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The Immune SystemI. IntroductionA. Vertebrates Must Fight Against Invasion by Microbes B. Vertebrates Have Evolved a Variety of Defenses Against Invaders II. Strategies Of Immune Surveilance A. Bacterial Cells Produce Restriction Endonucleases that Degrade Viral DNA B. Invertebrate Organisms Employ Negative Test Against Invaders 1. All body cells possess cell surface proteins that identify "self" 2. Cells lacking self protein are destroyed 3. Employ negative test to recognize foreign cells and invaders 4. Does not protect against copycat invaders C. Vertebrates Employ a Multilevel Defense 1. First line of defense is nonspecific a) Like walls and moats of medieval cities b) Skin and mucous membranes block entry of invaders 2. Second line of defense uses cells that function like roaming patrols a) Nonspecific defenses of chemicals and cells b) Act rapidly with infection c) Employ negative test that cannot be foiled by copycat foreign cells d) All cells possess major histocompatibility complex (MHC) proteins (1) Different in each individual (2) Genes encoding MHC proteins are highly polymorphic 3. Third line of defense is a positive test a) Identifies molecules characteristic of foreign microbes, cancer cells b) Scan surface of every cell encountered, like sentries c) Cells possess surface receptor molecules that recognize "non-self" molecules d) Two kinds of cellular sentries comprise vertebrate immune system (1) Cells that aggressively attack foreign identified cells (2) Cells that mark foreign cells for elimination by roaming patrols III. The First Battle In Vertebrate Defense Is On The Surface Of The Body A. Skin 1. Largest organ in human body 2. Physically protects against microbe entry 3. Provides chemical defenses on surface a) Oil and sweat glands make skin's surface acidic b) Inhibits growth of microorganisms c) Sweat contains lysozyme that digests bacterial cell walls 4. Prevents body water loss by evaporation 5. Composed of three layers: epidermis, dermis, subcutaneous tissue 6. Epidermis is the "bark" of the vertebrate body a) Stratum corneum is outermost layer (1) Constantly subjected to damage (2) Cells shed continuously (3) Replenished by stratum basale layer deep in epidermis b) Psoriasis: chronic skin disorder, cells reach epidermis faster than usual 7. Lower skin layers provide support and insulation a) Dermis is thicker than epidermis (1) Supports epidermis (2) Provides matrix for nerve endings, muscles, blood vessels (3) Wrinkling accompanying aging occurs here b) Subcutaneous tissue lies below dermis (1) Composed of adipose cells (2) Acts as shock absorber (3) Insulates body, conserves body heat (4) Thickness varies throughout body c) Other External Surfaces (1) Alternate routes of entry for invaders (2) Digestive tract ( a) Saliva contains lysozymes ( b) Stomach produces digestive acids ( c) Intestine produces protein-digesting enzymes (3) Respiratory tract ( a) Inner cells produce entrapping mucus, swept outward by cilia ( b) Ciliated epithelial cells trap microbes IV. Nonspecific Defenses A. Actions that Provide Response Without Determining Identity of Invader 1. Cells that directly ingest invading microbes 2. Antimicrobial proteins kill pathogens 3. Inflammatory response speeds defending cells to point of infection 4. Temperature response slows growth of invading bacteria B. Cells that Kill Invading Microbes 1. Three basic kinds a) Macrophages are one type of phagocyte (1) Directly ingest individual bacteria (2) Bacterium pulled inside via phagocytosis (3) Vacuole with bacterium attacked by cell`s lysosome (4) Most activity occurs in blood, lymph and extracellular fluid (5) Monocytes respond to infection and transform into macrophages b) Neutrophils are also phagocytic (1) White blood cells that directly ingest bacteria (2) Macrophages kill only one cell at a time (3) Neutrophils release bleach-like chemicals that kill many invaders at once (4) Also kill selves in process c) Natural killer cells do not attack microbes directly (1) Attack cells infected by microbes and especially viruses (2) Not phagocytic, create a pore in target cell membrane (3) Target cell absorbs water, swells and bursts 2. Cells distinguish "self" from "not self" a) Due to MHC proteins b) In autoimmune diseases defensive cells attack body's own tissues C. Proteins that Kill Invading Microbes 1. Complement system a) Named because it complements cellular defenses b) Complex