THE IMMUNE SYSTEM: INNATE AND ADAPTIVE BODY DEFENSES

THE IMMUNE SYSTEM: INNATE AND ADAPTIVE BODY DEFENSES

INNATE (NONSPECIFIC) DEFENSES
Includes two lines of defense: First Line of Defense: External Surface Barriers: Skin and Mucosae Second Line of Defense: Antimicrobial proteins Phagocytes Inflammation

Adaptive (Specific) Defense System
Third Line of Defense: Takes considerably more time to mount than the innate response Attacks particular foreign substances (antigens)

INNATE (NONSPECIFIC) DEFENSES
External Surface Barriers: Skin and Mucosae Skin, a highly keratinized epithelial membrane, represents a physical barrier to most microorganisms and their enzymes and toxins Mucous membranes line all body cavities open to the exterior and function as an additional physical barrier Secretions of the epithelial tissues include: Acidity of the skin secretions (pH 3 to 5) Inhibits bacterial growth Sebum contains chemicals that are toxic to bacteria Vaginal secretions of adult female are also very acidic Stomach: Mucosa secretes a concentrated hydrochloric acid solution and protein-digesting enzyme (both kill microorganisms) Saliva: Cleanses the oral cavity and teeth Lacrimal fluid of the eye contain lysozyme Enzyme that destroys bacteria Mucus (sticky): Traps many microorganisms that enter the digestive and respiratory passageways (hairs, cilia)

INTERNAL DEFENSES: CELLS AND CHEMICALS
Nonspecific cellular and chemical devices to protect itself: Recognize surface carbohydrates, proteins unique to infectious organisms (bacteria, viruses, and fungi) Phagocytes, natural killer cells, antimicrobial proteins, and fever The inflammatory response enlists macrophages, mast cells, all types of white blood cells, and dozens of chemicals that kill pathogens and help repair tissue Fever

PHAGOCYTES Confront microorganisms that branch the external barriers
Macrophages are the main phagocytes of the body Derive form white blood cells called monocytes that leave the bloodstream, enter the tissues, and develop into macrophages Free macrophages (alveolar macrophages of the lungs and dendritic cells of the epidermis) wander throughout the tissue spaces Fixed macrophages (Kupffer cells in the liver and microglia of the brain) are permanent residents of particular organs All macrophages are similar structurally and functionally

PHAGOCYTES Neutrophils: Eosinophils: Mast cells:
Most abundant type of white blood cell Become phagocytic on encountering infectious material in the tissues Are the first responders and become phagocytes when they encounter infectious material Eosinophils: Another type of white blood cell Are weakly phagocytic but are important in defending the body against parasitic worms Mast cells: Role in allergies Have the ability to bond with, ingest, and kill a wide range of bacteria Normally not included as a phagocyte but they share their capabilities

Mechanism of Phagocytosis
A phagocyte engulfs particulate matter much the way an amoeba ingests a food particle The phagosome thus formed is then fused with a lysosome to form a phagolysosome

Mechanism of Phagocytosis
Pathogens can sometimes elude capture because phagocytes cannot bind to their capsules (example: pneumococcus) Adherence is both more probable and more efficient when complement proteins and antibodies coat foreign particles, a process called opsonization Coating provides sites to which the phagocytes receptors can bind Exception: Neutrophils produce antibiotic-like chemicals (defensins) that pierce the pathogen’s membrane Unhappily, the neutrophils also destroy themselves in the process, whereas macrophages, which rely only on intracellular killing, can go on to kill another day

PHAGOCYTOSIS BY MACROPHAGES

Natural Killer Cells (NK)
Are able to lyse and kill cancer cells and virally infected cells before the adaptive immune system has been activated Are a small group of large granular lymphocytes UNLIKE lymphocytes of the adaptive immune system, which recognize and react only against specific virus-infected or tumor cells, Natural Killer cells are far less picky Detect the lack of “SELF” cell surface receptors and by recognizing certain surface sugars on the target cell Name “natural” reflects this non-specificity of these cells Are not phagocytic Mode of killing involves an attack on the target cell’s membrane and release of cytolytic chemicals called perforins Shortly after perforin release, channels appear in the target cell’s membrane and its nucleus disintegrates Also secrete potent chemical that enhance the inflammatory response

Inflammation: Tissue Response to Injury
Occurs any time the body tissues are injured by physical trauma, intense heat, irritating chemicals, or infection by viruses, fungi, or bacteria: The four cardinal signs of acute inflammation are redness, heat, swelling, and pain Chemicals cause dilation of surrounding blood vessels to increase blood flow to the area and increase permeability, which allows fluid containing clotting factors and antibodies to enter the tissues Soon after inflammation the damaged site is invaded by neutrophils and macrophages

