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Chapter 43 Immune System Preliminary Protective Measures Organism defense is summarized by . . . Nonspecific defenses • Skin and mucous membranes: 1st line of defense – Oil, sweat glands create acidic pH (3.5) • Prevents microbial growth • Normal flora of bacteria release acids – Antimicrobial proteins in saliva, tears, mucous secretions • Lysozyme in sweat, tears, saliva attack bacterial cell walls – Nostril hairs and mucus in lungs traps bacteria – Stomach acids kill many bacteria • Phagocytic cells – Neutrophils (60-70%of WBCs): phagocytosis of bacterial cells (cell lysis) – Monocytes (5% of WBCs); migrate to tissues, enlarge to become macrophages • Have ameboid locomotion; sometimes reside in lymph notes – Eosinophils: contain granules of cytotoxic chemicals against bacterial capsules; good against parasitic worms – Natural killer (NK) cells: kill body cells which are infected with a virus; not phagocytic, but attack plasma membrane and cause cell lysis Inflammatory response • At site of physical injury or bacterial entry . . . – Vasodilation: increases blood supply to area – Vessels become more permeable; allow localized edema • Chemical signals – Histamine: release from circulating basophils and mast cells in connective tissue – Prostaglandins promote blood flow to the area, reduce pain – Phagocytes attracted to the area by chemokines • Neutrophils kill bacteria, then monocytes transform into macrophages and clean up the area Simplified view of inflammation RTDC: Rubor, Tumor, Dolor, Calor (reddening, swelling, pain, localized heat -- fever) Systemic inflammation • Caused by severe infections (e.g. meningitis, appendicitis) • Bone marrow releases more neutrophils • Fever in response to bacteria toxins or pyrogens released by leukocytes – Moderate fever inhibits some microorganisms • Also facilitates phagocytosis and tissue repair Antimicrobial proteins • Complement proteins – Interact in a cascade which results in cell lysis • Interferons – Secreted from virally-infected cells: cause neighboring cells to make antiviral proteins which prevent infection – Most effective against short-term infections (e.g. colds, flu) Real Immune System Specific immunity • Distinguished from nonspecific immunity by demonstrating: – – – – Specificity Diversity Self/nonself recognition Memory cells Development and maturation of lymphocytes Perform different roles in immunity Specificity • Lymphocytes: two types and two different responses – B cells produce humoral immunity (antibodies float freely in blood plasma); cells mature in bone marrow and then circulate freely – T cells produce cell-mediated immunity (antibodies remain attached to lymphocytes); cells are produced in bone marrow then migrate to thymus gland for further development • Specificity = immune system’s ability recognize and eliminate specific “invaders” Diversity • Antigen (Ag) = foreign substance which elicits a response from the immune system • Antibody (Ab) = antigen-binding immunoglobulin (protein) which forms in response to the presence of an antigen Typical Antibody Molecule Variable (sticky) ends Light protein chain Heavy protein chain Disulfide bridges hold protein chains together • Antigens are large molecules displayed on surfaces of cells/organisms; have unique molecular shapes; are proteins or polysaccharides • Antigen receptor = lymphocyte membrane protein which binds an Ag to the cell – In B cells the antibodies migrate in a transmembrane fashion and are secreted from the lymphocytes – In T cells the antibodies are similar to B-cell Abs, but remain attached to leukocyte by their “stems” • Diversity = ability to recognize millions of Ags by their antigenic markers An antigen and its several epitopes (antigenic determinants) Source of specific responses • Each lymphocyte responds to only one kind of Ag • Response is determined during embryonic development -- before encountering any Ags • Encounter between Ag and lymphocyte activates a lymphocyte; it divides and differentiates -produces large groups (clones) of response lymphocytes (effector cells) • Therefore, each original Ag activates only a very small number of the millions of potential response cells. Clonal Selection Theory QuickTime™ and a Cinepak decompressor are needed to see this picture. Immune response sequences Long-lived memory cells Lag period Short-lived plasma cells Immunological memory • Based on memory cells • Memory cells are not active during primary response • Previously-encountered Ag activates clone of memory cells for secondary immune response • Acquired immunity (long term) is based on memory cells – Immunity to chicken pox, measles, mumps, etc. – Immunity to any vaccinations (contain antigens) Self and Nonself • Ability to distinguish between a body’s own molecules vs. foreign molecules • Ag receptors on lymphocytes detect foreign molecules; no lymphocytes exist to react against a body’s own molecules under normal circumstances – Self-tolerance = lack of destructive immune response to a body’s own cells • Failure of this mechanism results in autoimmune disorders Cell Surface Markers • Major Histocompatibility Complex (MHC) – Glycproteins on lymphocyte plasma membranes and other plasma membranes of other nucleated cells. – “Self markers” come from a family of genes – At least 20 MHC genes and 100 alleles exist for each gene. • Possible combinations are astronomical, not probable that any two individuals would inherit the same combinations of alleles – Two main