Module 5A: The Immune Defense 2018 PDF

MODULE 5A:THE IMMUNE DEFENSE, OVERVIEW OF IMMUNE DISORDERS, MICROBIAL-HOST INTERACTIONS INSTRUCTOR: DR. ELAINE VANTERPOOL BI241- GENERAL MICROBIOLOGY  FIRST LINE OF DEFENSE IN THE BODY DEFENSE MECHANISMS OF THE HOST 3 Host Defenses In...

MODULE 5A:THE IMMUNE DEFENSE, OVERVIEW OF IMMUNE DISORDERS, MICROBIAL-HOST INTERACTIONS INSTRUCTOR: DR. ELAINE VANTERPOOL BI241- GENERAL MICROBIOLOGY  FIRST LINE OF DEFENSE IN THE BODY DEFENSE MECHANISMS OF THE HOST 3 Host Defenses Innate, natural defenses: present at birth, provide nonspecific resistance to infection Adaptive immunities: specific, must be acquired DEFENSE MECHANISMS OF THE HOST 4 To protect the body against pathogens, the immune system relies on a multilevel network of physical barriers, immunologically active cells, and a variety of chemicals First line of defense – any barrier that blocks invasion at the portal of entry – nonspecific Second line of defense – protective cells and fluids; inflammation and phagocytosis – nonspecific Third line of defense – acquired with exposure to foreign substance; produces protective antibodies and creates memory cells – specific  GENERAL FEATURES OF HOST 5 DEFENSE 6  PHYSICAL OR ANATOMICAL BARRIERS: FIRST LINE OF DEFENSE 7 Skin and mucous membranes of respiratory, urogenital, eyes, and digestive tracts Outermost layer of skin is composed of epithelial cells compacted, cemented together, and impregnated with keratin; few pathogens can penetrate if intact Flushing effect of sweat glands Damaged cells are rapidly replaced Mucous coat impedes attachment and entry of bacteria Blinking and tear production Stomach acid Nasal hair traps larger particles 8  NONSPECIFIC CHEMICAL DEFENSES 9 Sebaceous secretions Lysozyme, an enzyme that hydrolyzes the cell wall of bacteria, in tears High lactic acid and electrolyte concentration in sweat Skin’s acidic pH Hydrochloric acid in stomach Digestive juices and bile of intestines Semen contains an antimicrobial chemical Vagina has acidic pH GENETIC DEFENSES 10 Some hosts are genetically immune to the diseases of other hosts Some pathogens have great specificity Some genetic differences exist in susceptibility  STRUCTURE AND FUNCTION OF THE ORGANS OF DEFENSE AND 11 IMMUNITY The study of the body’s second and third lines of defense is called immunology Functions of a healthy functioning immune system: 1. Surveillance of the body 2. Recognition of foreign material 3. Destruction of entities deemed to be foreign 12  IMMUNE SYSTEM 13 Large, complex, and diffuse network of cells and fluids that penetrate into every organ and tissue Four major subdivisions of immune system are: 1. Reticuloendothelial system (RES) 2. Extracellular fluid (ECF) 3. Bloodstream 4. Lymphatic system  IMMUNE SYSTEM DEFINITIONS 14 White blood cells (leukocytes) – innate capacity to recognize and differentiate any foreign material Nonself – foreign material Self – normal cells of the body Pathogen-associated patterns (PAMPs) – molecules shared by microorganisms Pathogen recognition receptors (PRRs) – receptors on WBCs for PAMPs  ORIGIN, COMPOSITION, AND FUNCTIONS OF THE BLOOD 15 Whole blood consists of plasma and formed elements (blood cells) Serum is the liquid portion of the blood after a clot has formed – minus clotting factors Plasma – 92% water, metabolic proteins, globulins, clotting factors, hormones, and all other chemicals and gases to support normal physiological functions 16  A SURVEY OF BLOOD CELLS 17 Hemopoiesis – production of blood cells Stem cells – undifferentiated cells, precursor of new blood cells Leukocytes – White blood cells Granulocytes: lobed nucleus Agranulocytes: unlobed, rounded nucleus 18  GRANULOCYTES 19 Neutrophils – 55-90% - lobed nuclei with lavender granules; phagocytes Eosinophils – 1-3% - orange granules and bilobed nucleus; destroy eukaryotic pathogens Basophils – 0.5% - constricted nuclei, dark blue granules; release potent chemical mediators Mast cells: nonmotile elements bound to connective tissue  AGRANULOCYTES 20 Lymphocytes – 20-35%, specific immune response B (humoral immunity) Activated B cells produce antibodies T cells (cell-mediated immunity) Activated T cells modulate immune functions and kill foreign cells Monocytes, macrophages – 3-7% - largest of WBCs, kidney-shaped nucleus; phagocytic Macrophages: final differentiation of monocytes Dendritic cells: trap pathogens and participate in immune reactions  ERYTHROCYTES AND PLATELET 21 LINES Erythrocytes: develop from bone marrow stem cells, lose nucleus, simple biconcave sacs of hemoglobin Platelets: formed elements in circulating blood that are not whole cells  IMMUNE