Introduction to Immunity PDF

Overview of Immune System Dr. Sneha Dokhale Assistant Professor BK Birla College (Autonomous), Kalyan  A Historical Perspective of Immunology  The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were thereafter protected...

Overview of Immune System Dr. Sneha Dokhale Assistant Professor BK Birla College (Autonomous), Kalyan  A Historical Perspective of Immunology  The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were thereafter protected from the disease.  The Latin term immunis, meaning “exempt,” is the source of the English word immunity, a state of protection from infectious disease.  In describing a plague in Athens, Thucydides wrote in 430 BC that only those who had recovered from the plague could nurse the sick because they would not contract the disease a second time.  Early Vaccination Studies Led the Way to Immunology The first recorded attempts to deliberately induce immunity were performed by the Chinese and Turks in the fifteenth century. They were attempting to prevent smallpox, a disease that is fatal in about 30% of cases and that leaves survivors disfigured for life. Reports suggest that the dried crusts derived from smallpox pustules were either inhaled or inserted into small cuts in the skin (a technique called variolation) in order to prevent this dreaded disease. In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador in Constantinople, observed the positive effects of variolation on the native Turkish population and had the technique performed on her own children.  Early Vaccination Studies Led the Way to Immunology The English physician Edward Jenner later made a giant advance in the deliberate development of immunity, again targeting smallpox. In 1798, intrigued by the fact that milkmaids who had contracted the mild disease cowpox were subsequently immune to the much more severe smallpox, Jenner reasoned that introducing fluid from a cowpox pustule into people (i.e., inoculating them) might protect them from smallpox. To test this idea, he inoculated an 8-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As predicted, the child did not develop smallpox. Although this represented a major breakthrough, as one might imagine, these sorts of human studies could not be conducted under current standards of medical ethics.  Early Vaccination Studies Led the Way to Immunology Louis Pasteur had succeeded in growing the bacterium that causes fowl cholera in culture, and confirmed this by injecting it into chickens that then developed fatal cholera. After returning from a summer vacation, he and colleagues resumed their experiments, injecting some chickens with an old bacterial culture. The chickens became ill, but to Pasteur’s surprise, they recovered. Interested, Pasteur then grew a fresh culture of the bacterium with the intention of trying this experiment again. But as the story is told, his supply of chickens was limited, and therefore he tested this fresh bacterial culture on a mixture of chickens; some previously exposed to the “old” bacteria and some new, unexposed birds. Unexpectedly, the chickens with past exposure to the older bacterial culture were completely protected from the disease and only the previously unexposed chickens died.  Early Vaccination Studies Led the Way to Immunology Pasteur hypothesized and later showed that aging had weakened the virulence of the bacterial pathogen and that such a weakened or attenuated strain could be administered to provide immunity against the disease. He called this attenuated strain a vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work with cowpox inoculation. Pasteur extended his discovery to other diseases, demonstrating that it was possible to attenuate a pathogen and administer the attenuated strain as a vaccine  Early Vaccination Studies Led the Way to Immunology In 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. 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. 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.  Vaccination Is an Ongoing, Worldwide Enterprise The emergence of the study of immunology and the discovery of vaccines are tightly linked. The goal of vaccination is to expose the individual to a pathogen (or a fragment of pathogen) in a safe way, allowing the immune cells to respond, developing and honing a strategy to fight this pathogen or others that are similar. When it works, this experiential learning process can produce extremely specific and long-lived memory cells, capable of protecting the host from the pathogen for many decades.  Vaccination Is an Ongoing, Worldwide Enterprise  In 1977, the last known case of naturally acquired smallpox was seen in Somalia. This dreaded disease was eradicated by universal application of a vaccine similar to that used by Jenner in the 1790s.  One consequence of eradication is that universal vaccination becomes unnecessary. This is a tremendous benefit, as most vaccines carry at least a slight risk to those vaccinated.  In many cases every individual does not need to be immune in order to protect most of the population.  