Immunity 15/05/12. Overview: Recogni3on and Response INTERCONNECTEDNESS REDUCE REUSE RECYCLE

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1 Overview: Recogni3on and Response Immunity INTERONNETEDNESS REDUE REUSE REYLE s, agents that cause disease, infect a wide range of animals, including humans The immune system recognizes foreign bodies and responds with the produc3on of immune s and proteins All animals have innate immunity, a defense ac3ve immediately upon infec3on ertebrates also have adap1ve immunity Figure 43.1 Innate immunity is present before any exposure to pathogens and is effec3ve from the 3me of birth It involves nonspecific responses to pathogens Innate immunity consists of external barriers plus internal ular and chemical defenses Figure 43.2 s (such as bacteria, fungi, and viruses) Adap3ve immunity, or acquired immunity, develops ajer exposure to agents such as microbes, toxins, or other foreign substances It involves a very specific response to pathogens INNATE IMMUNITY (all animals) Recognition of traits shared by broad ranges of pathogens, using a small set of s Rapid response Barrier defenses: Skin Mucous membranes Secretions Internal defenses: Phagocytic s Natural killer s Antimicrobial proteins Inflammatory response ADAPTIE IMMUNITY (vertebrates only) Recognition of traits specific to particular pathogens, using a vast array of s Slower response Humoral response: Antibodies defend against infection in body fluids. ell-mediated response: ytotoxic s defend against infection in body s. 1

2 oncept 43.1: In innate immunity, recogni3on and response rely on traits common to groups of pathogens Innate immunity is found in all animals and plants In vertebrates, innate immunity is a first response to infec3ons and also serves as the founda3on of adap3ve immunity Innate Immunity of Invertebrates In insects, an exoskeleton made of chi3n forms the first barrier to pathogens The diges3ve system is protected by a chi3n- based barrier and lysozyme, an enzyme that breaks down bacterial walls Hemocytes circulate within hemolymph and carry out phagocytosis, the inges3on and diges3on of foreign substances including bacteria Figure 43.3 PHAGOYTI ELL Hemocytes also secrete an3microbial pep3des that disrupt the plasma membranes of fungi and bacteria acuole Lysosome containing enzymes Figure 43.4 The immune system recognizes bacteria and fungi by structures on their walls An immune response varies with the class of pathogen encountered 2

3 Figure 43.5 RESULTS Figure 43.5a % survival 100 Wild type Mutant 25 Mutant drosomycin Mutant defensin Hours post-infection Fruit fly survival after infection by N. crassa fungi 100 RESULTS (part 1) 100 % survival Mutant 25 Wild type Mutant drosomycin Mutant defensin % survival Mutant drosomycin Wild type Mutant Mutant defensin Hours post-infection Fruit fly survival after infection by M. luteus bacteria Hours post-infection Fruit fly survival after infection by N. crassa fungi Figure 43.5b RESULTS (part 2) % survival Mutant drosomycin Wild type Mutant Mutant defensin Hours post-infection Fruit fly survival after infection by M. luteus bacteria Innate Immunity of ertebrates The immune system of mammals is the best understood of the vertebrates Innate defenses include barrier defenses, phagocytosis, an3microbial pep3des Addi3onal defenses are unique to vertebrates: natural killer s, interferons, and the inflammatory response Barrier Defenses Barrier defenses include the skin and mucous membranes of the respiratory, urinary, and reproduc3ve tracts Mucus traps and allows for the removal of microbes Many body fluids including saliva, mucus, and tears are hos3le to many microbes The low ph of skin and the diges3ve system prevents growth of many bacteria ellular Innate Defenses s entering the mammalian body are subject to phagocytosis Phagocy3c s recognize groups of pathogens by TLRs, Toll- like s 3