composed of about twenty circulating proteins (1) Proteins form membrane attack complex with bacteria or fungus (2) Forms pore in membrane, cell swells and bursts c) Aggregation also triggered by antibodies binding to invaders d) Augment other body defenses (1) Amplify immune response by stimulating histamine release (2) Attract phagocytes to area of infection (3) Coat invading microbes to help macrophages stick more readily 2. Interferons a) Released by virus-infected cells b) Diffuse into other cells, inhibit virus infection c) Sound alert for immune system D. The Inflammatory Response 1. Infected or injured cells release chemicals a) Include histamine and prostaglandin b) Promote dilation of blood vessels, increase local blood flow and temperature c) Increase permeability of capillaries (1) Produces edema and tissue swelling (2) Allow phagocytes to migrate from blood to extracellular fluid ( a) Neutrophils arrive first, make killing chemicals, produce pus ( b) Macrophages follow engulfing remains of dead cells 2. Autoimmune diseases like arthritis have inflammation without infection E. The Temperature Response 1. Pyrogens are chemicals released by macrophages a) Include interleukin-1 b) Carried by blood to brain 2. Induces fever: increased body temperature a) Stimulates phagocytosis, inhibits microbial growth b) Excessive fever may inactivate critical body enzymes V. Specific Immune Defenses A. Third Line of Defense Is More Difficult to Evade B. Remembers Previous Encounters with Potential Invaders 1. Catching many diseases results in permanent immunity to each disease 2. Immune system provides mechanism for immunity and resisting infection VI. Discovery Of The Immune Response A. Jenner and Smallpox 1. Milkmaids rarely developed smallpox infections 2. Cowpox conferred resistance to smallpox 3. First use of vaccination: injecting harmless microbe to confer resistance to harmful one B. Pasteur and Fowl Cholera 1. Isolated culture of organisms that would elicit disease in other fowl 2. Weakened culture caused minor symptoms and conferred immunity 3. Immune response reacted to foreign molecules on surface of bacteria a) Antigens: non-self foreign molecules b) Antibodies: proteins produced that recognize specific antigen c) Immune response: production of antibodies against specific antigen d) Primary immune response: antibody production by initial antigen e) Secondary immune response: amplified production of antibodies with f) Second exposure to same antigen VII. The Cells Of The Immune System A. Immune System Not Localized Within a Single Body Organ 1. Composed of individual white blood cells 2. Found in lymph nodes, spleen, liver, thymus and bone marrow 3. Produced in bone marrow, circulate in blood and lymph a) Nucleated white blood cells formed from hemopoietic stem cells b) Several kinds (1) Phagocyte cells: neutrophils, eosinophils, basophils, monocytes (2) Lymphocytes: T cells and B cells B. T Cells 1. Arise from bone marrow stem cells and travel to thymus a) Develop ability to identify invaders via surface antigens b) Different T cells recognize different antigens 2. Four kinds of T cells a) Inducer T cells: oversee development of T cells in thymus b) Helper T cells: initiate immune response c) Cytotoxic T cells: lyse cells infected with viruses d) Suppressor T cells: terminate immune response C. B Cells 1. Arise from and mature in bone marrow, do not travel to thymus 2. Circulate in blood and lymph 3. Individual cells specialized to recognize specific antigens 4. Antigen initiates rapid division of specific B cell a) B cell progeny differentiate into plasma cells b) Plasma cells produce antibody proteins that flag antigens c) Flagged cells are marked for destruction VIII. Surface Proteins Of Immune Cells A. Cell Surface Proteins Play Role in Immune Response B. MHC "Self" Proteins Recognized by Immune Receptors 1. MHC-1 present on every nucleated cell in body 2. MHC-II found only on macrophages, B cells and T4 cells 3. Human MHC proteins specified by highly variable HLA 4. (human leukocyte-associated antigen)genes C. Cell Identity Markers 1. Glycoproteins that identify particular types of cells 2. Human T cells identified by CD3 marker 3. Inducer and helper T cells (T4) exhibit CD4 protein 4. Cytotoxic and suppressor cells (T8) exhibit CD8 protein D. T and B Lymphocytes Possess Immune Receptor Proteins 1. Serve to identify foreign molecules, antigens 2. Encoded by genes assembled by somatic rearrangement 3. Two