Introduction to Immune Response

• The immune system protects animals against pathogenic microorganisms and cancer
• Cells and molecules work together to recognize and eliminate invaders in a dynamic complex network

Functional Immune Response

• Functional immune responses are divided into recognition and response activities
• Recognition is the ability to recognize a variety of cells and molecules and discriminate between foreign molecules, own cells, and proteins
• Response is an effector response to eliminate or neutralize the organism suited to eliminate the particular type of pathogen
• Later exposure to the same foreign organism includes a memory response
• Memory responses are characterized by more rapid immune reactions
• The immune system can fail or even turn against its own host

Historical Perspective

• The earliest reference to immunity can be traced back to 430 BC during the Peloponnesian War
• During the Peloponnesian War, it was noticed only those who had recovered from the plague could safely nurse the sick
• The Latin term Immunis means exempt and is the origin of the English word "Immunity"
• In the 15th century, Chinese and Turks attempted to prevent smallpox by variolation
• Variolation involved inhaling or scratching dried crusts of pustules onto the skin
• In 1718, the wife of the British ambassador in Constantinople had her children inoculated

Jenner's Contribution

• Jenner made a significant advancement in the deliberate development of immunity by targeting smallpox
• Milkmaids who contracted the mild disease cowpox were subsequently immune to the more severe smallpox
• Jenner reasoned that introducing fluid from a cowpox pustule into people might protect them from smallpox.
• Jenner inoculated an eight-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox to test this idea
• The child did not develop smallpox as predicted

Pasteur's Discoveries

• Pasteur grew the bacterium thought to cause fowl cholera and showed that chickens injected with cultured bacterium developed cholera
• After coming back, he injected some chickens with old culture, chickens became ill, but surprisingly they recovered
• Pasteur grew a fresh culture of bacterium to inject into fresh chickens but he was limited with the number of chickens he used
• He used the previously injected chickens and again the chickens were completely recovered from disease.
• Aging weakened the virulence of the pathogen and such attenuated strain might be administered to protect against the disease
• Pasteur called this attenuated strain a vaccine
• Pasteur vaccinated one group of sheep with heat-attenuated anthrax bacillus, which causes tissue destruction and breathing difficulty
• He then challenged the vaccinated sheep and some unvaccinated sheep with a virulent culture of the bacillus
• All vaccinated sheep lived, and all unvaccinated animals died
• In 1885, Pasteur administered his first vaccine to a human

Vaccination Efforts

• Vaccination is an ongoing, worldwide enterprise
• As a critical mass of people acquire protective immunity through vaccination or infection
• They can serve as a buffer for the rest via herd immunity
• Herd immunity works by decreasing the number of individuals who can harbor and spread an infectious agent
• This significantly decreases the chances that susceptible individuals will become infected

Types of Immunity

• Some scientists suggested that cells are responsible for immunity, while others suggested that fluid in plasma is responsible
• Metchnikoff observed that certain WBC, which he called "phagocytes," ingested microorganisms and other foreign material

Humoral Immunity

• The active immune component is in blood serum
• Serum can neutralize or precipitate toxins and agglutinate bacteria
• A fraction of serum is responsible for all these activities: antibodies
• Antiserum, the antibody-containing serum fraction from a pathogen-exposed individual, derived from horses, is used to treat snake or scorpion bite victims
• The treatment is called passive immunity
• Newborn infants benefit from passive immunity by the presence of maternal antibodies in their circulation
• Passive immunity can supply a quick, short-lived, and limited solution
• This is because the cells that produce these antibodies are not being transferred
• Administration of a vaccine or natural infection is called active immunity in the host
• It involves the production of one’s own immunity

Cell-Mediated Immunity

• In the 1940s, scientists succeeded in conferring immunity against tuberculosis by transferring WBCs between guinea pigs
• With the emergence of improved cell culture and transfer techniques in the 1950s, the lymphocyte was identified as the cell type responsible for both cellular and humoral immunity:
  • B lymphocytes
  • T lymphocytes
• Cellular immunity is imparted by T cells
• Antibodies produced by B cells confer humoral immunity