4 Figure 43.6 EXTRAELLULAR FLUID PHAGOYTI ELL ESILE pg DNA ds RNA Helper protein Lipopolysaccharide TLR9 TLR3 TLR4 Flagellin TLR5 Innate immune responses A white blood engulfs a microbe, then fuses with a lysosome to destroy the microbe There are different types of phagocy3c s Neutrophils engulf and destroy pathogens Macrophages are found throughout the body Dendri1c s s3mulate development of adap3ve immunity Eosinophils discharge destruc3ve enzymes ellular innate defenses in vertebrates also involve natural killer s These circulate through the body and detect abnormal s They release chemicals leading to death (apoptosis), inhibi3ng the spread of virally infected or cancerous s Many ular innate defenses involve the lympha3c system Thymus Peyer s patches (small intestine) Appendix (cecum) Figure 43.7 Adenoid Tonsils Lymphatic vessels Spleen Lymph nodes Blood capillary Tissue s Interstitial fluid Lymphatic vessel Lymphatic vessel Lymph node Masses of defensive s An1microbial Pep1des and Proteins Pep3des and proteins func3on in innate defense by azacking pathogens or impeding their reproduc3on Interferon proteins provide innate defense, interfering with viruses and helping ac3vate macrophages About 30 proteins make up the complement system, which causes lysis of invading s and helps trigger inflamma3on Inflammatory Responses The inflammatory response, such as pain and swelling, is brought about by s released upon injury of infec3on Mast s, a type of connec3ve 3ssue, release histamine, which triggers blood vessels to dilate and become more permeable Ac3vated macrophages and neutrophils release cytokines, signaling s that enhance the immune response 4

5 Figure Pus, a fluid rich in white blood s, dead pathogens, and debris from damaged 3ssues Mast Signaling s Splinter Macrophage apillary Red Neutrophil blood s Figure Figure Splinter Splinter Mast Signaling s Macrophage apillary Movement of fluid Mast Signaling s Macrophage apillary Movement of fluid Phagocytosis Red Neutrophil blood s Red Neutrophil blood s Evasion of Innate Immunity by s Inflamma3on can be either local or systemic (throughout the body) Fever is a systemic inflammatory response triggered by pyrogens released by macrophages and by toxins from pathogens Sep1c shock is a life- threatening condi3on caused by an overwhelming inflammatory response Some pathogens avoid destruc3on by modifying their surface to prevent recogni3on or by resis3ng breakdown following phagocytosis Tuberculosis (TB) is one such disease and kills more than a million people a year 5

6 oncept 43.2: In adap3ve immunity, s provide pathogen- specific recogni3on The adap3ve response relies on two types of lymphocytes, or white blood s Lymphocytes that mature in the thymus above the heart are called T s, and those that mature in bone marrow are called B s An1gens are substances that can elicit a response from a B or T Exposure to the pathogen ac3vates B and T s with an1gen s specific for parts of that pathogen The small accessible part of an an3gen that binds to an an3gen is called an epitope Figure 43.UN01 s B s and T s have proteins that can bind to foreign s Each individual lymphocyte is specialized to recognize a specific type of Mature B Mature T An3gen Recogni3on by B ells and An3bodies Each B an3gen is a Y- shaped with two iden3cal heavy chains and two iden3cal light chains The constant regions of the chains vary lizle among B s, whereas the variable regions differ greatly The variable regions provide an3gen specificity Figure 43.9 B antigen binding site Light chain Disulfide bridge binding site ariable regions onstant regions Transmembrane region Heavy chains Plasma membrane B ytoplasm of B 6

7 Figure Antibody Binding of a B an3gen to an an3gen is an early step in B ac3va3on This gives rise to s that secrete a soluble form of the protein called an an1body or immunoglobulin (Ig) Secreted an3bodies are similar to B s but lack transmembrane regions that anchor s in the plasma membrane B Epitope (a) B antigen s and antibodies Antibody A Antibody Antibody B (b) specificity Figure 43.10a Figure 43.10b Antibody Antibody B Antibody A Antibody B Epitope (a) B antigen s and antibodies (b) specificity An3gen Recogni3on by T ells Figure binding site Each T consists of two different polypep3de chains (called α and β) The 3ps of the chain form a variable () region; the rest is a constant () region T and B an3gen s are func3onally different T antigen Disulfide bridge ariable regions onstant regions Transmembrane region α chain β chain ideo: T ell Receptors T ytoplasm of T Plasma membrane 7