Inflammation Process Begins with a flood of inflammatory chemicals released into the extracellular fluid Toll-like receptors (TLRs): Macrophages and certain cells lining the gastrointestinal tract and respiratory tracts bear these surface membrane receptors Ten types have been identified: Each recognizing a specific class of attacking microbe Example: One type response to glycolipid in cell walls of tuberculosis bacterium One type response to a component of gram-negative bacteria such as salmonelle Triggers release of cytokines that promote inflammation and attracts WBCs Injured and stressed tissue cells, phagocytes, lymphocytes, mast cells, and blood proteins are all sources of inflammatory mediators Histamine, kinins, prostaglandins

Inflammation Process All chemicals produced cause small blood vessels in the injured area to dilate Local hyperemia results (accounting for the redness and heat of an inflamed region) Swelling presses on adjacent nerves contributing to pain Pain also results from the release of bacterial toxins, lack of nutrition to cells in the area, and the sensitizing effects of released prostaglandins and kinins Aspirin and some other anti-inflammatory drugs produce their analgesic (pain-reducing) effects by inhibiting prostaglandin synthesis Increases the permeability of local capillaries Exudate fluid: Contains clotting factors (gel like substances that isolate the area, preventing the spread of harmful agents) and antibodies Dilutes the harmful substances Brings in large quantities of oxygen and nutrients needed for repair

EVENTS IN INFLAMMATION

PHAGOCYTE MOBILIZATION
Soon after inflammation begins, the damaged area is invaded by more phagocytes—neutrophils lead, followed by macrophages If inflammation was provoked by pathogens A group of plasma proteins is activated Lymphocytes and antibodies invade the injured site

1.Leukocytosis: Chemicals called leukocytosis-inducing factors released by injured cells promote: Rapid release of neutrophils from red bone marrow Within a few hours the number of neutrophils in blood increases 4 to 5 fold Increase in WBCs Characteristic of inflammation

2.Margination (pavementing): Neutrophils adhesion molecules (CAMs) help them cling to the inner walls of the capillaries and post-capillary venules

3.Diapedesis (emigration): Continued chemical signaling prompts the neutrophils to squeeze through the capillary walls

4.Chemotaxis: Neutrophils usually migrate randomly, but inflammatory chemicals act as homing devices (chemotactic agents) Attract the neutrophils and other WBCs to the site of the injury Within an hour after the inflammatory response has begun, neutrophils have collected at the site and are devouring any foreign material present

Monocytes follow neutrophils into the injured area: Develop large numbers of lysosomes with insatiable appetites Replace the neutrophils in the battlefield Central actors in the final disposal of cell debris as an acute inflammation subsides, and they predominate at suites of prolonged, or chronic, inflammation

The ultimate goal of an inflammatory response is to clear the injured area of pathogens, dead tissue cells, and any other debris so that tissue can be repaired Once this is accomplished, healing usually occurs quickly

HOMEOSTATIC IMBALANCE
In severely infected areas, the battle takes a considerable toll on both sides, and creamy, yellow pus, a mixture of dead or dying neutrophils, broken-down tissue cells, and living and dead pathogens, may accumulate in the wound If the inflammatory mechanism fails to clear the area of debris, the sac of pus may be walled off by collagen fibers, forming an abscess Surgical drainage of abscesses is often necessary before healing can occur

Tuberculosis bacilli: Some escape resistant to digestion by macrophages Escape the effects of antibiotics by remaining enclosed within the macrophage host (infectious granulomas) Tumorlike growth can develop Central region of infected macrophages surrounded by uninfected macrophages encased by an outer fibrous capsule Could harbor these pathogens for years without symptoms Could break out and become active

Antimicrobial proteins
Enhance the innate defenses by attacking microorganisms directly or by hindering their ability to reproduce Interferon Complement proteins

Interferon Virally infected cells can do little to save themselves, some can secrete small proteins to help protect cells that have not yet been infected Small proteins produced by virally infected cells that help protect surrounding healthy cells Interferon diffuses to nearby cells, where they stimulate synthesis of a protein known as PKR, which then “interferes” with viral replication in the still-healthy cells by blocking protein synthesis at the ribosomes Not virus specific Produced against a particular virus—protects against a variety of other viruses

INTERFERON MECHANISM

Interferon Family of related proteins, produced by a variety of body cells, each having a slightly different physiological effect Lymphophytes secrete gamma (immune) interferon Most other leukocytes secrete alpha interferon Used to treat genital warts and hepatitis C (spread by blood and sexual intercourse) Fibroblasts secrete beta interferon Active in reducing inflammation Besides anti-viral effects, activates Macrophages and Natural Killer Cells

