BIO-106-Chapter-1.pdf

Chapter 1: INTRODUCTION TO THE IMMUNE SYSTEM A.Historical Perspectives of Immunology B. Basic Concepts of Immunology A. Historical Perspectives of Immunology Learning Objective: At the end of the lesson, the learners will be able to enumerate some...

Chapter 1: INTRODUCTION TO THE IMMUNE SYSTEM A.Historical Perspectives of Immunology B. Basic Concepts of Immunology A. Historical Perspectives of Immunology Learning Objective: At the end of the lesson, the learners will be able to enumerate some important events and personalities that lead to the advancement of immunology Diversity of potential pathogens The immune system defends the body against invaders as diverse as the tiny (~30 nm), intracellular polio virus and as large as the giant parasitic kidney worm Dioctophyme renale, which can grow to over 100 cm in length and 10 mm in width. Ø requires a range of recognition and destruction mechanisms Ø vertebrates have evolved a complicated and dynamic network of cells, molecules, and pathways https://www.cdc.gov v Immunity= a state of protection from infectious disease Ø From the Latin word immunis, meaning “exempt” v Thucydides Ø great historian of the Peloponnesian War Ø earliest written reference to the phenomenon of immunity Ø 430 BC: “only those who had recovered from the plague could nurse the sick because they would not contract the Statue of Greek philosopher Thucydides in front of Parliament disease a second time” building in Vienna, Austria. By Eye Ubiquitous—Getty Images ü almost 2000 years passed before this concept was successfully converted into medically effective practice Early Vaccination Studies Led the Way to Immunology v Chinese and Turks, 15th century Ø performed first recorded attempts to deliberately induce immunity Ø attempted to prevent smallpox, a fatal disease (about 30% of cases) ü according to reports, the dried crusts derived from smallpox pustules were either inhaled or inserted into small cuts in the skin in order to prevent this dreaded disease = VARIOLATION v Lady Mary Wortley Montagu, 1718 Ø wife of the British ambassador in Constantinople Ø observed the positive effects of variolation on the native Turkish population Ø had the technique performed on her own children v Edward Jenner (English physician) Ø made a giant advance in the deliberate development of immunity, targeting smallpox Ø observed that milkmaids who had contracted the mild disease cowpox were subsequently immune to the much more severe smallpox (1798) Ø reasoned that introducing fluid from a cowpox pustule into people might protect them from small The eradication of smallpox by vaccination After a period of 3 years in which no cases of smallpox were recorded, the World Health Organization was able to announce in 1979 that smallpox had been eradicated. v Louis Pasteur Ø succeeded in growing the bacterium that causes cholera in culture Ø hypothesized and later showed that aging had weakened the virulence of the pathogen and that such a weakened or attenuated strain could be administered to provide immunity against the disease ü VACCINE § from the Latin vacca, meaning “cow” v Louis Pasteur Ø extended findings to other diseases ü anthrax bacteria (1881) § Pasteur first vaccinated one group of sheep with anthrax bacteria (Bacillus anthracis) that were attenuated by heat treatment. § He then challenged the vaccinated sheep, along with some unvaccinated sheep, with a virulent culture of the anthrax bacillus. § All the vaccinated sheep lived and all the unvaccinated animals died. § These experiments marked the beginnings of the discipline of immunology. Science History Images / Alamy Stock Photo v Louis Pasteur Ø extended findings to other diseases ü rabies (1885) § Pasteur administered his first vaccine to a human, a young boy who had been bitten repeatedly by a rabid dog. § The boy, Joseph Meister, was inoculated with a series of attenuated rabies virus preparations. Joseph lived, and later became a caretaker at the Pasteur Institute, which was opened in 1887 to treat the many rabies victims that began to flood in when word of Pasteur’s success spread; it remains to this day an institute dedicated to the prevention and treatment of infectious disease. § The rabies vaccine is one of very few that can be successful when administered shortly after exposure, as long as the virus has not yet reached the central nervous system and begun to induce neurologic symptoms. Louis Pasteur in his laboratory, holding a jar containing Wood engraving of Louis Pasteur watching Joseph Meister the spinal cord of a rabbit infected with rabies, which he receive the rabies vaccine. [Source: From Harper’s Weekly used to develop a vaccine against the disease. Science 29:836; courtesy of the National Library of Medicine.] History Institute/Gregory Tobias v Robert Koch (19th Century) Ø proved that infectious diseases are caused by microorganisms ü when Jenner introduced vaccination he knew nothing of the infectious agents Ø discovered rod-shaped bacteria now known as Bacillus anthracis in the blood of cattle that had died of anthrax Ø cultured the bacteria on nutrients and then injected samples of the