8 T s bind to an3gen s displayed or presented on a host These an3gen s are bound to - surface proteins called MH s MH (major histocompa1bility complex) s are host proteins that display the an3gen s on the surface In infected s, MH s bind and transport an3gen s to the surface, a process called an1gen presenta1on A T can then bind both the an3gen and the MH This interac3on is necessary for the T to par3cipate in the adap3ve immune response Figure Figure 43.12a Displayed antigen MH T T antigen Displayed antigen MH T T antigen Host (a) recognition by a T Top view MH Host (b) A closer look at antigen presentation Host (a) recognition by a T Figure 43.12b B ell and T ell Development MH Host Top view The adap3ve immune system has four major characteris3cs Diversity of lymphocytes and s Self- tolerance; lack of reac3vity against an animal s own s B and T s proliferate ajer ac3va3on Immunological memory (b) A closer look at antigen presentation 8

9 Genera1on of B and T ell Diversity By combining variable elements, the immune system assembles a diverse variety of an3gen s The immunoglobulin (Ig) gene encodes one chain of the B Many different chains can be produced from the same gene by rearrangement of the DNA Rearranged DNA is transcribed and translated and the an3gen formed Figure DNA of undifferentiated B DNA of differentiated B pre-mrna mrna Light-chain polypeptide J 5 ap 39 J 5 ariable region 1 Recombination deletes DNA between randomly selected segment and J segment J 5 Functional gene 2 Transcription Intron 3 RNA processing 4 Translation Intron onstant region Poly-A tail B J 1 J 2 J 3 J 4 J 5 Intron Origin of Self- Tolerance An3gen s are generated by random rearrangement of DNA As lymphocytes mature in bone marrow or the thymus, they are tested for self- reac3vity Some B and T s with s specific for the body s own s are destroyed by apoptosis, or programmed death The remainder are rendered nonfunc3onal Prolifera1on of B ells and T ells In the body there are few lymphocytes with an3gen s for any par3cular epitope In the lymph nodes, an an3gen is exposed to a steady stream of lymphocytes un3l a match is made This binding of a mature lymphocyte to an an3gen ini3ates events that ac3vate the lymphocyte Figure Once ac3vated, a B or T undergoes mul3ple divisions This prolifera3on of lymphocytes is called clonal selec1on Two types of clones are produced: short- lived ac3vated effector s that act immediately against the an3gen and long- lived memory s that can give rise to effector s if the same an3gen is encountered again B s that differ in antigen specificity Antibody Memory s Plasma s 9

10 Immunological Memory Immunological memory is responsible for long- term protec3ons against diseases, due to either a prior infec3on or vaccina3on The first exposure to a specific an3gen represents the primary immune response During this 3me, selected B and T s give rise to their effector forms In the secondary immune response, memory s facilitate a faster, more efficient response Figure Primary immune response to antigen A produces antibodies to A. Antibody concentration (arbitrary units) Secondary immune response to antigen A produces antibodies to A; primary immune response to antigen B produces antibodies to B. Antibodies to A Antibodies to B Anima3on: Role of B ells Exposure to antigen A Exposure to antigens A and B Time (days) oncept 43.3: Adap3ve immunity defends against infec3on of body fluids and body s Acquired immunity has two branches: the humoral immune response and the - mediated immune response In the humoral immune response an3bodies help neutralize or eliminate toxins and pathogens in the blood and lymph In the - mediated immune response specialized T s destroy affected host s Helper T ells: A Response to Nearly All An3gens A type of T called a helper t triggers both the humoral and - mediated immune responses Signals from helper T s ini3ate produc3on of an3bodies that neutralize pathogens and ac3vate T s that kill infected s An1gen- presen1ng s have class I and class II MH s on their surfaces Figure lass II MH s are the basis upon which an3gen- presen3ng s are recognized An3gen s on the surface of helper T s bind to the an3gen and the class II MH ; then signals are exchanged between the two s The helper T is ac3vated, proliferates, and forms a clone of helper T s, which then ac3vate the appropriate B s Humoral immunity presenting ytokines 3 B 1 2 lass II MH Accessory protein Helper T ytotoxic T ellmediated immunity Anima3on: Helper T ells 10