COMPLEMENT Complement (fills up or completes) refers to a group of about 20 plasma proteins that provide a major mechanism for destroying foreign pathogens in the body Normally circulate in the blood in an inactive state C1 through C9 B, D, and P, plus several regulatory proteins Activation unleashes chemical mediators that amplify virtually all aspects of the inflammatory process Non-specific defense mechanism

COMPLEMENT Can be activated by two pathways:
Classical: involves antibodies, water-soluble protein molecules that the adaptive immune system produces to fight off foreign invaders Alternative: triggered when factors B, D, and P interact with polysaccharide molecules present on the surface of certain microorganisms Each mechanism involves a cascade

EVENTS AND RESULTS OF COMPLEMENT ACTIVATION

Fever Abnormally high body temperature, is a systemic response to microorganisms Systemic (whole body rather than to one of its parts) response to invading microorganisms The hypothalamus (body temperature) is reset in response to chemicals called pyrogens, secreted by leukocytes and macrophages exposed to foreign substances in the body High fevers are dangerous Denature proteins

Innate/Adaptive Defenses
Unlike the innate system, which is always ready and able to react, the adaptive system must “meet” or be primed by an initial exposure to a specific foreign substance (antigen) before it can protect the body against that substance, and this priming takes precious time

ADAPTIVE (SPECIFIC) DEFENSES
Aspects of the Adaptive Immune Response It is specific: Recognize and destroy the specific antigen that initiated the response It is systemic: Not limited (restricted) to the initial infection site It has “memory”: After an initial exposure the immune response is able to recognize the same antigen and mount a faster and stronger defensive attack

ADAPTIVE DEFENSES Humoral (humors: fluids) immunity:
Antibody-mediated immunity Provided by antibodies present in the body’s “humors” or fluids Produced by B lymphocytes Circulate freely in the blood and lymph Mark bacteria, bacterial toxins, viruses for destruction by phagocytes or complement

ADAPTIVE DEFENSES Cellular (cell-mediated) immunity:
Protective factor is a living cell Cellular targets: Virus-infected tissue cells Parasite-infected tissue cells Cancer cells of foreign graft Lymphocytes act either: Directly by lysing the foreign cells Indirectly by releasing chemical mediators that enhance the inflammatory response or activate other lymphocytes or macrophages Associated with T lymphocytes and has living cells as its protective factor

ANTIGENS Substances that can mobilize the immune system and provoke an immune response Ultimate targets of all immune responses Most are large, complex molecules (both natural and synthetic) that are not normally present in the body (NONSELF) Can be complete or incomplete

COMPLETE ANTIGENS Two important functional properties are:
1. Immunogenicity: ability to stimulate the proliferation of specific lymphocytes and antibodies 2. Reactivity: Ability react with the activated lymphocytes and produced antibodies Limitless variety: All foreign proteins, nucleic acids, some lipids, and many large polysaccharides Proteins are the strongest antigens Pollen, microorganisms, fungi, viruses

ANTIGENS Haptens are incomplete antigens that are not capable of stimulating the immune response, but if they interact with proteins of the body they may be recognized as potentially harmful Small peptides, nucleotides, and many hormones—are NOT immunogenic Certain chemicals: antibiotics, chemicals in poison ivy, animal dander, detergents, cosmetics, etc.—NOT immunogenic BUT, if they link up with the body’s own proteins, the adaptive immune system may recognize the combination as foreign and mount an attack that is harmful rather than protective (allergies) Have reactivity but NOT immunogenicity

ANTIGENIC DETERMINANTS
Specific part of an antigen that has immunogenic properties: Bind to free antibodies or activated lymphocytes in much the same manner as an enzyme binds to a substrate

Large proteins have hundreds of chemically different antigenic determinants, which accounts for their high immunogenicity and reactivity Large simple molecules such as plastics, which have many identical, regularly repeating units, have little or no immunogenicity Such substances are used to make artificial implants

Self-Antigens: MHC Proteins
The external surface of all our cells are dotted with a huge variety of protein molecules These self-antigens are not foreign or antigenic to us, BUT they are strongly antigenic to other individuals MHC proteins: major histocompatibility complex Group of glycoproteins: surface proteins that mark a cell as SELF Coded for by genes Only identical twins have the same gene code Two major groups: Class I: found on virtually all body cells Class II: found only on certain cells that act in the immune response

ADAPTIVE (SPECIFIC) DEFENSES
Cells of the Adaptive Immune System Three cell types: Two types of lymphocytes: B lymphocytes (B cells) Oversees humoral immunity T lymphocytes (T cells) Non-antibody-producing Constitute the cell-mediated arm of adaptive immunity Antigen-presenting cells (APCs) Do not respond to specific antigens but instead play essential auxiliary roles

