18 Natural Defenses against Disease 18 Natural Defenses

18 Natural Defenses against Disease

18 Natural Defenses against Disease • Animal Defense Systems • Nonspecific Defenses • Specific Defenses: The Immune System • B Cells: The Humoral Immune Response • T Cells: The Cellular Immune Response • The Genetic Basis of Antibody Diversity • Disorders of the Immune System

18 Animal Defense Systems • Animal defense systems are based on the distinction between self and nonself. • There are two general types of defense mechanisms: § Nonspecific defenses, or innate defenses, are inherited mechanisms that protect the body from many different pathogens. § Specific defenses are adaptive mechanisms that protect against specific targets.

18 Animal Defense Systems • Components of the defense system are distributed throughout the body. • Lymphoid tissues (thymus, bone marrow, spleen, lymph nodes) are essential parts of the defense system. • Blood plasma suspends red and white blood cells and platelets. • Red blood cells are found in the closed circulatory system. • White blood cells and platelets are found in the closed circulatory system and in the lymphatic system.

18 Animal Defense Systems • Lymph consists of fluids that accumulate outside of the closed circulatory system in the lymphatic system. • The lymphatic system is a branching system of tiny capillaries connecting larger vessels. • These lymph ducts eventually lead to a large lymph duct that connects to a major vein near the heart. • At sites along lymph vessels are small, roundish lymph nodes. • Lymph nodes contain a variety of white blood cells.

Figure 18. 1 The Human Lymphatic system

18 Animal Defense Systems • White blood cells are important in defense. • All blood cells originate from stem cells in the bone marrow. • White blood cells (leukocytes) are clear and have a nucleus and organelles. • Red blood cells are smaller and lose their nuclei before they become functional. • White blood cells can leave the circulatory system. • The number of white blood cells sometimes rises in response to invading pathogens.

18 Animal Defense Systems • There are two main groups of white blood cells: phagocytes and lymphocytes. • Phagocytes engulf and digest foreign materials. • Lymphocytes are most abundant. There are two types: B and T cells. • T cells migrate from the circulation to the thymus, where they mature. • B cells circulate and also collect in lymph vessels, and make antibodies.

Figure 18. 2 Blood Cells (Part 1)

Figure 18. 2 Blood Cells (Part 2)

Figure 18. 2 Blood Cells (Part 3)

18 Animal Defense Systems • Four groups of proteins play key roles in defending against disease: § Antibodies, secreted by B cells, bind specifically to certain substances. § T cell receptors are cell surface receptors that bind nonself substances on the surface of other cells. § Major histocompatibility complex (MHC) proteins are exposed outside cells of mammals. These proteins help to distinguish self from nonself. § Cytokines are soluble signal proteins released by T cells. They bind alter the behavior of their target cells.

18 Nonspecific Defenses • The skin acts as a physical barrier to pathogens. • Bacteria and fungi on the surface of the body (normal flora) compete for space and nutrients against pathogens. • Tears, nasal mucus, and saliva contain the enzyme lysozyme that attacks the cell walls of many bacteria. • Mucus and cilia in the respiratory system trap pathogens and remove them. • Ingested pathogens can be destroyed by the hydrochloric acid and proteases in the stomach. • In the small intestine, bile salts kill some pathogens.

18 Nonspecific Defenses • Vertebrate blood contains about 20 antimicrobial complement proteins. • Complement proteins provide three types of defenses: § They attach to microbes, helping phagocytes recognize and destroy them. § They activate the inflammation response and attract phagocytes to the site of infection. § They lyse invading cells.

18 Nonspecific Defenses • Interferons are produced by cells that are infected by a virus. • All interferons are glycoproteins consisting of about 160 amino acids. • They increase resistance of neighboring cells to infections by the same or other viruses. • Each vertebrate species produces at least three different interferons.

18 Nonspecific Defenses • Phagocytes ingest pathogens. There are several types of phagocytes: § Neutrophils attack pathogens in infected tissue. § Monocytes mature into macrophages. They live longer and consume larger numbers of pathogens than do neutrophils. Some roam and others are stationary in lymph nodes and lymphoid tissue. § Eosinophils kill parasites, such as worms, that have been coated with antibodies. § Dendritic cells have highly folded plasma membranes that can capture invading pathogens.

18 Nonspecific Defenses • Natural killer cells are a class of nonphagocytic white blood cells • They can initiate the lysis of virus-infected cells and some tumor cells.

18 Nonspecific Defenses • The inflammation response is used in dealing with infection or tissue damage. • Mast cells and white blood cells called basophils release histamine, which triggers inflammation. • Histamine causes capillaries to become leaky, allowing plasma and phagocytes to escape into the tissue. • Complement proteins and other chemical signals attract phagocytes. Neutrophils arrive first, then monocytes (which become macrophages).

18 Nonspecific Defenses • The macrophages engulf invaders and debris and are responsible for most of the healing. • They produce several cytokines, which may signal the brain to produce a fever. • Pus, composed of dead cells and leaked fluid, may accumulate.