As a critical mass of people acquires protective immunity, either through vaccination or recovery from infection, they can serve as a buffer for the rest.  This principle, called herd immunity, works by decreasing the number of individuals who can harbor and spread an infectious agent, significantly reducing the chances that susceptible individuals will become infected.  Vaccination Is an Ongoing, Worldwide Enterprise  This presents an important altruistic consideration: although many of us could survive infectious diseases for which we receive a vaccine (such as the flu), this is not true for everyone.  Some individuals cannot receive the vaccine (e.g., the very young or immune compromised), and vaccination is never 100% effective.  In other words, the susceptible, nonimmune individuals among us can benefit from the pervasive immunity of their neighbors.  For good reason, the balance of personal choice and public good is an area of heated debate  Immunology Is about More than Just Vaccines and Infectious Disease  For some diseases, immunization programs may be the best or even the only effective defense.  At the top of this list are infectious diseases that can cause serious illness or even death in unvaccinated individuals.  Those transmitted by microbes that spread rapidly between hosts are especially good candidates for vaccination.  However, vaccination, a costly process, is not the only way to prevent or treat infectious disease.  Many infections are prevented, first and foremost, by other means. For instance, access to clean water, good hygiene practices, and nutrient-rich diets go a long way toward inhibiting transmission of infectious agents.  Immunology Is about More than Just Vaccines and Infectious Disease  In addition, some infectious diseases are self-limiting, easily treatable, and nonlethal for most individuals; these diseases are unlikely targets for expensive vaccination programs.  They include the common cold, caused by rhinovirus infection, and cold sores that result from herpes simplex virus infection.  Finally, some infectious agents are just not amenable to vaccination.  This could be due to a range of factors, such as the number of different molecular variants of the organism, the complexity of the regimen required to generate protective immunity, or an inability to establish the needed immunologic memory responses  The Immune Response Is Composed of Two Interconnected Arms Passive Active Immunity Immunity Innate Immunity “possessed at birth, possessed as an essential characteristic” Always present Adaptive Immunity Humoral Immunity Cell Mediated “to make suitable to or fit to a specific Immunity use or situation” Created and modified These two systems collaborate to protect the body against foreign invaders The Immune Response Is Composed of Two Interconnected Arms  Innate Immunity  Innate immunity includes built-in molecular and cellular mechanisms that are evolutionarily primitive and aimed at preventing infection or quickly eliminating common invaders.  This includes physical and chemical barriers to infection, as well as the DNA-encoded receptors recognizing common chemical structures of many pathogens.  These are inherited from our parents and constitute a quick-and-dirty response; rapid recognition and subsequent phagocytosis or destruction of the pathogen is the outcome.  Innate immunity also includes a series of preexisting serum proteins, collectively referred to as complement, that bind common pathogen-associated structures and initiate a cascade of labeling and destruction events  This highly effective first line of defense prevents most pathogens from taking hold, or eliminates infectious agents within hours of encounter.  The recognition elements of the innate immune system are fast, some occurring within seconds of a barrier breach, but they are not very specific and are therefore unable to distinguish between small differences in foreign antigens.  Adaptive Immunity  Adaptive immunity is much more attuned to subtle molecular differences.  This part of the system, which relies on B and T lymphocytes, takes longer to come on board but is much more antigen specific.  Typically, there is an adaptive immune response against a pathogen within 5 or 6 days after the barrier breach and initial exposure, followed by a gradual resolution of the infection.  Adaptive immunity is slower partly because fewer cells possess the perfect receptor for the job: the antigen-specific receptors on T and B cells that are generated via DNA rearrangement, mentioned earlier.  It is also slower because parts of the adaptive response rely on prior encounter and “categorizing” of antigens undertaken by innate processes. After antigen encounter, T and B lymphocytes undergo selection and proliferation  Although slow to act, once these B and T cells have been selected, replicated, and have honed their attack strategy, they become formidable opponents that can typically resolve the infection.  Adaptive Immunity  The adaptive arm of the immune response evolves in real time in response to infection and adapts (thus the name) to better recognize, eliminate, and remember the invading pathogen.  