classes • Class I MHC: found on nucleated cells • Class II MHC: found on specialized cells, i.e. macrophages, B cells and activated T cells – MCHs function to present Ag on the cell surface by binding to it, thus facilitating Ag binding to a T cell Antigen Presentation Any nucleated cell Identifies “self” in immune syst. Any specialized cell Role of Helper T Cells and their descendents QuickTime™ and a Cinepak decompressor are needed to see this picture. Immune Responses • Humoral immunity – Response to toxins, free bacteria, and viruses – Antibodies are secreted and circulated in blood • Cell-mediated immunity – Response to intracellular bacteria and viruses, fungi, protozoans, worms, transplanted tissues, and cancer cells – Depends on direct action of certain lymphocytes, not antibodies Cytotoxic T cells • When Ag-activated TC cells are inhabited by pathogens – Infected cell displays MHCI molecules – TC cells recognize MHCI and bind to cell • Surface molecule CD8 has an affinity for MHCI • TC releases perforin (protein) which forms a lesion (hole) in target cell membrane; cell lyses and released Ags (viruses) are now exposed to circulating Abs • TC cells continue to live after destroying the target cells; also can kill cancer cells which develop continuously in the body TC and Cancer • Cancer cells display distinctive markers called tumor antigens • TC cells recognize markers as nonself, attach, and lyse cells • Some types of cancer cells have reduced MHCI proteins so that TC cells have less ability to recognize and destroy them Humoral Response • B cells produce Abs against extracellular pathogens – Response occurs when Ag epitope binds to B cell receptors • B cells differentiate into clones of plasma cells (Absecreting cells) and memory cells Humoral Response QuickTime™ and a Cinepak decompressor are needed to see this picture. Helper T lymphocytes • They function in both humoral and cellmediated immunity • Antigen-presenting cells (APC) – . . . are cells which ingest Ags – B cells and macrophages • They alert Imm. Sys. (via TH cells) that foreign molecules are present • They can phagocytose foreign material • TH cells bind to MHC II (on specialized cells) and become induced to differentiate into: – Activated TH cells: secrete cytokines, i.e. interleukin-2 (IL-2); - stimulate B cells --->plasma cells; - induce TC cells ---> active “killers” – Memory TH cells: IL-1 from APCs activates TH and IL-2 secretes from activated TH cells – Suppressor T Cells: may suppress immune system when Ag is no longer present Summary: Cascade of interactions in response to Ag Ag from bacterial cell Differentiation into either: CD4 protein enhances binding Cytotoxic T cells • Ag-activated TC cells kill cells that are infected by pathogens (TC cells can recognize any type nucleated cell which is infected) – Infected cells displays MHCI molecules • TC recognizes MHCI and binds to cell – Surface molecule CD8 has affinity for MHCI – TC releases perforin (protein) which forms a lesion (hole)in plasma membrane of target cell; cell lyses » Released Ags are now exposed to circulating Abs » TC cells continue to live after destroying target cells; also can kill cancer cells which constantly develop in the body Cytotoxic T Cell Reaction QuickTime™ and a Cinepak decompressor are needed to see this picture. TC and Cancer • Cancer cells display distinctive markers called tumor antigen • TC cells recognize markers as nonself, attach, and lyse the cancer cells • Some types of cancer cells have reduced MHCI proteins so that TC cells have less ability to recognize and destroy them Humoral Response • B cells produce Abs against extracellular pathogens (bacteria, viruses) – Response occurs when Ag epitope binds to B cell receptors • B cells differentiate into clones of plasma cells (Ab-secreting cells) and B memory cells Mechanisms of B cell activation • T-dependent antigens: Ags from infected cells evoke cooperation between macrophages, TH cells, and B cells – Produce Abs only WITH involvement of TH cells via cytokines such as IL-2 – Most Ags are T-dependent – Memory cells are produced in T-dependent responses • T-independent antigens: Ags trigger humoral responses without macrophages OR T cell involvement – Usually long chains of repeating units such as those found in bacterial capsules and flagellae – B cell is stimulated directly by Ag (long chains) – Ab response is usually much weaker response caused by T-dependent Ags – No memory cells produced in this response • All B cells (no matter the stimulation) produce plasma clones – 2,000 Abs/sec for 4-5 day life span of plasma cell Antibody reaction with epitope Variable region Constant region Antibody only recognizes this part Antibody Groups: based on heavy-chain constant regions Circulating; respond to initial exposure; activates the complement pathway. MOST ABUNDANT; circulating; against bacteria, viruses, toxins; triggers the complement reaction Most from cells with mucous membranes; prevents attachment by bacteria and viruses; in tears, saliva, sweat, and colostrum (1st 3 days of milk from breasts) Most are on exterior of B cells; probably is the Ag-receptor that initiates B cell differentiation “stem” attaches to mast cells/ basophils; triggers the release of histamine and other allergy-causing chemicals Role of antibodies in ridding the body of antigens -- cellular or soluble QuickTime™ and a Cinepak decompressor are needed to see this picture. Result = phagocytosis or cytolysis Monoclonal Antibodies (Mabs) • Ordinary Abs in an organism