culture into healthy animals ü when these animals became sick and died, Koch isolated the bacteria in their blood and compared them with the originally isolated bacteria ü he found that the two sets of blood cultures contained the same bacteria v Emil von Behring and Shibasaburo Kitasato (1890) Ø discovered that the serum of animals immune to diphtheria or tetanus contained a specific 'anti toxic activity' that could confer short-lived protection against the effects of diphtheria or tetanus toxins in people Ø Von Behring experimented initially with iodine trichloride and zinc chloride as potential treatments for diphtheria and tetanus infections ü 1898, working with Koch's Japanese student Shibasaburo Kitasato, Behring showed that injections of serum from an animal with tetanus could confer immunity to the disease in other animals, and also Emil von Behring and Shibasaburo Kitasato were that the same was true for diphtheria. honoured philatelically on a stamp issued by Transkei in 1991 (Stanley Gibbons 273, Scott 255). v Elie Metchnikoff Ø discovered that many microorganisms could be engulfed and digested by phagocytic cells, which he called 'macrophages’ Ø received (with Paul Ehrlich) the 1908 Nobel Prize for Physiology or Medicine v Vaccination Ø yielded some of the most profound success stories in terms of improving mortality rates worldwide, especially in very young children ü 1977= last known case of naturally acquired smallpox in Somalia § However, vaccination for smallpox largely ended (early to mid-1970s), leaving over half of the current world population susceptible to the disease smallpox, or a weaponized version is now considered a potential bioterrorism threat new and safer vaccines against smallpox are still being developed today Ø herd immunity ü as a critical mass of people acquire protective immunity, either through vaccination or infection, they can serve as a buffer for the rest ü works by decreasing the number of individuals who can harbor and spread an infectious agent, significantly decreasing the chances that susceptible individuals will become infected v Vaccination Ø eliminated a host of childhood diseases that were the cause of death for many young children 50 years ago: Measles Mumps Chickenpox Whooping cough (pertussis) Tetanus Diphtheria Polio ü now extremely rare or nonexistent ü the cost to treat these illnesses and their aftereffects or sequelae (such as paralysis, deafness, blindness, and mental retardation) is immense and dwarfs the costs of immunization ü however, many vaccine challenges still remain: § e.g. design of effective vaccines for major killers such as malaria and AIDS  Despite the record of worldwide success of vaccines in improving public health, some opponents claim that vaccines do more harm than good, pressing for elimination or curtailment of childhood vaccination programs. There is no dispute that vaccines represent unique safety issues, since they are administered to people who are healthy. Furthermore, there is general agreement that vaccines must be rigorously tested and regulated, and that the public must have access to clear and complete information about them. Although the claims of vaccine critics must be evaluated, many can be answered by careful and objective examination of records. A recent example is the claim that vaccines given to infants and very young children may contribute to the rising incidence of autism. This began with the suggestion that thimerosal, a mercury-based additive used to inhibit bacterial growth in some vaccine preparations since the 1930s, was causing autism in children. In 1999 the U.S. Centers for Disease Control and Prevention (CDC) and the American Association of Pediatricians (AAP) released a joint recommendation that vaccine manufacturers begin to gradually phase out thimerosal use in vaccines.  This recommendation was based on the increase in the number of vaccines given to infants and was aimed at keeping children at or below Environmental Protection Agency (EPA)- recommended maximums in mercury exposure. However, with the release of this recommendation, parent-led public advocacy groups began a media-fueled campaign to build a case demonstrating what they believed was a link between vaccines and an epidemic of autism. These AAP recommendations and public fears led to a dramatic decline in the latter half of 1999 in U.S. newborns vaccinated for hepatitis B. To date, no credible study has shown a scientific link between thimerosal and autism. In fact, cases of autism in children have continued to rise since thimerosal was removed from all childhood vaccines in 2001. Despite evidence to the contrary, some still believe this claim. A 1998 study appearing in The Lancet, a reputable British medical journal, further fueled these parent advocacy groups and anti-vaccine organizations. The article, published by Andrew Wakefield, claimed the measles-mumps-rubella (MMR) vaccine caused pervasive developmental disorders in children, including autism spectrum disorder.  