classes: B receptors and T receptors a) T receptors remain on surface of T cells b) B receptors secreted by B cells, also called antibodies IX. Architecture Of The Immune Defense A. Immediate Response 1. Infected cell secretes interferons a) Stimulate natural killer cells and macrophages b) Natural killer cells pierce holes in infected cells c) Macrophages engulf cells (1) Enzymatically degrade protein coat of engulfed virus (2) Display coat fragments on cell surface (3) Prepare viral surface antigens for recognition by T cells (4) Called "antigen-presenting cells" d) Response peak: 1-2 days (natural killer cells), 1 week (macrophages) 2. Macrophages also secrete regulatory cytokine molecules a) -interferon activates other monocytes to mature into macrophages b) Interleukin-1 activates helper T cells, prepares them to proliferate 3. Macrophages initiate immune response B. Immune Response 1. Helper T cells activate T cell and B cell immune defenses a) T cells recognize and destroy infected body cells b) B cells provide second defense, antibodies provide long-term protection 2. The cell-mediated immune response a) Proliferation (1) Activated helper T cells secrete lymphokines, including interleukin-2 (2) Interleukin-2 initiates division of T cells (3) Also called T cell growth factor (4) Cytotoxic, helper and suppressor T cells proliferate b) Activation (1) Second lymphokine: macrophage migration inhibition factor (2) Attracts macrophages to site of infection, inhibits migration c) Induction d) Helper T cells activate inducer T cells in the thymus (1) Triggers maturation of immature lymphocytes to mature T cells e) Attack (1) T receptors on cytotoxic T cell recognize virus-infected body cells (2) Bind to viral coat proteins on cell surface and to MHC-I antigen (3) Disrupts plasma membrane of infected cell, lyses cell (4) Called cell-mediated because of interaction between cytotoxic T cells (5) and infected cells Cytotoxic response peaks one week after infection (6) fig 50.12b Response causes rejection in tissue transplants f) Suppression (1) Suppressor T cells block response of cytotoxic T cells to antigen (2) Slow proliferation prevents early blocking of cytotoxic attack (3) Significant numbers present after one to two weeks g) Memory (1) Persistence of a population of helper and cytotoxic T cells (2) Memory T cells provide accelerated response to later infection C. The humoral immune response 1. Key players in this response are B cells 2. Response named humoral because antibodies circulate in blood plasma 3. Proliferation a) B receptors bind to free viral antigens b) Helper T cells detect bound B cells, bind to antigen, MHC-II c) T cells release lymphokines that induce B cell proliferation 4. Differentiation and secretion a) Proliferated B cells form plasma cells b) Plasma cells produce and secrete B receptor, called antibodies or immunoglobulins (Igs) c) First secrete class M (IgM) antibodies, peaks after one week d) Then secrete class G (IgG) antibodies, peaks after three weeks 5. Attack a) IgM antibodies bind to antigens, cause aggregation of complement system (1) Proteins form pore, pierce infected cells (2) Water enters, cell bursts b) IgG antibodies mark cell for phagocytosis by macrophages 6. Suppression: response shut down after several weeks 7. Memory: persistence of memory B cells X. How Do Antibodies Recognize Antigens? A. Antigens Recognized With Great Precision, Related to Receptor Structure B. Antibody Structure 1. Composed of two short, light chains and two long, heavy chains a) Both chains evolved from single ancestral sequence b) Light contains two units, heavy contains three or four units 2. Chains held together by disulfide bonds, forming Y-shaped molecule 3. Specificity resides in arms of Y a) Variable regions located on ends of arms b) Three hypervariable segments form cleft that serves as binding site 4. Stem formed by the "constant" regions of heavy chain a) Antibodies may have identical clefts and bind to same antigen b) Five classes of heavy chains (1) IgM: used in first antibody secreted by B cells (2) IgG: used in antibodies secreted later (3) IgE: bind to mast cells, associated with inflammatory response via histamines (4) IgA: may provide immune protection to nursing babies (5) IgD: function unknown C. Structure of the T Receptor fig 50.22a 1. Simultaneously recognizes antigen and MHC protein 2. Structure resembles one arm of B receptor 3. Two chains called alpha and beta, resemble light and