11 ytotoxic T ells: A Response to Infected ells ytotoxic T s are the effector s in the - mediated immune response ytotoxic T s recognize s of foreign proteins produced by infected s and possess an accessory protein that binds to class I MH s The ac3vated cytotoxic T secretes proteins that disrupt the membranes of target s and trigger apoptosis Figure ytotoxic T Accessory protein lass I MH Infected 1 Anima3on: ytotoxic T ells Figure Figure ytotoxic T ytotoxic T Released cytotoxic T Accessory protein lass I MH Perforin Pore Infected 1 2 Granzymes Accessory protein lass I MH Perforin Pore Infected 1 2 Granzymes 3 Dying infected B ells and An3bodies: A Response to Extraular s The humoral response is characterized by secre3on of an3bodies by B s Ac1va1on of B ells Ac3va3on of the humoral immune response involves B s and helper T s as well as proteins on the surface of pathogens In response to cytokines from helper T s and an an3gen, a B proliferates and differen3ates into memory B s and an3body secre3ng effector s called plasma s 11

12 Figure Figure presenting -presenting B lass II MH Accessory protein lass II MH Accessory protein ytokines 1 Helper T Helper T 1 2 Activated helper T Figure An1body Func1on -presenting lass II MH Accessory protein B ytokines Memory B s An3bodies do not kill pathogens; instead they mark pathogens for destruc3on In neutraliza3on, an3bodies bind to viral surface proteins preven3ng infec3on of a host An3bodies may also bind to toxins in body fluids and prevent them from entering body s Helper T 1 2 Activated helper T Plasma s 3 Secreted antibodies Figure In opsoniza3on, an3bodies bind to an3gens on bacteria crea3ng a target for macrophages or neutrophils, triggering phagocytosis An3gen- an3body complexes may bind to a complement protein which triggers a cascade of complement protein ac3va3on Ul3mately a membrane azack complex forms a pore in the membrane of the foreign, leading to its lysis Neutralization Antibody irus Opsonization Bacterium Macrophage Activation of complement system and pore formation Foreign omplement proteins Formation of membrane attack complex Flow of water and ions Pore 12

13 Figure 43.19a Figure 43.19b Neutralization Opsonization Antibody irus Bacterium Macrophage Figure 43.19c Activation of complement system and pore formation omplement proteins Formation of membrane attack complex Flow of water and ions Pore B s can express five different forms (or classes) of immunoglobulin (Ig) with similar an3gen- binding specificity but different heavy chain regions IgD: Membrane bound IgM: First soluble class produced IgG: Second soluble class; most abundant IgA and IgE: Remaining soluble classes Foreign Summary of the Humoral and ell- Mediated Immune Responses Both the humoral and - mediated responses can include primary and secondary immune response Memory s enable the secondary response Ac3ve and Passive Immuniza3on Ac1ve immunity develops naturally when memory s form clones in response to an infec3on It can also develop following immuniza1on, also called vaccina1on In immuniza3on, a nonpathogenic form of a microbe or part of a microbe elicits an immune response to an immunological memory 13

14 Figure Humoral (antibody-mediated) immune response ell-mediated immune response (1st exposure) Engulfed by Key Stimulates Gives rise to Passive immunity provides immediate, short- term protec3on It is conferred naturally when IgG crosses the placenta from mother to fetus or when IgA passes from mother to infant in breast milk It can be conferred ar3ficially by injec3ng an3bodies into a nonimmune person B presenting Helper T Memory helper T s ytotoxic T (2nd exposure) Plasma s Memory B s Memory cytotoxic T s Active cytotoxic T s Secreted antibodies Defend against extraular pathogens Defend against intraular pathogens and cancer Figure 43.20a Figure 43.20b B Helper T ytotoxic T Humoral (antibody-mediated) immune response ell-mediated immune response (1st exposure) Engulfed by Key Stimulates Gives rise to Memory helper T s presenting (2nd exposure) Plasma s Memory B s Memory cytotoxic T s Active cytotoxic T s B Helper T ytotoxic T Secreted antibodies Defend against extraular pathogens Defend against intraular pathogens and cancer An3bodies as Tools An3body specificity and an3gen- an3body binding has been harnessed in research, diagnosis, and therapy Polyclonal an3bodies, produced following exposure to a microbial an3gen, are products of many different clones of plasma s, each specific for a different epitope Monoclonal an1bodies are prepared from a single clone of B s grown in culture Figure Endoplasmic reticulum of plasma 2 µm 14