Figure 18. 4 Interactions of Cells and Chemical Signals in Inflammation (Part 1)

Figure 18. 4 Interactions of Cells and Chemical Signals in Inflammation (Part 2)

18 Nonspecific Defenses • An invading pathogen is a signal that triggers the body’s defense mechanisms. • A signal transduction pathway acts as the link between a signal and the immune response. • The membrane protein toll is the receptor. • Toll is part of a protein kinase cascade that results in the transcription of at least 40 genes involved in both specific and nonspecific defenses. • The signal molecules are made only by microbes.

Figure 18. 5 Cell Signaling and Defense

18 Specific Defenses: The Immune System • Four characteristics of the immune system: § 1. Specificity: Antigens are organisms or molecules that are specifically recognized by T cell receptors and antibodies. q The sites on antigens that the immune system recognizes are the antigenic determinants (or epitopes). q Each antigen typically has several different antigenic determinants. q The host creates T cells and/or antibodies that are specific to the antigenic determinants.

Figure 18. 6 Each Antibody Matches an Antigenic Determinant

18 Specific Defenses: The Immune System § 2. Diversity: It is estimated that the human immune system can distinguish and respond to 10 million different antigenic determinants. § 3. Distinguishing self from nonself: q Each normal cell in the body bears a tremendous number of antigenic determinants. It is crucial that the immune system leave these alone. § 4. Immunological memory: q q Once exposed to a pathogen, the immune system remembers it and mounts future responses much more rapidly.

18 Specific Defenses: The Immune System • The immune system has two responses against invaders: The humoral immune response and the cellular immune response. • The two responses operate in concert and share mechanisms.

18 Specific Defenses: The Immune System • The humoral immune response involves antibodies that recognize antigenic determinants by shape and composition. • Some antibodies are soluble proteins that travel free in blood and lymph. Others are integral membrane proteins on B cells. • When a pathogen invades the body, it may be detected by and bound by a B cell whose membrane antibody fits one of its potential antigenic determinants. • This binding activates the B cell, which makes multiple soluble copies of an antibody with the same specificity as its membrane antibody.

18 Specific Defenses: The Immune System • The cellular immune response is able to detect antigens that reside within cells. • It destroys virus-infected or mutated cells. • Its main component consists of T cells. • T cells have T cell receptors that can recognize and bind specific antigenic determinants.

18 Specific Defenses: The Immune System • Several questions arise that are fundamental to understanding the immune system. § How does the enormous diversity of B cells and T cells arise? § How do B and T cells specific to antigens proliferate? § Why don’t antibodies and T cells attack and destroy our own bodies? § How can the memory of postexposure be explained?

18 Specific Defenses: The Immune System • Clonal selection explains much of this. • The healthy body contains a great variety of B cells and T cells, each of which is specific for only one antigen. • Normally, the number of any given type of B cell present is relatively low. • When a B cell binds an antigen, the B cell divides and differentiates into plasma cells (which produce antibodies) and memory cells. • Thus, the antigen “selects” and activates a particular antibody-producing cell.

Figure 18. 7 Clonal Selection in B Cells

18 Specific Defenses: The Immune System • An activated lymphocyte (B cell or T cell) produces two types of daughter cells: effector and memory cells. • Effector B cells, called plasma cells, produce antibodies. • Effector T cells release cytokines. • Memory cells live longer and retain the ability to divide quickly to produce more effector and more memory cells.

18 Specific Defenses: The Immune System • When the body encounters an antigen for the first time, a primary immune response is activated. • When the antigen appears again, a secondary immune response occurs. This response is much more rapid, because of immunological memory.

Figure 18. 8 Immunological Memory

18 Specific Defenses: The Immune System • Artificial immunity is acquired by the introduction of antigenic determinants into the body. • Vaccination is inoculation with whole pathogens that have been modified so they cannot cause disease. • Immunization is inoculation with antigenic proteins, pathogen fragments, or other molecular antigens. • Immunization and vaccination initiate a primary immune response that generates memory cells without making the person ill.

18 Specific Defenses: The Immune System • Antigens used for immunization or vaccination must be processed so that they will provoke an immune response but not cause disease. There are three principle ways to do this: § Attenuation involves reducing the toxicity of the antigenic molecule or organism. § Biotechnology can produce antigenic fragments that activate lymphocytes but do not have the harmful part of the protein toxin. § DNA vaccines are being developed that will introduce a gene encoding an antigen into the body.

18 Specific Defenses: The Immune System • The body is tolerant of its own molecules, even those that would cause an immune response in other individuals of the same species. • Failure to do so results in autoimmune disease. • This self tolerance is based on two mechanisms: clonal deletion and clonal anergy.

18 Specific Defenses: The Immune System • Clonal deletion eliminates B or T cells from the immune system at some point during differentiation. • About 90 percent of all B cells made in the bone marrow are removed in this way. • Any immature B cell in the marrow that could mount an immune response against self antigens is eliminated. • The same is true for T cells, but the selection occurs in the thymus. • Elimination is accomplished by means of apoptosis.