Recognizing Foreign Substances

• An antigen is any substance that elicits a specific response by B or T lymphocytes
• Nonpathogenic substances, such as RBC from other species, can also serve as antigens
• Injecting an animal with any nonself organic chemical can induce production of antibodies that would bind specifically to the chemical
• Studies demonstrated that antibodies have a capacity for an almost unlimited range of reactivity
• Molecules differing in the smallest detail, such as a single amino acid, can be distinguished by their reactivity with different antibodies
• Two major theories were proposed to account for this specificity: the selective theory and the instructional theory

Selective Theory

• Paul Ehrlich proposed the selective theory to explain the origin of serum antibody
• Ehrlich proposed that cells in the blood express a variety of receptors that could bind to infectious agents and inactivate them
• Binding of the receptor to an infectious agent was like the fit between a lock and key
• Interaction between an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity
• Cells were pluripotent and expressed a number of different receptors, each of which could be individually “selected.”
• The specificity of the receptor was determined in the host before its exposure to the foreign antigen, and therefore the antigen selected the appropriate receptor.
• Ehrlich's theory proved mostly correct, with minor refinements:
  • Instead of one cell making many receptors, each cell makes many copies of just one membrane-bound receptor, meaning each cell has only one specificity
  • Army of cells, each with a different antigen specificity, is required
• The selected B cell can be triggered to proliferate and to secrete many copies of these receptors in soluble form once it has been selected by antigen binding

Instructional Theories

• The selective theory was challenged by instructional theories in the 1930s and 1940s
• These theories held that antigens played a central role in determining the specificity of the antibody molecule
• According to instructional theorists, a particular antigen would serve as a template around which antibody would fold
• The antibody molecule would thereby assume a configuration complementary to that of the antigen template

Clonal Selection Theory

• According to this theory, an individual B or T lymphocyte expresses many copies of a membrane receptor that is specific for a single, distinct antigen
• This unique receptor specificity is determined in the lymphocyte before it is exposed to the antigen
• Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of daughter cells with the same receptor specificity as the parent cell

Immune Response Tailoring

• Pathogen recognition involves an interaction between the foreign organism and a recognition molecule expressed by host cells
• Recognition molecules are frequently membrane-bound receptors; however, soluble or secreted recognition molecules can also be engaged
• Ligands for recognition molecules can include whole pathogens, antigenic fragments of pathogens, or products secreted by these foreign organisms

Components of Immune Response

• The entirety of the immune response is the engagement of a complex system of cells
• These cells can recognize and kill or engulf a pathogen, which is known as cellular immunity
• In addition, soluble proteins help to orchestrate labeling and destruction of foreign invaders, which is known as humoral immunity

Viral Infections

• All viruses are tiny, obligate, intracellular pathogens that spend the majority of their life cycle residing inside host cells
• An effective defense strategy must involve identification of infected host cells with recognition of the surface of the pathogen
• Some immune cells must be capable of detecting changes in an infected host cell
• This is achieved by a range of cytotoxic cells but especially cytotoxic T lymphocytes, a cellular arm of immunity
• Sacrifice of virally infected cells is often the only way to truly eradicate this type of pathogen
• HIV infects a type of T cell called a T helper cell
• T helper cells guide the behavior of other immune cells, including B cells, and they are pivotal for selecting the pathway taken by the immune response

Extracellular Pathogens

• Extracellular pathogens, fungi, most bacteria, and parasites rely primarily on cell surface or soluble recognition molecules that probe the extracellular spaces of the body
• B cells and the antibodies they produce as a part of humoral immunity play major roles in response to extracellular pathogens
• Antibodies can squeeze into spaces in the body where B cells themselves may not be able to reach, helping to identify pathogens hiding in these out-of-reach places

Parasites

• Large parasites present a problem because they are too big for phagocytic cells to envelop
• Cells that can deposit toxic substances or that can secrete products that induce expulsion (e.g., sneezing, coughing, vomiting) become a better strategy against large parasites