LYMPHOCYTES Originate in the red bone marrow from hematopoietic stem cells When released from bone marrow, the immature lymphocytes are essentially identical Maturation (into T cells / B cells) depends on where in the body they become immunocompetent, that is, able to recognize a specific antigen by binding to it

LYMPHOCYTES T cells mature in the Thymus under direction of thymic hormone Positive selection produces self-MHC restricted T cells Those cells that are able to recognize SELF are allowed to continue the maturation process Those that fail undergo apoptosis (programmed death of cells) Negative selection identifies T cells that are self-tolerant Those that react too vigorously with self MHC are selected against and eliminated This ensures that the T cells surviving this second screening process exhibit self tolerance (relative unresponsiveness to self antigens)

T CELL SELECTION IN THE THYMUS

LYMPHOCYTES B cells become immunocompetent and self-tolerant in bone marrow Mechanism is not completely understood but appears to be very similar to the thymus

Lymphoid Organs Location where lymphocytes become immunocompetent
Primary lymphoid organs: Thymus Bone marrow Secondary lymphoid organs: All other organs

LYMPHOCYTES When B or T cells become immunocompetent, they display a unique type of receptor on their surface: Enable the lymphocyte to recognize and bind to a specific antigen Once these receptors appear, the lymphocyte is committed to react to one distinct antigenic determinant, and one only, because all of its antigen receptors are the same Lymphocytes become immunocompetent before meeting the antigens they may later attack It is our genes, not antigens, that determine what specific foreign substances our immune system will be able to recognize and resist Only some of the antigens our lymphocytes are programmed to resist will ever invade our bodies: Only some of our immunocompetent cells are mobilized in our life-time Others are forever idle

LYMPHOCYTES Immunocompetent (still immature) T cells and B cells are exported to the lymph nodes, spleen, and other secondary lymphoid organs, where the encounters with antigens occur When the lymphocytes complete their differentiation into fully functional—mature, antigen-activated—T cells and B cells

LYMPHOCYTE TRAFFIC

Antigen-Presenting Cells APC
Engulf antigens and present fragments of these antigens on their surface where they can be recognized by T cells They present antigens to the cells that will destroy them Examples: Dendritic cells in connective tissues Langerhan’s cells of the skin epidermis Also secrete soluble proteins that activate T cells Macrophages (lymphoid organs and connective tissues Activated B lymphocytes Activated T cells, in turn, release chemicals that rev up the mobilization and maturation of dendritic cells and macrophages and secrete bactericidal chemicals Interaction between various lymphocytes, and between lymphocytes and APCs, underlie virtually all phases of the immune response

HUMORAL IMMUNE RESPONSE
Humoral refers events taking place in blood or body fluids The first encounter between an immunocompetent but naïve B lymphocyte and an invading antigen, usually takes place in the spleen or in a lymph node, but it may happen in any lymphoid tissue Activated when antigens bind to its surface receptors

HUMORAL IMMUNE RESPONSE
Clonal selection is the process of the B cell growing and multiplying to form an army of cells that are capable of recognizing the same antigen The resulting family of identical cells, all descended from the same ancestor cell, is called a clone It is the antigen that does the selecting in clonal selection by “choosing” a lymphocyte with complementary receptors

Clonal selection of a B Cell stimulated by Antigen Binding

Most cells of the clone become plasma cells
HUMORAL IMMUNE RESPONSE Clonal Selection and Differentiation of B Cells Most cells of the clone become plasma cells Plasma cells are the antibody-secreting cells of the humoral response Although B cells secrete limited amounts of antibodies, plasma cells develop the elaborate internal machinery (largely rough endoplasmic reticulum) needed to secrete antibodies at the unbelievable rate of about 2000 molecules per second Each plasma cell functions at this pace for 4-5 days and then dies The secreted antibodies, each with the same antigen-binding properties as the receptor molecules on the surface of the parent B cell, circulate in the blood or lymph, where they bind to free antigens and mark them for destruction by other specific or nonspecific mechanisms

The clones that do not become plasma cells develop into memory cells
HUMORAL IMMUNE RESPONSE Clonal Selection and Differentiation of B Cells The clones that do not become plasma cells develop into memory cells Mount an almost immediate humoral response if they encounter then same antigen again at some future time

Clonal selection of a B Cell stimulated by Antigen Binding

HUMORAL IMMUNE RESPONSE Immunological Memory
The primary immune response (explained on the previous slides) occurs on first exposure to a particular antigen with a lag time of about 3-6 days Allowing time for the few B cells specific for that antigen to proliferate and for their offspring to differentiate into plasma cells After the mobilization period, plasma antibody levels rise, reach peak levels in about 10 days, and then decline