More than a decade of subsequent research has been unable to substantiate these claims, and 10 of the original 12 authors on the paper later withdrew their support for the conclusions of the study. In 2010, The Lancet retracted the original article when it was shown that the data in the study had been falsified to reach desired conclusions. Nonetheless, in the years between the original publication of the Lancet article and its retraction, this case is credited with decreasing rates of MMR vaccination from a high of 92% to a low of almost 60% in certain areas of the United Kingdom. The resulting expansion in the population of susceptible individuals led to endemic rates of measles and mumps infection, especially in several areas of Europe, and is credited with thousands of extended hospitalizations and several deaths in infected children. Why has there been such a strong urge to cling to the belief that childhood vaccines are linked with developmental disorders in children despite much scientific evidence to the contrary? One possibility lies in the timing of the two events. Based on current AAP recommendations, in the United States most children receive 14 different vaccines.  In 1983, children received less than half this number of vaccinations. Couple this with the onset of the first signs of autism and other developmental disorders in children, which can appear quite suddenly and peak around 2 years of age. This sharp rise in the number of vaccinations young children receive today and coincidence in timing of initial autism symptoms is credited with sparking these fears about childhood vaccines. Add to this the increasing drop in basic scientific literacy by the general public and the overabundance of ways to gather such information (accurate or not). As concerned parents search for answers, one can begin to see how even scientifically unsupported links could begin to take hold as families grapple with how to make intelligent public health risk assessments. The notion that vaccines cause autism was rejected long ago by most scientists. Despite this, more work clearly needs to be done to bridge the gap between public perception and scientific understanding. Gross, L. 2009. A broken trust: Lessons from the vaccine–autism wars. PLoS Biology 7:e1000114. Larson, H.J., et al. 2011. Addressing the vaccine confidence gap. Lancet 378:526. Immunology Is More Than Just Vaccines and Infectious Disease v Introduction of Antibiotics (1920s) Ø antibiotics= chemical agents designed to destroy certain types of bacteria Ø one major breakthrough in the treatment of infectious disease v Antiviral drugs Ø also available but most are not effective against many of the most common viruses, including influenza B. Basic Concepts of Immunology Learning Objective: At the end of the lesson, the learners will be able to identify concepts in immunology that will help bridge the gap between their current knowledge and the subsequent chapters 1. Pathogens come in many forms and must first breach natural barriers v Pathogens Ø organisms causing disease v Pathogenesis Ø process by which pathogens induce illness in the host v Immune pathways do not become engaged until foreign organisms first breach the physical barriers of the body v Each encounter with pathogen engages a distinct set of strategies that depends on the nature of the invader and on the microenvironment Ø Some areas of the body (e.g. central nervous system) are virtually “off limits” for the immune system because the immune response could do more damage than the pathogen. Ø Some foreign compounds that enter via the digestive tract, including the commensal microbes that help us digest food, are tolerated by the immune system. ü However, when these same foreigners enter the bloodstream they are typically treated much more aggressively 2. The Immune Response Quickly Becomes Tailored to Suit the Assault v An effective defense relies heavily on the nature of the invading pathogen offense Ø cells and molecules that become activated depend on the chemical structures present on the pathogen, whether it resides inside or outside of host cells, and the location of the response ü E.g. cytotoxic T lymphocytes § immune cells capable of detecting changes that occur in a host cell after it becomes infected § bind to viral proteins present in the cytosol and initiate an early warning system, alerting the cell to the presence of an invader 3. Pathogen Recognition Molecules Can Be Encoded in the Germline or Randomly Generated v Pattern recognition receptors (PRRs) Ø a variety of receptors naturally expressed by the WBC Ø specifically recognize polysaccharides that encapsulate bacteria Ø proteins encoded in the genomic DNA and are always expressed by many different immune cells v B- and T- lymphocytes Ø express unique recognition molecule, resulting in a population with the theoretical potential to respond to any antigen that may come along  Generation of diversity and clonal selection in T and B lymphocytes. Maturation in T and B cells, which occurs in primary lymphoid organs (bone marrow for B cells and thymus for T cells) in the absence of antigen, produces cells with a committed antigenic specificity, each of which expresses many copies of surface receptor that binds to one particular antigen. Different clones of