CELL TYPES 22 LYMPHATIC SYSTEM 23 1. Provides an auxiliary route for return of extracellular fluid to the circulatory system 2. Acts as a drain-off system for the inflammatory response 3. Renders surveillance, recognition, and protection against foreign material 24  LYMPHATIC VESSELS 25 Lymphatic capillaries permeate all parts of the body except the CNS, bone, placenta, and thymus Thin walls easily permeated by extracellular fluid which is then moved through contraction of skeletal muscles Functions to return lymph to circulation; flow is one-direction – toward the heart – eventually returning to blood stream  LYMPHOID ORGANS AND TISSUES 26 Classified as primary and secondary Primary lymphoid organs – sites of lymphocytic origin and maturation – thymus and bone marrow Secondary lymphoid organs and tissues – circulatory-based locations such as spleen and lymph nodes; collections of cells distributed throughout body tissues – skin and mucous membranes – SALT, GALT, MALT  LYMPHOID ORGANS 27 Thymus – high rate of growth and activity until puberty, then begins to shrink; site of T-cell maturation Lymph nodes – small, encapsulated, bean-shaped organs stationed along lymphatic channels and large blood vessels of the thoracic and abdominal cavities Spleen – structurally similar to lymph node; filters circulating blood to remove worn out RBCs and pathogens Miscellaneous – GALT, Peyer’s patch 28 ACTIONS OF THE SECOND LINE OF DEFENSE 29 Recognition Inflammation Phagocytosis Interferon Complement RECOGNITION 30 Protein receptors within cell membrane of macrophages, called Toll-like receptors Detect foreign molecules and signal the macrophage to produce chemicals which: Stimulate an inflammatory response (nonspecific) Promote the activity of B and T cells (specific) 31  TOLL LIKE RECEPTORS (TLR) Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the latter three are not found in humans.  INFLAMMATORY RESPONSE 33 Classic signs and symptoms characterized by: Redness – increased circulation and vasodilation in injured tissues in response to chemical mediators and cytokines Warmth – heat given off by the increased blood flow Swelling – increased fluid escaping into the tissue as blood vessels dilate – edema; WBC’s, microbes, debris, and fluid collect to form pus; helping prevent spread of infection Pain – stimulation of nerve endings Possible loss of function 34 35 Insert figure 14.13 Events in inflammation 36  UNIQUE CHARACTERISTICS OF LEUKOCYTES 37 Diapedesis – migration of cells out of blood vessels into the tissues Chemotaxis – migration in response to specific chemicals at the site of injury or infection  Diapedesis and chemotaxis of leukocytes 38  FEVER 39 Initiated by circulating pyrogens which reset the hypothalamus to increase body temperature; signals muscles to increase heat production and vasoconstriction Exogenous pyrogens – products of infectious agents Endogenous pyrogens – liberated by monocytes, neutrophils, and macrophages during phagocytosis; interleukin-1 (IL-1) and tumor necrosis factor (TNF) Benefits of fever: Inhibits multiplication of temperature-sensitive microorganisms Impedes nutrition of bacteria by reducing the available iron Increases metabolism and stimulates immune reactions and protective physiological processes  PHAGOCYTOSIS 40 General activities of phagocytes: 1. To survey tissue compartments and discover microbes, particulate matter, and dead or injured cells 2. To ingest and eliminate these materials 3. To extract immunogenic information from foreign matter  PHAGOCYTES AND PHAGOCYTOSIS 41 Main types of phagocytes: 1. Neutrophils – general-purpose; react early to bacteria and other foreign materials, and to damaged tissue – Eosinophils – attracted to sites of parasitic infections and antigen-antibody reactions 2. Macrophages – derived from monocytes; scavenge and process foreign substances to prepare them for reactions with B and T lymphocytes  MECHANISMS OF 42 PHAGOCYTIC RECOGNITION, ENGULFMENT, AND KILLING Chemotaxis and ingestion: phagocytes migrate and recognize PAMPs Phagosome Phagolysosome: lysosome fused with phagosome (death ~30 minutes) Destruction and elimination Oxygen-dependent system (respiratory burst) Liberation of lactic acid, lysozyme, and nitric oxide 43  INTERFERON 44 Small protein produced by certain white blood cells and tissue cells Interferon alpha – lymphocytes and macrophages Interferon beta – fibroblasts and epithelial cells Interferon gamma – T cells Produced in response to viruses, RNA, immune products, and various antigens Bind to cell surfaces and induce expression of antiviral proteins Inhibit expression of cancer genes 45  COMPLEMENT 