Primary and Secondary Humoral Responses

HUMORAL IMMUNE RESPONSE Immunological Memory
When re-exposed to the same antigen, whether it’s the second or the twenty-second time, a secondary immune response occurs It is faster, more prolonged, and more effective, because the immune system has already been primed to the antigen, and sensitized memory cells are already in place (on alert) Within hours after recognition of the old antigen, a new army of plasma cells is being generated Within 2-3 days the antibody concentration in the blood rises steeply Secondary antibodies not only bind with greater affinity, but their blood levels remain high for weeks to months Memory cells persist for long periods in humans and many retain their capacity to produce powerful secondary humoral responses for life The same general phenomena occur in the cellular immune response: A primary response sets up a pool of activated lymphocytes (in this case, T cells) and generates memory cells that can then mount secondary responses

Active Humoral Immunity
When B cells encounter antigens and produce antibodies against them 1.Naturally acquired when you get a bacterial or viral infection, during which time you may develop symptoms of the disease and suffer a little (or a lot) 2.Artifically acquired when you receive vaccines

TYPES OF ACQUIRED IMMUNITY

Active Humoral Immunity
Active immunity occurs when the body mounts an immune response to an antigen Naturally acquired active immunity occurs when a person suffers through the symptoms of an infection Artificially acquired active immunity occurs when a person is given a vaccine Once it was realized that secondary responses are so much more vigorous than primaries, the race was on to develop vaccines to “prime” the immune response by providing a first meeting with the antigen

VACCINES Most contain dead or attenuated (living, but extremely weakened) pathogens, or their components Two benefits: 1.They spare us most of the symptoms and discomfort of the disease that would otherwise occur during the primary response 2.Their weakened antigens provide functional antigenic determinants that are both immunogenic and reactive Vaccine booster shots: may intensify the immune response at later meetings with the same antigen Shortcomings: Lots of antibodies are formed that provide immediate protection, but cellular immunological memory is only poorly established In rare cases, vaccines cause the very disease they are trying to prevent because the attenuated antigen isn’t weakened enough Vaccines may trigger an allergic response

Passive Humoral Immunity
Differs from active immunity: In the antibody source: Instead of being made by your plasma cells, the antibodies are harvested from the serum of an immune human or animal donor In the degree of protection it provides: Your B cells are NOT challenged by antigens Immunological memory does NOT occur Protection provided by the “borrowed” antibodies ends when they naturally degrade in the body

TYPES OF ACQUIRED IMMUNITY

Passive Humoral Immunity
Occurs when a person is given preformed antibodies Naturally acquired passive immunity occurs when a mother’s antibodies enter fetal circulating through the placenta Artificially acquired immunity occurs when a person is given preformed antibodies that have been harvested from another person Some diseases are rapidly fatal and would kill a person before active immunity could be established The denoted antibodies provide immediate protection, but their effect is short-lived (2-3 weeks) Gamma globulin Antivenom (snake bites) Antitoxin (tetanus) Rabies Botulism

ANTIBODIES Also called immunoglobulins
Constitute the gamma globulin part of blood proteins Proteins secreted by activated B cells or plasma cells in response to an antigen that are capable of binding to that antigen

ANTIBODIES The basic antibody structure consists of four looping polypeptide chains linked together by disulfide bonds: Two identical chains (Heavy: H chains) contain approximately 400 amino acids Two identical chains (Light: L chains) fewer amino acids Flexible at the hinge region

ANTIBODIES V region: Variable region: the H and L chains combine to form an antigen-binding site shaped to fit a specific antigenic determinant

ANTIBODIES C region: forms the stem of the antibody:
Determines the antibody class Common function in all antibodies Effector region dictates: 1.The cells and chemicals the antibody can bind to 2. How the antibody class functions in antigen elimination Example: some antibodies can fix complement, some circulate in blood, some in body secretions, some cross the placental barrier, etc.

BASIC ANTIBODY STRUCTURE

ANTIBODIES Grouped into five classes:
Antibodies are divided into five classes: Based on the C regions in their heavy (H) chains (structure): IgM, IgA, IgD, IgG, IgE Remember the name MADGE All have the same Y-shape structure (are monomers) Different biological roles and locations in the body: IgM: released to the blood by plasma cells IgA: primarily in mucus and other secretions IgD: bound to B cell receptor IgG: most abundant antibody in the plasma Only class that crosses the placental barrier IgE: almost never found in the blood Involved in some allergies

Mechanism of Antibody Diversity
Embryonic cells contain a few hundred gene segments that are shuffled and combined to form all of the different B cells that are found in the body