Pathogen Recognition Molecules

• Most pathogens express at least a few chemical structures that are not typically found in mammals
• Pathogen-associated molecular patterns (PAMPs) are common foreign structures that characterize whole groups of pathogens.
• These unique antigenic structures are what the immune system frequently recognizes first
• WBC naturally express a variety of receptors, pattern recognition receptors (PRRs), that specifically recognize these sugar residues, as well as other common foreign structures
• PRRs are proteins encoded in the genomic DNA that are always expressed by many different immune cells
• When PRRs detect PAMPs, a cascade of events labels the target pathogen for destruction
• These conserved, germline-encoded recognition molecules are a first line of defense for the quick detection of many of the typical chemical identifiers carried by the most common invaders

Generation of Diversity

• Generation of diversity is employed only by developing B and T lymphocytes
• The result is a group of B and T cells where each expresses many copies of one unique recognition molecule
• This results in a population with the theoretical potential to respond to any antigen that may come along
• This is accomplished by rearranging and editing the genomic DNA that encodes the antigen receptors expressed by each B or T lymphocyte
• In B lymphocytes, these recognition molecules are B-cell receptors when they are surface structures and antibodies in their secreted form
• In T lymphocytes, where no soluble form exists, they are T-cell receptors

Tolerance

• One consequence of generating random recognition receptors is that some could recognize and target the host
• The immune system must avoid accidentally recognizing and destroying host tissues in order for this strategy to work effectively
• This principle, which relies on self/nonself discrimination, is called tolerance
• To establish tolerance, the antigen receptors present on developing B and T cells must first pass a test of nonresponsiveness against host structures
• This process begins shortly after these randomly generated receptors are produced
• Tolerance is achieved by the destruction or inhibition of any cells that have inadvertently generated receptors with the ability to harm the host
• Successful maintenance of tolerance ensures that the host always knows the difference between self and non-self

Danger Hypothesis

• Immune system constantly evaluates each new encounter more for its potential to be dangerous to the host than for whether it is self or not
• Dysfunctional tolerance is at the root of most autoimmune diseases

Two Arms of the Immune System

• The immune system is composed of two interconnected arms:
  • Innate Immunity
  • Adaptive Immunity

Innate Immunity

• The less specific component of the immune system
• It is the first line of defense against infection
• The components of innate immunity are present before the onset of infection
• Innate immunity constitutes a set of disease-resistance mechanisms that are not specific to a particular pathogen
• Innate immunity includes cellular and molecular components
• Phagocytic cells such as macrophages and neutrophils, barriers such as skin, and a variety of antimicrobial compounds synthesized by the host are part of innate immunity
• Four types of defensive barriers: anatomic, physiologic, phagocytic, and inflammatory
  • Complement:
    • Serum proteins circulate in an inactive state
    • A variety of mechanisms convert inactive forms of complement proteins into an active state with the ability to damage membranes of pathogens
    • Complement functions as an effector system triggered by the binding of antibodies to certain cell surfaces
    • Complement may be activated by reactions between complement molecules and certain components of microbial cell walls

Adaptive Immunity

• Adaptive immunity comes into play when there is an antigenic challenge to the organism
• It responds to challenges with a high degree of specificity and has a “memory” property
• Adaptive immunity is mobilized within 5 or 6 days after initial exposure to that antigen
• Re-exposure to the same antigen results in a memory response
• The immune response to the second challenge occurs more quickly than the first, is stronger, and is often more effective in neutralizing and clearing pathogen
• Adaptive immunity is slower because the antigen-specific, randomly generated receptors are found on B and T cells
• 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
• Once these B and T cells have been selected and have honed their attack strategy, they can resolve the infection