46 Consists of 26 blood proteins that work in concert to destroy bacteria and viruses Complement proteins are activated by cleavage (cascade reaction) Pathways Classical – activated by the presence of antibody bound to microorganism Lectin pathway – nonspecific reaction of a host serum protein that binds mannan Alternative – begins when complement proteins bind to normal cell wall and surface components of microorganisms  STAGES IN THE COMPLEMENT 47 CASCADE Initiation Amplification and cascade Polymerization Membrane attack 48 MEMBRANE ATTACK COMPLEX (MAC ) 49  4 CYTOKINE FAMILIES Chemokines-are chemotactic and chemokinetic for leukocytes. Play a key role in the inflammatory response Hematopoietins-are responsible for stimulation and regulation of the growth and differentiation process in blood cell formation Interleukins- are produced by the WBCs with many functions (see table 32.2) Tumor necrosis factor (TNF) family- are cytotoxic for tumor cells, apoptotic inducer and pro-inflammatory. 51 ADAPTIVE (SPECIFIC IMMUNITY)  SPECIFIC IMMUNITY – ADAPTIVE LINE OF DEFENSE 53 Third line of defense – acquired Dual System of B and T lymphocytes Immunocompetence Antigen – Molecules that stimulate a response by T and B cells Two features that characterize specific immunity: Specificity – antibodies produced, function only against the antigen that they were produced in response to Memory – lymphocytes are programmed to “recall” their first encounter with an antigen and respond rapidly to subsequent encounters  OVERVIEW OF SPECIFIC IMMUNE RESPONSES 54 Separate but related activities of the specific immune response: Development and differentiation of the immune system Lymphocytes and antigen processing The cooperation between lymphocytes during antigen presentation B lymphocytes and the production and actions of antibodies (humoral response) T lymphocyte responses (cell-mediated response) 55 56  DEVELOPMENT OF THE IMMUNE RESPONSE SYSTEM 57 Cell receptors or markers confer specificity and identity of a cell Major functions of receptors are: 1. To perceive and attach to nonself or foreign molecules 2. To promote the recognition of self molecules 3. To receive and transmit chemical messages among other cells of the system 4. To aid in cellular development MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)58 Receptors found on all cells except RBCs Also known as human leukocyte antigen (HLA) Plays a role in recognition of self by the immune system and in rejection of foreign tissue  FUNCTIONS OF MHC 59 Genes for MHC clustered in a multigene complex: Class I – markers that display unique characteristics of self molecules and regulation of immune reactions Required for T lymphocytes Class II – regulatory receptors found on macrophages, dendritic cells, and B cells Involved in presenting antigen to T-cells 60  ANTIGEN PRESENTATION Cells display self antigens from inside on its surface. If all antigens are normal self antigens, an immune response won’t be elicited. If antigens that are displayed on the MHCs are abnormal or not self proteins (i.e. tumor antigens, pathogen antigens), those cells will elicit an immune response. Phagocytic cells are primarily antigen presenting cells.  62 LYMPHOCYTE RECEPTORS Lymphocyte’s role in surveillance and recognition is a function of their receptors B-cell receptors – bind free antigens T-cell receptors – bind processed antigens together with the MHC molecules on the cells that present antigens to them  63 CLONAL SELECTION THEORY Lymphocytes use 500 genes to produce a tremendous variety of specific receptors Undifferentiated lymphocytes undergo a continuous series of divisions and genetic changes that generate millions of different cell types Each cell has a particular/unique receptor specificity  64 Lymphocyte specificity is preprogrammed, existing in the genetic makeup before an antigen has ever entered the system Each genetically different type of lymphocyte (clone) expresses a single specificity First introduction of each type of antigen into the immune system selects a genetically distinct lymphocyte Causes it to expand into a clone of cells that can react to that antigen 65  SPECIFIC B-CELL RECEPTOR: 66 IMMUNOGLOBULIN Receptor genes of B cells govern immunoglobulin (Ig) synthesis Large glycoproteins that serve as specific receptors of B cells Composed of 4 polypeptide chains: 2 identical heavy chains (H) 2 identical light chains (L) Y shaped arrangement – ends of the forks formed by light and heavy chains contain a wide range of variable antigen binding sites Variable regions Constant regions 67  68 DEVELOPMENT OF RECEPTORS Immunoglobulin genes lie on 3 different