Antibody Targets and Functions Antigen-antibody (immune) complexes
Though antibodies cannot themselves destroy antigens, they can inactivate them and tag them for destruction Complement fixation and activation: Used against cellular antigens (bacteria, mismatched Red Blood Cells) Occurs when complement (C regions) binds to antibodies attached to antigens, and leads to lysis of the cell Molecules released amplify the inflammatory response, promote phagocytosis via opsonization (coating of foreign antigens that makes them more susceptible)

Neutralization: Occurs when antibodies block specific sites on viruses or bacterial exotoxins (toxic chemicals secreted by bacteria) Loses its toxic effects because it cannot bind to receptors on tissue cells to cause injury The antigen-antibody complexes are eventually destroyed by phagocytes Occurs when antibodies block specific sites on viruses or bacterial exotoxins, causing them to lose their toxic effects

Agglutination occurs when antibodies cross-link to antigens on cells, causing clumping: Because antibodies have more than one antigen-binding site, they can bind to the same determinant on more than one antigen at a time Consequently, antigen-antibody complexes can be cross-linked into large lattices Basis of blood typing

Precipitation: Occurs when soluble molecules are cross-linked into large complexes that settle out of solution More easily captured and engulfed by phagocytes than are freely moving antigens

A quick way to remember how antibodies work is to remember they have a PLAN of action—Precipitation, Lysis (by complement), Agglutination, and Neutralization

MECHANISM OF ANTIBODY ACTION

Monoclonal Antibodies
Produced by descendents of a single cell Produce a single type of antibody Are commercially prepared antibodies specific for a single antigenic determinant Used to diagnose: Pregnancy STDs Types of cancer Hepatitis Rabies Used to treat: Leukemia (WBC) Lymphomas (Lymph nodes)

CELL-MEDIATED IMMUNE RESPONSE
Despite their immense versatility, antibodies provide only partial immunity Their prey is the obvious pathogen They are fairly useless against infectious microorganisms like the tuberculosis bacillus which quickly slips inside body cells to multiply there In these cases, the cell-mediated arm of adaptive immunity comes into play

CELL-MEDIATED IMMUNE RESPONSE
The T cells that mediate cellular immunity are a diverse lot, much more complex than B cells in both classification and function There are two major types of effector T cells based on which of a pair of structurally related cell differentiation glycoproteins (CD4 or CD8) is displayed by a mature T cell These glycoprotein surface receptors, which are distinct from the T cell antigen receptors, play a role in interactions between a tissue cell and other cells or foreign antigens CD4 cells (T4 cells) are primarily helper T cells (TH) CD8 cells (T8 cells) are cytotoxic T cells (TC) Role is to destroy any cells in the body that harbor anything foreign In addition to these two major groups of T cells, there are suppressor T cells (TS), memory T cells, and some fairly rare subgroups The stimulus for clonal selection and differentiation of T cells is binding of antigen, although their recognition mechanism is different from B cells

T CELL TYPES

COMPARISON HUMORAL RESPONSE Antibodies produced by plasma cells
Specialized to latch onto bacteria and soluble foreign molecules in extracellular environments (body secretions, tissue fluid, blood, lymph) Never invade solid tissue lesion is present Antibody production and pathogen multiplication are in a race against each other Forming antibody-antigen complexes does not destroy the antigens Prepares them for destruction by innate defenses and activated T cells CELLULAR RESPONSE In contrast to B cells and antibodies, T cells cannot “see” antigens T cells can recognize and respond only to processed fragments of protein antigens displayed on body cell surfaces (APCs and others) and then only under specific circumstances T cells are best suited for cell-to-cell interactions Most of their direct attacks on antigens (mediated by the cytotoxic T cells) target body cells: Infected by viruses or bacteria Abnormal or cancerous body cells Cells of infused or transplanted foreign tissues

Clonal Selection and Differentiation of T Cells
The stimulus for clonal selection and differentiation of T cells is the same in B cells and T cells—binding of antigen However, the mechanism by which T cells recognize “their” antigen is very different than that seen in B cells and has some unique restrictions

However, T cells must accomplish double recognition:
Clonal Selection and Differentiation of T Cells Antigen Recognition and MHC Restriction Like B cells, immunocompetent T cells are activated when the variable regions of their surface receptors bind to a “recognized” antigen However, T cells must accomplish double recognition: They must simultaneously recognize nonself (the antigen) and self (a MHC protein of a body cell) Two types of MHC (Major Histocompatibility Complex) proteins are important to T cell activities

Clonal Selection and Differentiation of T Cells Antigen Recognition and MHC Restriction
Class I MHC proteins: Displayed by virtually all body cells except red blood cells and are always recognized by CD8 T cells (cytotoxic T cells: TC) Pick up peptide fragments in the ER: May be derived from self-proteins Or from ENDOGENOUS ANTIGENS (foreign) : viral proteins or cancer proteins made within the cell Migrates to the plasma membrane to display its attached protein fragment Widely distributed