15 Immune Rejec3on ells transferred from one person to another can be azacked by immune defenses This complicates blood transfusions or the transplant of 3ssues or organs Blood Groups An3gens on red blood s determine whether a person has blood type A (A an3gen), B (B an3gen), AB (both A and B an3gens), or O (neither an3gen) An3bodies to nonself blood types exist in the body Transfusion with incompa3ble blood leads to destruc3on of the transfused s Recipient- donor combina3ons can be fatal or safe Tissue and Organ Transplants MH s are different among gene3cally noniden3cal individuals Differences in MH s s3mulate rejec3on of 3ssue grajs and organ transplants hances of successful transplanta3on increase if donor and recipient MH 3ssue types are well matched Immunosuppressive drugs facilitate transplanta3on Lymphocytes in bone marrow transplants may cause the donor 3ssue to reject the recipient oncept 43.4: Disrup3ons in immune system func3on can elicit or exacerbate disease Some pathogens have evolved to diminish the effec3veness of host immune responses Exaggerated, Self- Directed, and Diminished Immune Responses If the delicate balance of the immune system is disrupted, effects range from minor to some3mes fatal 15

16 Allergies Figure Allergies are exaggerated (hypersensi3ve) responses to an3gens called allergens In localized allergies such as hay fever, IgE an3bodies produced ajer first exposure to an allergen azach to s on mast s IgE Allergen Histamine Granule Mast Autoimmune Diseases The next 3me the allergen enters the body, it binds to mast associated IgE s Mast s release histamine and other mediators that cause vascular changes leading to typical allergy symptoms An acute allergic response can lead to anaphylac3c shock, a life- threatening reac3on, within seconds of allergen exposure In individuals with autoimmune diseases, the immune system loses tolerance for self and turns against certain s of the body Autoimmune diseases include systemic lupus erythematosus, rheumatoid arthri3s, insulin- dependent diabetes mellitus, and mul3ple sclerosis Figure Exer1on, Stress, and the Immune System Moderate exercise improves immune system func3on Psychological stress has been shown to disrupt immune system regula3on by altering the interac3ons of the hormonal, nervous, and immune systems Sufficient rest is also important for immunity 16

17 Immunodeficiency Diseases Inborn immunodeficiency results from hereditary or developmental defects that prevent proper func3oning of innate, humoral, and/or - mediated defenses Acquired immunodeficiency develops later in life and results from exposure to chemical and biological agents Acquired immunodeficiency syndrome (AIDS) is caused by a virus Evolu3onary Adapta3ons of s That Underlie Immune System Avoidance s have evolved mechanisms to thwart immune responses An1genic aria1on Through an3genic varia3on, some pathogens are able to change epitope expression and prevent recogni3on The human influenza virus mutates rapidly, and new flu vaccines must be made each year Human viruses occasionally exchange genes with the viruses of domes3cated animals This poses a danger as human immune systems are unable to recognize the new viral strain Millions of parasites per ml of blood Figure Antibodies to variant 1 appear Antibodies to variant 2 appear Antibodies to variant 3 appear ariant 1 ariant 2 ariant Weeks after infection Latency Some viruses may remain in a host in an inac3ve state called latency Herpes simplex viruses can be present in a human host without causing symptoms ALack on the Immune System: HI Human immunodeficiency virus (HI) infects helper T s The loss of helper T s impairs both the humoral and - mediated immune responses and leads to AIDS HI eludes the immune system because of an3genic varia3on and an ability to remain latent while integrated into host DNA Anima3on: HI Reproduc3ve ycle 17

18 Figure Latency AIDS Helper T concentration (in blood (s/mm 3 ) Relative anti-hi antibody concentration Relative HI concentration Helper T concentration People with AIDS are highly suscep3ble to opportunis3c infec3ons and cancers that take advantage of an immune system in collapse The spread of HI is a worldwide problem The best approach for slowing this spread is educa3on about prac3ces that transmit the virus Years after untreated infection ancer and Immunity The frequency of certain cancers increases when adap3ve immunity is impaired 20% of all human cancers involve viruses The immune system can act as a defense against viruses that cause cancer and cancer s that harbor viruses In 2006, a vaccine was released that acts against human papillomavirus (HP), a virus associated with cervical cancer Figure Figure 43.UN02 ell division and gene rearrangement Stem Figure 43.UN03 Elimination of self-reactive B s lonal selection Formation of activated populations Antibody Memory B s Plasma s Receptors bind to antigens 18