chromosomes Undifferentiated lymphocyte has 150 different genes for the variable region of light chains and 250 for the variable region and diversity region of the heavy chain During development, recombination causes only the selected V and D genes to be active in the mature cell Once synthesized, immunoglobulin is transported to cell membrane and inserted there to act as a receptor  LYMPHOCYTE RESPONSES 69 AND ANTIGENS B-cell maturation Directed by bone marrow sites that harbor stromal cells, which nurture the lymphocyte stem cells and provide hormonal signals Millions of distinct B cells develop and “home” to specific sites in the lymph nodes, spleen, and GALT Come into contact with antigens throughout life Have immunoglobulin as surface receptors for antigens  LYMPHOCYTE RESPONSES 70 AND ANTIGENS T-cell maturation Maturation is directed by the thymus gland and its hormones Different classes of T-cell receptors termed CD - Cluster of differentiation CD4 and CD8 Mature T cells migrate to lymphoid organs ENTRANCE AND PROCESSING OF ANTIGENS AND CLONAL 71 SELECTION Antigen (Ag) is a substance that provokes an immune response in specific lymphocytes Property of behaving as an antigen is antigenicity Foreignness, size, shape, and accessibility CHARACTERISTICS OF ANTIGENS 72 Perceived as foreign, not a normal constituent of the body Foreign cells and large complex molecules over 10,000 MW are most antigenic Antigenic determinant, epitope – small molecular group that is recognized by lymphocytes Antigen has many antigenic determinants 73  SPECIAL CATEGORIES OF 74 ANTIGENS Alloantigens – cell surface markers and molecules that occur in some members of the same species but not in others Superantigens – potent T cell stimulators; provoke an overwhelming response Allergen – antigen that evokes allergic reactions Autoantigens – molecules on self tissues for which tolerance is inadequate  COOPERATION IN IMMUNE 75 REACTIONS TO ANTIGENS The basis for most immune responses is the encounter between antigens and white blood cells Lymph nodes and spleen concentrate the antigens and circulate them so they will come into contact with lymphocytes  ANTIGEN PROCESSING AND PRESENTATION TO LYMPHOCYTES 76 T-cell dependent antigens must be processed by phagocytes called antigen presenting cells (APC) APCs modify the antigen; then the Ag is moved to the APC surface and bound to MHC receptor Antigen presentation involves a direct collaboration among an APC, and a T helper cell Interleukin-1 is secreted by APC to activate TH cells Interleukin-2 is produced by TH to activate B and other T cells 77  B CELL RESPONSES 78 B-cell activation and antibody production Once B cells process the Ag, interact with TH cells, and are stimulated by growth and differentiation factors, they enter the cell cycle in preparation for mitosis and clonal expansion Divisions give rise to plasma cells that secrete antibodies and memory cells that can react to the same antigen later 79 ANTIBODY STRUCTURE AND FUNCTIONS 80 Immunoglobulins (Ig) Large Y-shaped protein Consist of 4 polypeptide chains Contains 2 identical fragments (Fab) with ends that bind to specific antigen Fc binds to various cells and molecules of the immune system 81 82  ANTIBODY-ANTIGEN INTERACTIONS Principle 83 antibody activity is to unite with the Ag, to call attention to, or neutralize the Ag for which it was formed Opsonization – process of coating microorganisms or other particles with specific antibodies so they are more readily recognized by phagocytes Agglutination – Ab aggregation; cross-linking cells or particles into large clumps Neutralization – Abs fill the surface receptors on a virus or the active site on a microbial enzyme to prevent it from attaching Antitoxins are a special type of Ab that neutralize bacterial exotoxins  Opsonization- additional components that has been added to pathogenic organisms which enhances the ability of immune cells to uptake the organism  FUNCTION OF THE AB 85 FUNCTIONS OF THE FC FRAGMENT 86 Fc fragment binds to cells – macrophages, neutrophils, eosinophils, mast cells, basophils, and lymphocytes Certain antibodies have regions on the Fc portion for fixing complement Binding of Fc may cause release of cytokines CLASSES OF IMMUNOGLOBULINS 87 5 classes of immunoglobulins (Ig): 1. IgG – monomer, produced by plasma cells (primary response) and memory cells (secondary), most prevalent 2. IgA – monomer circulates in blood, dimer in mucous and serous secretions 3. IgM – five monomers, first class synthesized following Ag encounter 4. IgD – monomer, serves as a receptor for antigen on B cells 5. IgE – Involved in allergic responses and