MHC class I proteins pick up peptide fragments in the ER

Class II MHC proteins: Typically found only on the surface of mature B cells, some T cells, and antigen-presenting cells, where they enable the cells of the immune system to recognize one another Like Class I MHC, synthesized at the ER and bind to peptide fragments EXOGENOUS ANTIGENS (foreign): antigens that have been phagocytosed and broken down in the phagolysosome vesicle Class II MHC protein moves from the ER through the Golgi apparatus and into a phagolysosome Ultimately attach to cell surface for recognition by CD4 (T4 cells: helper T cells: TH)

MHC class II proteins pick up peptide fragments from endocytosed vesicles

Role of MHC Proteins in the Immune Response
Provide the means for signaling to immune system cells that infectious microorganisms are hiding in body cells

T Cell Activation Two-Step Process: Antigen binding Co-stimulation

Antigen Binding T cell antigen receptors (TCRs) bind to an antigen-MHC complex on the surface of a body cell Helper T cells (CD4)(T4 cells)(TH) can bind only to antigens linked to class II MHC proteins Cytotoxic T cells (CD8)(T8 cells)(TC) activated by antigen fragments complexed with class I MHC proteins

Cloning Selection of TC and TH Cells
Both cells are stimulated to proliferate (clone) and complete their differentiation when they bind to parts of foreign antigens complexed to MHC proteins Immunocompetent TC cells are activated when they bind to endogenous antigens (nonself)—part of a virus in this example—complexed to a class I MHC protein Activation of TH cells is similar, except that the processed antigen is complexed with a class II MHC protein

Clonal selection of cytotoxic (Tc) and helper (TH) T cells involves simultaneous recognition of self and antiself

Co-stimulation (a) Before a T cell can proliferate and form a clone, it must recognize one or more co-stimulatory signals Other receptors on an APC (antigen-presenting cell) Cytokine chemicals: proteins produced by WBCs which regulate immune responses Interleukins chemicals: enable communication between WBCs in immune response reactions Stimulates mitosis Once activated, a T cell enlarges and proliferates to form a clone of cells that differentiate and perform functions according to their T cell class Once they have done their job, the effector T cells are unnecessary and thus disposable

CENTRAL ROLE OF HELPER T CELLS

Specific T Cell Roles(b)
Helper T cells (TH) (primed by APC presentation of antigen) stimulate proliferation of other T cells and B cells that have already become bound to antigen Without TH there is NO immune response Their cytokines furnish the chemical help needed to recruit other immune cells to fight off intruders, prodding the B cells into more rapid divisions Signal for antibody formation to begin Unleash the protective potential of B cells

CENTRAL ROLE OF HELPER T CELLS

Specific T Cell Roles Cytotoxic T cells (TC), also called killer T cells, are the only T cells that can directly attack and kill other cells displaying antigen to which they have been sensitized Circulate in and out of the blood and lymph Main targets are virus-infected cells, but they also attack tissue cells infected by certain intracellular bacteria or parasites, cancer cells, and foreign cells introduced into the body by blood transfusions or organ transplants Induce target cell lysis

Cytotoxic T cells attack infected and cancerous cells

Specific T Cell Roles Suppressor T cells (TS) release cytokines that suppress the activity of both B cells and other types of T cells Regulatory cells Though to be vital for winding down and finally stopping the immune response after an antigen has been inactivated or destroyed Helps prevent runaway or unnecessary immune system activity Because of their inhibitory role, presumed to be important in preventing autoimmune reactions Activation process is still hypothetical Gamma delta T cells (Tgd): Found in the intestine and are more similar to NK (natural killer) cells than other T cells Without helper T cells there is no adaptive immune response because the helper T cells direct or help complete the activation of all other immune cells

PRIMARY IMMUNE RESPONSE

Organ Transplants and Prevention of Rejection
Grafts: Autografts are tissue grafts transplanted from one body site to another in the same parson Isografts are grafts donated to a patient by a genetically identical individual such as an identical twin Allografts are grafts transplanted from individuals that are not genetically identical but belong to the same species Xenografts are grafts taken from another animal species Example: transplanting a baboon heart into a human being Transplant success depends on the similarity of the tissues because cytotoxic T cells, NK cells, and antibodies work to destroy foreign tissues Following surgery the patient is treated with immunosuppressive therapy involving drugs of the following categories: 1. Corticosteroid drugs to suppress inflammation 2. Antiproliferative drugs 3. Immunosuppressant drugs Suppresses immune system Increases susceptibility to viral and bacterial infections Key to success is to provide enough immunosuppression to prevent rejection but not enough to be toxic, and to use antibiotics to keep infection under control