Adaptive responses involve a complex and interconnected system of cells and chemical signals that come together to finish the job initiated during the innate immune response.  The goal of all vaccines against infectious disease is to elicit the development of specific and long-lived adaptive responses, so that the vaccinated individual will be protected in the future when the real pathogen comes along.  This arm of immunity is orchestrated mainly via B and T lymphocytes following engagement of their randomly generated antigen recognition receptors.  The full development of the adaptive response is dependent on earlier innate pathways.  Signaling - Cytokines of ct k illing CD8 Tc Cell Mediated Dire he cell + t Immunity Tc Tc N MHC -I Endogenous Ags- K Cytosolic pathway Target cells APCs MHC - B Cells II Memory B Macrophages Ag-Ab Dendritic Cells Exogenous Ags- Endocytic pway Th B cells complexes - Th1 CD4+ cells Plasma B - Th2 cells Humoral Complement Immunity System 19  Adaptive Immunity  Adaptive immunity is capable of recognizing and selectively eliminating specific foreign microorganisms and molecules (i.e., foreign antigens). Unlike innate immune responses, adaptive immune responses are not the same in all members of a species but are reactions to specific antigenic challenges.  Adaptive immunity displays four characteristic attributes:  Adaptive Immunity  The antigenic specificity of the immune system permits it to distinguish subtle differences among antigens.  Antibodies can distinguish between two protein molecules that differ in only a single amino acid.  The immune system is capable of generating tremendous diversity in its recognition molecules, allowing it to recognize billions of unique structures on foreign antigens.  Once the immune system has recognized and responded to an antigen, it exhibits immunologic memory; that is, a second encounter with the same antigen induces a heightened state of immune reactivity.  Because of this attribute, the immune system can confer life-long immunity to many infectious agents after an initial encounter.  Finally, the immune system normally responds only to foreign antigens, indicating that it is capable of self/nonself recognition.  The ability of the immune system to distinguish self from nonself and respond only to nonself molecules is essential, as the outcome of an inappropriate response to self molecules can be fatal. Adaptive Immunity-Primary & Secondary Response  Adaptive Immunity-Primary & Secondary Response  When an antigen is introduced for the first time in a host, it activates T and B cells.  Activation of B- cells produces memory cells and plasma cells.  Plasma cells produce antibodies whereas memory cells are long lived and remain in blood for a long time.  This immune response induced for the first time in host is called primary immune response.  Duration from the entry (injection) of antigen to the appearance of first antibody in blood is called lag phase which is normally of 4-7 days in a primary immune response.  T and B-cells are activated during this phase for the production of antibodies.  The level of antibody increases continuously, reaches the peak level and then declines  Adaptive Immunity-Primary & Secondary Response  If same antigen is injected into the same host for the second time in life, secondary immune response is induced.  Secondary immune response occurs due to the persistence of memory cells in the blood.  These memory cells directly get converted into plasma cells when activated by antigen.  In this case, activation and mitosis of T and B cells are not required because of which the lag phase is shorter (1-3 days) in secondary immune response.  Usually, 100 times more antibodies are produced in secondary immune response.  Unlike in primary immune response, IgG is produced instead of IgM in secondary response.  Antibodies produced in secondary response have greater affinity for antigen than the antibody produced in primary immune response. Adaptive Immune Response Humoral Cellular  Humoral Immunity  Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids.  Humoral immunity is named so because it involves substances found in the humors, or body fluids.  It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody- mediated immunity.  Humoral immunity refers to antibody production and the coinciding processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, and affinity maturation and memory cell generation.  It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.  Cell Mediated Immunity  Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.  Cellular immunity protects the body through:  T-cell mediated immunity or T-cell immunity: activating antigen-specific cytotoxic T cells that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;  Macrophage and natural killer cell action: enabling the destruction of pathogens via recognition and secretion of cytotoxic granules (for natural killer cells) and phagocytosis (for macrophages); and  Stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.  Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but