parasitic worm infections  IgG- most abundant type found in the blood (great long term immunity) IgD IgD- assist in antigen recognition ? IgE- involved in allergies and parasitic infections IgM- first Ig on the scene IgA- is found in most mucosal layers (because of the J chain), is the secretory antibody  PRIMARY AND SECONDARY RESPONSES TO ANTIGENS 90 Primary response – after first exposure to an Ag immune system produces IgM and a gradual increase in Ab titer (concentration of antibodies) with the production of IgG Secondary response – after second contact with the same Ag, immune system produces a more rapid, stronger response due to memory cells Anamnestic response 91  T CELLS & CELL-MEDIATED IMMUNITY 92 Cell-mediated immunity requires the direct involvement of T lymphocytes T cells act directly against Ag and foreign cells when presented in association with an MHC carrier T cells secrete cytokines that act on other cells Sensitized T cells proliferate into long-lasting memory T cells CHARACTERISTICS OF T CELL SUBSETS 93  TYPES OF T CELLS 94 1. T helper cells (CD4 or TH) most prevalent type of T cell; regulate immune reaction to antigens, including other T and B cells; also involved in activating macrophages and increasing phagocytosis; differentiate into T helper 1 (TH1) cells or T helper 2 (TH2) cells 2. Cytotoxic T cells (CD8 or TC) destroy foreign or abnormal cells by secreting perforins that lyse cells 3. Natural killer cells – lack specificity; circulate through the spleen, blood, and lungs See95 figure 33.8 for co- stimulation  T CELLS AND SUPERANTIGENS 96 Reaction has drastic consequences Superantigens are a form of a virulence factor Provoke overwhelming immune responses by large numbers of T cells Release of cytokines Blood vessel damage Toxic shock Multiorgan damage TYPES OF IMMUNITY  HYPERSENSITIVITIES Type 1 Hypersensitivity- allergic response (can result in specific IgE productions (called reagin). Usually hereditary. Can result in anaphylaxis (can be local or systemic) Type II Hypersensitivity- also called cytolytic or cytotoxic reaction. Specific IgM and IgE are inappropriately directed to attack your tissue antigens. Can stimulate complement as well). Will result in cell death.  HYPERSENSITIVITIES Hypersensitivity III- usually involves immune complexes triggering a massive inflammatory response. Is usually not cleared well and can involve complement. May get lodged in tissues leading to organ failure. Hypersensitivity IV- is more of a delayed immune response. The cell mediated (T-cells) are responsible for this. (example is the TB skin test)  AUTOIMMUNITY 100 In certain type II & III hypersensitivities, the immune system has lost tolerance to autoantigens and forms autoantibodies and sensitized T cells against them Disruption of function can be systemic or organ specific: Systemic lupus erythematosus Rheumatoid arthritis Endocrine autoimmunities Myasthenia gravis Multiple sclerosis THE ORIGINS OF AUTOIMMUNE DISEASE 101 Sequestered antigen theory – during embryonic growth some tissues are immunologically privileged Forbidden clones – some clones were not subjected to the tolerance process, and they attack tissues carrying self molecules Theory of immune deficiency – mutations in the receptor genes of some lymphocytes render them reactive to self Molecular mimicry, viral infection, microbial etiology  IMMUNODEFICIENCY DISEASES 102 Components of the immune response system are absent. Deficiencies involve B and T cells, phagocytes, and complement 2 general categories: Primary immunodeficiency – congenital; usually genetic errors Secondary diseases – acquired after birth; caused by natural or artificial agents  103 Primary immunodeficiency – lack of B-cell and/or T cell activity B cell defect – agammaglobulinemia – patient lacks antibodies T cell defect – thymus is missing or abnormal DiGeorge syndrome Severe combined immunodeficiency (SCID) - Both limbs of lymphocyte system are missing or defective; no adaptive immune response Adenosine deaminase deficiency  104 Secondary diseases – due to damage after birth Caused by: infection, organic disease, chemotherapy, or radiation AIDS most common – T helper cells are targeted; numerous opportunistic infections and cancers  THE IMMUNE SYSTEM AND CANCER 105 New growth of abnormal cells Tumors may be benign (nonspreading) self- contained; or malignant that spreads from tissue of origin to other sites Appear to have genetic alterations that disrupt the normal cell division cycle Possible causes include: errors in mitosis, genetic damage, activation of oncogenes, or retroviruses Immune surveillance, immune system keeps cancer “in check”