tend to be polyclonal Abs (produced in response to too many epitopes) – Unsuited for research work -- too many undesirable, interfering cross reactions • Monoclonal technique developed in 1975 produced a pure and eternal supply of Abs all from one clone of cells Monoclonal Antibody Method Treat variety of B-cells with aminopterin (only hybridomas will survive) Pure monoclonal antibodies will react with only one Ag such as HCG -- the basis of pregnancy tests. Some autoimmune disorders • 1. Lupus erythematosis: against components of body’s own cells -- especially DNA • 2. Rheumatoid arthritis: inflammation of cartilage and bones in joints • 3. Insulin-dependent diabetes (Type 1): against insulin-producing beta cells of the pancreas • 4. Multiple sclerosis (MS): T cells infiltrate CNS (central nervous system) and destroy myelin of neurons • 5. Heart valve/tissue damage: reaction to repeated streptococcal infections Immunity and blood types • Immune reactions dictate which blood types may or may not be transfused • ABO blood groups are good example of nonself recognition • Transfusion reaction occurs when RBCs agglutinate when wrong type is transfused Blood types and serum antibodies RBC Antigen Serum antibody (ies) A Anti-B B Anti-A AB none O Anti-A and anti-B Rh Factor • Another blood group Ag; found originally in Rhesus monkeys (research animals) • Rh incompatibility occurs when father is Rh+, mother is Rh-, and the fetus is Rh+ – Small amounts of blood from the fetus leak across the placenta; mother’s lymphocytes react with IgG anti-Rh Abs; subsequent pregnancies anti-Rh Abs pass across placenta into fetus and destroy fetal RBCs; baby is born either dead or as a “blue baby” -erythroblastosis fetalis – Can be prevented in subsequent children by injecting mother with anti-anti-Rh Abs which destroy Rh+ RBCs before mother develops imunological memory. Tissue Grafts • Recall that the MHC is a “biological fingerprint” unique to each individual – Foreign MHCs elicit cell-mediated response from cytotoxic T cells – Use of immunosuppressant drugs increases chances of successful transplant • Cyclosporin A • FK 506 – For bone marrow transplants: recipient’s immune system is total destroyed by radiation; therefore any rejection comes from the grafted lymphocytes against the recipient’s MHC -close matchings are required Allergies • Allergy = hypersensitivity to an allergen (environmental antigen) – IgE Abs are commonly involved; these recognize pollen as allergens • IgE attach their tails to noncirculating mast cells in connective tissue; pollen grain bridges the gap between two adjacent IgEs and mast cell responds with degranulation -- release of histamine and other inflammatory agents – Histamine causes dilation/increased permeability of arterioles; results in typical symptoms of allergies » Antihistamine drugs suppress excess histamine This event triggers the mast cell to degranulate that is, to release histamines and other inflammatory agents from vesicles called granules. Random throughout connective tissue Anaphylactic shock • Life-threatening – Caused by injected/ingested Ags – Acute allergic response • Histamine from degranulation of mast cells causes sudden dilation in peripheral circulation; blood pressure drops dangerously low – Death may occur in 2-3 minutes • Countermeasure is injection of epinephrine directly through chest wall into the heart Immune deficiencies • SCID = severe combined immunodeficiency – Congenital; failure of both humoral and cell-mediated immunity • Hodgkin’s disease (cancer) causes a type of immunodeficiency • Some viral infections depress immune system • Physical/emotional stress compromises immune system – Nerves penetrate deep into thymus and affect its impact on T cells – Lymphocytes have receptors for neurotransmitters HIV/AIDS • HIV-1 (most common and virulent), HIV-2 also a major strain – Viruses infect CD4 cells (TH) • Also requires a coreceptor such as fusin or CCR5 • HIV RNA is reverse-transcribed to DNA and is integrated into the host DNA (a provirus now); DNA directs production of new viruses from this privileged location – Provirus is “invisible” to the immune system – Rapid mutation of Ags during replication changes epitopes – Population of TH declines; can’t participate in cell-mediated immunity – Secondary infections occur: Karposi’s sarcoma, Pneumocystis carinii (protozoan) pneumonia HIV budding from a CD4 cell; cell eventually perishes • HIV-positive means presence of Abs have been detected – About six weeks into the infection • AIDS is late stage of HIV infection (10 years incubation is average) HIV treatment • Multiple-drug (“cocktail”) approach is used to slow viral replication – DNA synthesis inhibitors – Reverse transcriptase inhibitors (AZT, ddI) – Protease inhibitors • It’s all expensive and can only prolong life -- is not a cure • No vaccine currently exists because no stable epitope can be found Invertebrate immune systems • Sponges: intermingled sponge fragments from two organisms can re-form separately and exclude fragments from the other sponge • Coelomocytes: amoeboid cells which destroy foreign material have been found in many invertebrates • Earthworms demonstrate memory when given body wall grafts from same or different populations – From same population lasts about 8 weeks – From a different population is rejected in two weeks • A second graft from same donor to the same recipient rejected in less than one week -- is this a memory reaction?? 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