in aiding defense against viral and other intracellular infections through production of cytokines(IFN-? ; regulated by type I interferons (IFN-? /? ) †¢ Mast cells, eosinophils, and basophils are specialized in defense against multicellular parasites, such as helminthes; regulated by several cytokines, including IL-4, IL-5, IL-9, and IL-13 Strategies of Innate Immune Recognition 1. Recognition of microbial nonself – ref erred to as pattern recognition, based on the recognition of molecular structures that are unique to microorganisms and not produced by the host 2. Recognition of missing self – based on the recognition of molecules expressed only on normal, uninfected cells of the host Targets of Innate Immune Recognition †¢ PAMPs (pathogen-associated molecular patterns) – molecular structures produced by microbial pathogens, but not by the host organism †¢ PRRs (pattern recognition receptors) – receptors of the innate immune system and represents targets of the innate immune system Targets of Innate Immune Recognition Examples of PAMPs include: (1) LPS of gram-negative bacteria (2) LTA of gram-positive bacteria (3) Peptidoglycans (4) Lipoproteins of bacteria (cell wall) (5) Lipoarabinomannan of mycobacteria (6) dsRNA produced by virus during the infection cycle (7) ? -glucans and mannans found in fungal cell wall Receptors of the Innate Immune System †¢ Broad categories of PRRs: (1) PRRs that signal the presence of infection; expressed on the cell surface or intracellularly Categories of gene products: a. pr oteins and peptides that have direct antimicrobial effector functions (antimicrobial peptides and lysozyme) b. nflammatory cytokines and chemokines (TNF, IL-1, IL-8) c. gene products that control activation of the adaptive immune response (MHC, CD80/CD86, IL-12) Receptors of the Innate Immune System †¢ Broad categories of PRRs: (2) Phagocytic (or endocytic) PRRs; expressed on the surface of macrophages, neutrophils, and dendritic cells(DCs) (3) Secreted PRRs (mannan-binding lectin and peptidoglycan-recognition proteins Function: a. activate complement b. opsonize microbials cells to facilitate their phagocytosis c. ccessory proteins for PAMP recognition by transmembrane receptors (TLR) Receptors of the Innate Immune System †¢ Toll-like Receptors – comprise a family of type 1 transmembrane receptors characterized by leucine rich repeats (LRRs) in the extracellular portion and an intracellular TIR (Toll/IL-1 receptor) domain; grouped into two classes: (1) TLRs 1, 2, 4 , 5, and 6 are expressed on the plasma membrane and detect bacterial and fungal cell wall components; (2) TLRs 3, 7, and 9 are expressed in endosomal compartments and recognize viral nucleic acids Toll-like receptor 4 (TLR4) †¢ expressed predominantly in the cells of the immune system, including macrophages, DC, neutrophils, mast cells, and B cells †¢ also expressed on endothelial cells, fibroblasts, surface epithelial cells, and muscle cell †¢ Signal transducing receptor for LPS, heat sensitive protein associated with the cell walls of MTB †¢ Together with CD14 shown to mediate responsiveness to the fusion (F) protein of RSV Toll-like receptor 2 (TLR2) †¢ Involved in recognition of LTA and peptidoglycan from gram-positive bacteria, bacterial lipoproteins, mycoplasma lipoprotein, mycobacterial lipoarabinomannan, a phenol-soluble modulin from S. epidermidis, zymosan of yeast cell walls, and lipoglycosylphosphotidylinositol T. cruzi †¢ Also shown to recognize two kinds of atypical LPS: L. interrogans and Porphyromonas gingivitis Toll-like receptor 3 (TLR3) Receptor for dsRNA †¢ Can mediate responses to poly(IC) †¢ Expressed on DCs, macrophages, and surface epithelial cells, including instestinal epithelium †¢ Also expressed in CD8+ DCs Toll-like receptor 7 (TLR7) †¢ Involved in viral recognition and both detect nucleic acids together with TLR9 †¢ Recognizes viral ssRNA (derived from RNA viruses); TLR9 (unmethylated DNA derived from DNA viruses) †¢ Expressed primarily on plasmacytoid dendritic cells †¢ Activated by small antiviral compunds, e. g. imiquinoid †¢ TLR7-mediated recognition takes place inside the late lysosomes Toll-like receptor 9 (TLR9) †¢ Involved in the antiviral host defense; especially on recognition of DNA viruses (HSV) †¢ Expressed in type-I INF-producing plasmacytoid DCs Phagocytic Receptors †¢ Scavenger receptors – cell-surface glycoproteins that are defined by their ability to bind to modified LDL †¢ Macrophage Mannose Receptor (MR) – type I transmembrane protein expressed primarily in macrophages; involved in phagocytosis of bacterial (MTB, P. eruginosa, K. pneumonia), fungal (S. cerevisae, C. albicans), and protozoan pathogens (P. carinii) Cells of the Innate Immune System †¢ Macrophages – most central and essential functions and have multiple roles in host defense (e. i. â€Å"housekeeping functions†); in red pulp of the spleen, it phagocytose and remove from circulation senescent RBCs †¢ Neutrophils †¢ Mast Cells – best known effectors of aller gic response; protective role is by rapid production of TNF-? nd leukotriene B4 (neutrophil recruitement) Cells of the Innate Immune System †¢ Eosinophils – found primarily in the respiratory, intestinal, and genitourinary tracts; contains cationic effector proteins toxic to parasitic worms; poor phagocytes †¢ Dendritic Cells – immature DCs reside in peripheral tissues and are highly active in macropinocytosis and receptor-mediated endocytosis; expresses PRRs and TLRs; have roles in the initiation of adaptive immune response Cells of the Innate Immune System Suface Epithelium – lines the mucosal surfaces of the intestinal, respiratory, and genitourinary tracts provide an important physical barrier The Effector Mechanisms of the Innate Immune System The Major Categories of Antimicrobial Effector Enzymes that hydrolyze components of microbial cell walls Antimicrobial proteins and petides that disrupt the integrity of microbial cell walls †¢ Lysozyme †¢ Chitinases †¢ Phospholipase A2 †¢ †¢ †¢ †¢ †¢ BPI Defensins Cathelicidins Complement Eosinophil cationic protein Microbicidal serine proteases Proteins that sequester iron and zinc Enzymes that generate toxic oxygen and nitrogen derivatives †¢ Seprocidins †¢ Lactoferrin †¢ NRAMP †¢ calprotein †¢ Phagocytic oxidase †¢ Nitric oxide synthase †¢ myeloperoxidase The Effector Mechanisms of the Innate Immune System †¢ Lysozyme – a. k. a. muramidase; degrades the peptidoglycan of some gram(+) bacteria; highly concentrated in secretions such as tears and saliva †¢ Chitinases – enzymes that degrade chitin; secreted by activated macrophages and presumably play a role in antifungal defense The Effector Mechanisms of the Innate Immune System †¢ Defensins – cationic peptides with a broad spectrum of antimicrobial activities against gram(+) and gram(-) bacteria, fungi, parasites, and some envelope viruses; kill microorganisms by forming pores in the membranes; divided into ? – and ? defensins †¢ ? -defensins – presynthesized and stored in granules of neutrophils and Paneth cells of the small intestine †¢ ? -defensins – produced by epithelial cells and not stored in cytoplasmic granules The Effector Mechanisms of the Innate Immune System †¢ Cathelicidins – active against gram(+) and gram(-) bacteria and fungi; produced in neutrophils and stored as inactive proproteins in the secondary granules †¢ Serprocedins – comprise a family of cationic serine proteases with antimicrobial activity (neutrophil elastase, proteinase 3, cathepsin G, and azurocidin); exert its antimicrobial activity by either perturbation of microbial membranes or by proteolysis The Effector Mechanisms of the Innate Immune System †¢ Lactoferrin, NRAMP, and Calprotectin – antimicrobial activities are due to the ability to sequester iron and zinc †¢ Lactoferrin – found in the secondary granules of neutrophils, in epithelial secretions (e. i. breast milk), in the intestinal epithelium of infants, and in airway fluids; bacteriostatic (iron sequestration) and bacteriocidal (perturbation of microbial membranes) The Effector Mechanisms of the Innate Immune System NRAMP (natural resistance-associated macrophage protein) – integral membrane protein that functions as an ion pump in the phagocytic vacuoles of macrophage and neutrophils †¢ Calprotectin – member of the family of calciumbinding proteins; microbial activity is by chelation and sequestration of zinc ion ACUTE PHASE REACTANTS †¢ Soluble factors which are normal constituents that increase or decrease rapidly as produ †¢ Not a function of a single defined ph ysiologic system; rather, it is a product of multiple and diverse defense mechanisms How to cite Medical Immunology, Essay examples