Immunodeficiencies are any congenital or acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally Severe combined immunodeficiency (SCID) is a congenital condition that produces a deficit of B and T cells Little or no protection against disease-causing organisms of any type Successful transplants of bone marrow tissue or cultured stem cells from umbilical cord blood improve survival rates Genetic engineering using virus vectors is still experimental Acquired immune deficiency syndrome (AIDS) cripples the immune system by interfering with helper T cells

Autoimmune diseases occur when the immune system loses its ability to differentiate between self and nonself and ultimately destroys itself Hodgkin’s disease: cancer of the lymph nodes Leads to immunodeficiency by depressing lymph node cells AIDS (acquired immune deficiency syndrome) Cripples the immune system by interfering with the activity of helper T cells (TH) HIV (human immunodeficiency virus) (RNA virus) coat glycoprotein fits into the CD4 of TH receptor like a plug fits into a socket Once inside, HIV uses the enzyme reverse transcriptase to produce DNA from the information encoded in its (viral) RNA This DNA inserts itself into the target cell’s DNA and directs the cell to produce viral RNA and proteins so that the virus can multiply and infect other cells HIV reverse transcriptase enzyme is not very accurate and produces errors frequently, causing HIV’s high mutation rate and its changing resistance to drugs

AUTOIMMUNE DISEASES Immune system loses its ability to distinguish self from foreign antigens Immune system turns on itself Body produces antibodies (autoantibodies) and sensitized TC cells that destroy its own tissues Multiple sclerosis: destroys the white matter of the brain and spinal cord Injection of genetically engineered antibodies to the CD4 receptors on TH cells seem to stabilize the condition Myasthenia gravis: impairs communication between nerves and skeletal muscles Grave’s disease: prompts the thyroid gland to produce excessive amounts of thyroxine Type I (juvenile) diabetes mellitus: destroys pancreatic beta cells, resulting in a deficit of insulin and inability to use carbohydrates Systemic lupus erythematosus (SLE): systemic (whole body not part) disease that particularly affects the kidneys, heart, lungs, and skin Glomerulonephritis: severe impairment of renal function Rheumatoid arthritis: systematically destroys joints More recent is the drug thalidomide Morning sickness drug for pregnant women (birth defects) Inhibits the immune system’s production of TNF (Tumor necrosis factor: enhances nonspecific killing)

HYPERSENSITIVITIES ALLERGIES
Allergies, are the result of the immune system causing tissue damage as it fights off a perceived threat that would otherwise be harmless Term allergen is used to distinguish the antigen from those producing essentially normal responses

Immediate hypersensitivities (acute: Type1) begin within seconds after contact and last about half an hour (pollen, bee sting, spider bite, food, antibiotics, dust mites, etc.) When IgE antibody molecules bind to mast cells and basophils, sensitization is complete Most common type is anaphylaxis: Initial meeting with an allergen produces no symptoms but it sensitizes the person Anaphylaxis is triggered at later encounters with the same allergen Induces an enzymatic cascade that causes the mast cells and basophils to degranulate, releasing a flood of histamine and other inflammatory chemicals

MECHANISM OF AN ACUTE ALLERGIC RESPONSE

Subacute hypersensitivities take 1-3 hours to occur and last hours Caused by antibodies IgG and IgM Can be transferred via blood or serum Type II: Stimulates phagocytosis and comlement-mediated lysis of the cellular antigens Transfusion of mismatched blood Type III: Insoluble antigen-antibody complexes are widespread throughout the body and blood Cannot be cleared Intense inflammatory reaction Cell lysis and killing that damages tissue Farmer’s lung: inhaling moldy hay Glomerulonephritis Systemic lupus erythematosus Rheumatoid arthritis

Delayed hypersensitivities reactions take 1-3 days to occur and may take weeks to go away Type IV: Can be passively transferred in blood transfusions Contact dermatitis: Poison ivy Heavy metals ( lead, mercury, etc.) Certain cosmetic and deodorant chemicals Tuberculin test

DEVELOPMENTAL ASPECTS OF THE IMMUNE SYSTEM
Embryologic Development Stem cells of the immune system originate in the liver and spleen during weeks 1-9 of embryonic development; later the bone marrow takes over this role In late fetal life and shortly after birth the young lymphocytes develop self-tolerance and immunocompetence Later in life the ability and efficiency of our immune system declines

THE IMMUNE SYSTEM: INNATE AND ADAPTIVE BODY DEFENSES

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THE IMMUNE SYSTEM: INNATE AND ADAPTIVE BODY DEFENSES

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