B cells (1, 2, 3, and 4) are illustrated in this figure. Cells that do not die or become deleted during this maturation and weeding-out process move into the circulation of the body and are available to interact with antigen. There, clonal selection occurs when one of these cells encounters its cognate or specific antigen. Clonal proliferation of an antigen- activated cell (number 2 or pink in this example) leads to many cells that can engage with and destroy the antigen, plus memory cells that can be called upon during a subsequent exposure. The B cells secrete antibody, a soluble form of the receptor, reactive with the activating antigen. Similar processes take place in the T-lymphocyte population, resulting in clones of memory T cells and effector T cells; the latter include activated TH cells, which secrete cytokines that aid in the further development of adaptive immunity, and cytotoxic T lymphocytes (CTLs), which can kill infected host cells 4. Tolerance Ensures That the Immune System Avoids Destroying the Host v The immune system must somehow avoid accidentally recognizing and destroying host tissues = TOLERANCE Ø Frank Macfarlane Burnet and Peter Medawar in 1960 (Nobel Prize in Physiology or Medicine, 1960) ü Burnet= first to propose that exposure to non-self antigens during certain stages of life could result in an immune system that ignored these antigens later ü Medawar= later proved the validity of Burnet’s theory using mouse embryo  5. The Immune Response Is Composed of Two Interconnected Arms: Innate and Adaptive Immunity v These two collaborate to protect the body against foreign invaders Ø Innate immunity ü includes built-in molecular and cellular mechanisms that are encoded in the germline ü evolutionarily more primitive ü nonspecific ü aimed at preventing infection or quickly eliminating common invaders ü includes physical and chemical barriers to infection, and DNA-encoded receptors Ø Adaptive immunity ü much more attuned to subtle molecular differences ü relies on B and T lymphocytes ü takes longer to come on board but is much more antigen specific § partly because fewer cells possess the perfect receptor for the job § rely on prior encounter and “categorizing” of antigens undertaken by innate processes ü once the B and T cells have been selected and have honed their attack strategy, they become formidable opponents that can typically resolve the infection ü evolves in real time in response to infection and adapts to better recognize, eliminate, and remember the invading pathogen ü involve a complex and interconnected system of cells and chemical signals that come together to finish the job initiated during the innate immune response  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 1. SKIN ü Epithelial cells of the outermost layer (stratum corneum) compacted together, and impregnated with an insoluble protein, KERATIN o result is a thick, tough layer that is highly impervious and waterproof o few pathogens can penetrate this unbroken barrier, especially in regions such as the soles of the feet or the palms of the hands, where the stratum corneum is much thicker than on other parts of the body  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 1. SKIN ü other cutaneous barriers: hair follicles and skin glands hair shaft is periodically extruded, and the follicle cells are shed flushing effect of sweat glands also helps remove microbes nasal hair traps larger particles  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 2. MUCOCUTANEOUS MEMBRANES ü found in the digestive, urinary, and respiratory tracts and of the eye ü mucous coat= impedes the entry and attachment of bacteria ü blinking and tear production (lacrimation)= flush the eye’s surface with tears and rid it of irritants ü constant flow of saliva= helps carry microbes into the harsh conditions of the stomach ü vomiting and defecation= evacuate noxious substances or microorganisms from the body  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 2. MUCOCUTANEOUS MEMBRANES ü copious flow of mucus and fluids in rhinitis helps to flush out the nasal passageways ü irritation of the nasal passage initiates a sneeze, which expels a large volume of air ü acute sensitivity of the bronchi, trachea, and larynx to foreign matter triggers coughing, which ejects irritants  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 3. URINE ü the genitourinary tract derives partial protection from the passage of urine through the ureters and from periodic bladder emptying that flushes the urethra  NON-SPECIFIC HOST RESISTANCE A. Physical or Anatomical Barriers at the Body’s Surface 4. MICROBIOTA ü normal microbial residents can create an unfavorable environment for pathogens by competing for limited nutrients or by altering the chemical make up of various body regions  NON-SPECIFIC HOST RESISTANCE B. Nonspecific Chemical Defenses Ø skin and mucous membranes possess chemical defenses: ü sebaceous secretions= exert an antimicrobial effect, ü meibomian glands of the eyelids= lubricate the conjunctiva with an antimicrobial secretion ü lysozyme in saliva= hydrolyzes the peptidoglycan in the cell wall of bacteria  NON-SPECIFIC