heavy chains 4. Exhibit constant and variable regions D. Structure of MHC Proteins 1. MHC-I a) Is a single polypeptide chain b) Associated with small beta-2 microglobin protein c) Possess segments like repeated sequences in light and heavy chains 2. MHC-II a) Is composed of two polypeptide chains b) Possess antibody-like amino acid sequences XI. How Can The Immune System Recognize So Many Different Foreign Antigens? A. Clonal Selection Model 1. Millions of different kinds of stem cells within the bone marrow 2. Antigen causes ones encoding appropriate receptor to proliferate B. Mechanism for Generating Millions of Different Stem Cells 1. Somatic rearrangement a) Receptor genes are not single nucleotide sequences b) Assembled by combining three or four DNA segments c) Chromosomal sites composed of a cluster of similar sequences d) One sequence selected at random from each cluster e) Selected sequences combined with DNA recombination 2. Variability of composite receptors in humans a) B receptor heavy chain sequences selected from three clusters (1) Identified as V (variable), D (diversity) and J (joining) (2) 200 V genes, 20 D genes, 4 J genes = 16,000 possible chains b) B receptor light chains (1) Possess only V and J genes (2) 300 V genes X 4 J genes = 1200 possible light chains 3. Generation of additional sequences (1) Segments joined off register, shifts reading frame during translation 4. Somatic mutation 5. All effects produce 200 million mathematical combinations XII. The Primary And Secondary Immune Response A. Primary Response 1. Occurs the first time a pathogen enters the body 2. Antibodies are formed within several days 3. Memory B cells are produced B. Secondary Response 1. Faster and stronger due to presence of memory cells 2. Response stronger with each successive attack by same pathogen C. Advantages of Memory Cells 1. Can survive for decades 2. Vaccinations stimulate production of these cells 3. Some diseases reoccur with no memory cell protection a) Invading cell`s surface-specifying genes mutate rapidly b) New strains each year, not recognized by memory cells c) Example: flu XIII. Why Are There Few Antibodies Directed Against "Self" Molecules? A. Immunological Tolerance B. Natural a) Mature animal does not respond to its own tissue as foreign b) Acceptance of self cells 2. Acquired a) Embryo can respond to both foreign and self molecules b) Looses ability to respond to self as development proceeds c) Foreign tissue introduced before immune system develops is not recognized as foreign 3. Both result from elimination or suppression of certain lymphocyte clones a) "Self" antigen clones are eliminated during stem cell maturation b) Surviving clones are suppressed by suppressor T cells 4. Maintenance of self-tolerance requires presence of "self" antigen C. Autoimmune Diseases: Spontaneous Breakdown of Natural Tolerance a) Myasthenia gravis: antibody against muscle acetylcholine receptors b) Rheumatoid arthritis c) Systemic lupus erythematosus XIV. Defeat Of The Immune System A. Antigen Shifting 1. Vary nature of surface antigens 2. Occurs in viruses that cause influenza 3. Exhibited by trypanosomes: protists that cause sleeping sickness a) Possess thousands of versions of gene that codes for coat protein b) Genes lack individual promoters, are not transcribed c) Promotor located within a transposable element that jumps at random d) Coat changes frequently, cannot mount immunological defense B. T Cell Destruction: AIDS 1. Most sensitive target to destroy is the T4 cells a) Helper T cells induce proliferation of T and B cells b) Inducer T cells required for maturation of all T cells 2. Example: human immunodeficiency virus (HIV) causes AIDS a) Directly attacks macrophages and T4 lymphocytes b) Recognizes CD4 antigen surface of those cells c) Alterations to HIV-infected T4 cells (1) Cells die after releasing replicated HIV viruses (2) Secrete suppressing factor that blocks response of other T cells (3) Blocks transcription of MHC gene, infected T4 cells not recognized d) T4 cells become extremely rare e) Destroys defense against infection, causes death from common diseases f) Destroys defense against cancer cells g) Disease is fatal but not highly communicable (1) Transmitted via infected blood fluids (2) Not all exposed individuals develop disease (3) Infected individuals do not live for more than a few years h) Trying to develop a vaccine using vaccinia virus or harmless strain Layout by J.T. Poirier © 2001 |