Immune System Communication

• The two systems, innate and adaptive, must be able to communicate by both cell-cell contact and by soluble messengers
• Most of these soluble proteins are cytokines
• Cytokines and cell surface ligands can bind with receptors found on responding cells and signal these cells to perform new functions, such as synthesis of other soluble factors or differentiation to a new cell type
• A subset of these soluble signals are called chemokines because they have chemotactic activity
• Chemokines can recruit specific cells to the site

Adaptive Immune Responses and Memory

• During a first encounter with a foreign antigen, adaptive immunity undergoes a primary response
• Key lymphocytes used to eradicate the pathogen are clonally selected and enlisted to resolve the infection
• All subsequent encounters with the same antigen or pathogen are referred to as the secondary response
• During a secondary response, memory cells trained during the primary response are re-enlisted to fight again
• Memory cells provide the means for a response that is rapid, antigen-specific, and effective
• Sometimes, as with some vaccines, one round of antigen encounter and adaptation is not enough to impart protective immunity from the pathogen in question
• In many of these cases, immunity can develop after a second or even a third round of exposure to an antigen

Immune Dysfunction

• Common manifestations of immune dysfunction:
  • Hypersensitivity (allergy and asthma)
  • Graft rejection
  • Autoimmune disease
  • Immunodeficiency

Allergy

• Allergy and asthma result from inappropriate immune responses, often to common antigens such as plant pollen or food
• Most allergic reactions in humans are not rapidly fatal
• A specific allergic or anaphylactic response usually involves one type of antibody, immunoglobulin E
• Binding of immunoglobulin E to a specific antigen (allergen) releases substances that cause irritation and inflammation
• Symptoms may include sneezing and difficulty in breathing (asthma), among others

Anaphylaxis

• Successful vaccination results in phylaxis (protection)
• Anaphylaxis (anti-protection) is an extreme, rapid, and often lethal overreaction of the immune response to something it has encountered before
• Anaphylaxis can result in certain cases in which exposure to an antigen is repeated
• The term is used today to describe a severe life-threatening, allergic response
• Fortunately, most hypersensitivity or allergic reactions in humans are not rapidly fatal

Autoimmune Disease

• An autoimmune disease occurs when the immune system malfunctions by losing its sense of self and nonself, permitting an immune attack upon the host
• Multiple sclerosis is due to an autoimmune attack on the brain and central nervous system
• Rheumatoid arthritis is an attack on the joints of arms and legs
• Crohn’s disease is an attack on intestinal tissues that leads to the destruction of gut epithelia and poor absorption of food

Immunodeficiency

• Immunodeficiency occurs when any component of innate or adaptive immunity is defective
• Immunodeficiency can arise due to inherited genetic factors (primary)
• Immunodeficiency can arise due to disruption, by chemical, physical, or biological agents
• A rare but much more extreme deficiency is severe combined immunodeficiency (SCID), which affects both B and T cells and basically wipes out adaptive immunity
• When untreated, SCID frequently results in death from infection at an early age
• AIDS results from infection with HIV, which causes the infection and destruction of T helper cells
• Collapse of the immune system occurs as a result of infection by HIV
• AIDS is fatal within 8-10 years after infection
• Candida albicans, present nearly everywhere and causing no issues for most individuals, can cause an irritating rash and a spreading infection of the mucosal surface of the mouth and vagina in patients suffering from immune deficiency
• If left unchecked, Candida albicans can spread, causing systemic candidiasis, a life-threatening condition
  • Opportunistic infections occur when the host immune system is deficient

Tissue Transplantation

• The immune system is a significant challenge when dealing with tissue transplantation
• The immune response renders tissue transplantation challenging
• When the immune system encounters foreign cells or tissue, it responds strongly
• The immune system recognizes the transplant as non-self and attacks it
• Rejection can be suppressed by drugs, but the drugs suppress all the immune functions

Cancer

• Many tumor cells express unique or developmentally inappropriate proteins
• These proteins make tumor cells potential targets for immune cell recognition and elimination, as well as targets for therapeutic intervention
• With many microbial pathogens, the increased genetic instability of rapidly dividing cancer cells gives them an advantage in terms of evading immune detection and elimination machinery