HOST RESISTANCE B. Nonspecific Chemical Defenses Ø skin and mucous membranes possess chemical defenses: ü defensins= produced by various cells and tissues in the skin and intestines damage cell membranes and lyse bacteria and fungi ü lactic acid and electrolytes in sweat and the skin’s acidic pH and fatty acid content= inhibitory to many microbes  NON-SPECIFIC HOST RESISTANCE B. Nonspecific Chemical Defenses Ø skin and mucous membranes possess chemical defenses: ü hydrochloric acid content of the stomach= renders protection against many pathogens that are swallowed ü intestine’s digestive juices and bile= potentially destructive to microbes  NON-SPECIFIC HOST RESISTANCE C. Genetic Resistance to Infection Ø the genetic makeup of an individual is different enough to ensure protection from some pathogens ü examples: humans carrying genes for sickle-cell anemia are resistant to malaria genetic differences exist in susceptibility to tuberculosis, leprosy, and certain systemic fungal infections  SECOND-LINE DEFENSE A. INFLAMMATION Ø a normal and necessary process that helps to clear away invading microbes and cellular debris left by immune reactions  SECOND-LINE DEFENSE A. INFLAMMATION Ø major events:  SECOND-LINE DEFENSE A. INFLAMMATION Ø major events :  SECOND-LINE DEFENSE v Fever Ø adjunct to inflammation Ø inhibits multiplication of temperature-sensitive microorganisms Ø impedes the nutrition of bacteria by reducing the availability of iron Ø increases metabolism and stimulates immune reactions and naturally protective physiological processes  SECOND-LINE DEFENSE B. PHAGOCYTOSIS Ø ingestion and destruction by white blood cells Ø summary of the major activities of phagocytes: ü survey of tissue compartments and target microbes, particulate matter (dust, carbon particles, antigen-antibody complexes), and injured or dead cells; ü ingestion and elimination of these materials; and ü extraction of immunogenic information (antigens) from foreign matter  SECOND-LINE DEFENSE C. INTERFERON Ø a small protein produced naturally by certain white blood and tissue cells Ø used in therapy against certain viral infections and cancer and can be used as an immune enhancer  SECOND-LINE DEFENSE D. COMPLEMENT Ø a versatile backup system Ø three primary defensive features ü membrane attack complex (MAC), which kills pathogens directly ü coating of pathogens with molecules that make them more attractive to phagocytes (opsonization) ü recruitment of inflammatory cells and triggering of cytokine release  ADAPTIVE IMMUNITY v also called acquired immunity or third line of defense v specific v responsible for the long-term protection we develop through infections (measles or mumps) or vaccinations  ADAPTIVE IMMUNITY v lymphocytes Ø types of white blood cells Ø originate from stem cells in the bone marrow ü some migrate to the thymus, an organ in the thoracic cavity above the heart develop into T lymphocyte ü B Lymphocyte or B cells- remain in the bone marrow  ADAPTIVE IMMUNITY v in adaptive immunity, recognition occurs when a B or T cell binds to an antigen via a protein called an antigen receptor Ø Antigen= any substance that elicits a B or T cell response ü e.g. bacterial or viral protein  ADAPTIVE IMMUNITY v the small, accessible portion of an antigen that binds to an antigen receptor is called an epitope  ADAPTIVE IMMUNITY v B CELLS AND ANTIBODIES Ø antigen recognition: ü B cell antigen receptor= Y-shaped molecule  ADAPTIVE IMMUNITY v B CELLS AND ANTIBODIES Ø antigen recognition: ü binding of a B cell antigen receptor to an antigen leads to formation of cells that secrete a soluble form of the receptor this secreted protein is called an antibody, also known as an immunoglobulin (Ig)  ADAPTIVE IMMUNITY v B CELLS AND ANTIBODIES Ø antigen recognition: ü B cell antigen receptors and antibodies bind to intact antigens in the blood and lymph  ADAPTIVE IMMUNITY v T Cells Ø antigen recognition: ü T cell antigen receptor consists of an α chain and a β chain  ADAPTIVE IMMUNITY v T Cells Ø antigen recognition: ü Near the base of the T cell antigen receptor is a transmembrane region that anchors the molecule in the cell’s plasma membrane  ADAPTIVE IMMUNITY v T Cells Ø antigen recognition: ü recognition of protein antigens by T cells begins when a pathogen or part of a pathogen either infects or is taken in by a host cell ü Major histocompatibility complex (MHC) molecules bind peptide fragments derived from pathogens and display them on the cell surface for recognition  ADAPTIVE IMMUNITY v T Cells Ø Helper T cell (CD4) ü A type of T cell that triggers: humoral immune responses o occurs in the blood and lymph o antibodies help neutralize or eliminate toxins and pathogens in the blood and lymph cell-mediated immune responses o specialized T cells that destroy infected host cells  ADAPTIVE IMMUNITY v T Cells Ø Cytotoxic T cells (TC or CD8) ü recognize and react to foreign cells, cancer cells, and graft tissues and secrete chemicals that directly damage and kill these cells.  ADAPTIVE IMMUNITY v T Cells Ø Natural killer cells (NK) ü responsible for early killing of infected cells and cancer cells in response to various cytokines