18 Specific Defenses: The Immune System • Clonal anergy is the suppression of the immune response. • Before a mature T cell mounts an immune response, it must recognize both an antigen on a cell and another molecule, CD 28 (co-stimulatory signal), which is not present on most body cells. • CD 28 is present only on certain antigen-presenting cells, including macrophages and the dendritic cells in the linings of the respiratory and digestive tracts.

18 Specific Defenses: The Immune System • Immunological tolerance is a poorly understood but clearly observable phenomenon. • Exposing a fetus to an antigen before birth provides later tolerance to the antigen. • Continued exposure is necessary to maintain the tolerance. • Some individuals experience the opposite effect; they lose tolerance to themselves, which results in autoimmune disease.

18 B Cells: The Humoral Immune Response • B cells are the basic component of the humoral immune system. • For a B cell to differentiate into a plasma cell, it must bind an antigenic determinant. • A helper T cell (TH) must also bind the same determinant as it is presented by an antigenpresenting cell. • Cellular division and differentiation of the B cell is stimulated by a signal from the activated TH cell. • Activated B cells become plasma cells and memory cells.

Figure 18. 9 A Plasma Cell

18 B Cells: The Humoral Immune Response • Antibody molecules are proteins called immunoglobulins. • All are composed of one or more tetramers consisting of four polypeptide chains. • Two identical light chains and two identical heavy chains make up the tetrameric units. • Disulfide bonds hold the chains together. • Both the light and heavy chains on each peptide have variable and constant regions. • The constant regions are similar among the immunoglobulins and determine the class of the antibody.

18 B Cells: The Humoral Immune Response • The variable regions differ in the amino acid sequences at the antigen-binding site and are responsible for the diversity of antibody specificity. • The heavy and light chain variable regions align and form the binding sites. • Each tetramer has two identical antigen-binding sites, making the antibody bivalent. • The enormous range of antibody specificities is made possible by the recombination of numerous versions of coding regions for the variable regions.

Figure 18. 10 Structure of Immunoglobulins (Part 1)

Figure 18. 10 Structure of Immunoglobulins (Part 2)

18 B Cells: The Humoral Immune Response • The five immunoglobulin classes are based on differences in the constant regions of the heavy chain. • Ig. G molecules make up 80 percent of the total immunoglobulin content of the bloodstream. • They are the primary product of a secondary immune response. • The constant regions of Ig. G antibodies are like handles that make it easier for a macrophage to grab and ingest antibody-coated antigens.

Figure 18. 11 Ig. G Antibodies Promote Phagocytosis

Table 18. 3 Antibody Classes (Part 1)

Table 18. 3 Antibody Classes (Part 2)

18 B Cells: The Humoral Immune Response • The normal antibody response is polyclonal: Because most antigens have more than one antigenic determinant, animals injected with a single antigen generally produce several different antibodies. • Polyclonal antibodies may have some crossreactivity with other molecules that have similar regions within the molecule.

18 B Cells: The Humoral Immune Response • A monoclonal antibody is made by a single clonal line of B cells and binds to only one antigenic determinant. • Monoclonal antibodies are very useful for immunoassays to determine the concentrations of other molecules that are present in minute amounts. • Monoclonal antibodies are also used in immunotherapy and passive immunization.

18 B Cells: The Humoral Immune Response • B cells cannot be cultured. To overcome this problem, a cancerous myeloma cell is fused to the plasma cell artificially. • These new cells, called hybridomas, live long and produce monoclonal antibodies.

Figure 18. 12 Creating Hybridomas for the Production of Monoclonal Antibodies (Part 1)

Figure 18. 12 Creating Hybridomas for the Production of Monoclonal Antibodies (Part 2)

18 T Cells: The Cellular Immune Response • T cells, like B cells, possess specific surface receptors. • The genes that code for T cell receptors are similar to those for immunoglobulins. • T cell receptors also have constant and variable regions. • A major difference between antibodies and T cell receptors is that T cell receptors bind only to an antigenic determinant that is displayed on the surface of an antigen-presenting cell.

Figure 18. 13 A T Cell Receptor

18 T Cells: The Cellular Immune Response • Activated T cells give rise to two types of effector cells. • Cytotoxic cells, or TC, recognize virus-infected cells and kill them by causing them to lyse. • Helper T cells, or TH cells, assist both the cellular and humoral immune systems. • Activated helper T cells proliferate and stimulate both B and TC cells to divide.

Figure 18. 14 Cytotoxic T Cells in Action

18 T Cells: The Cellular Immune Response • The major histocompatibility complex (MHC) gene products are plasma membrane glycoproteins. • These molecules are called human leukocyte antigens (HLA) in humans and H-2 proteins in mice. • There are three classes of MHC proteins.

18 T Cells: The Cellular Immune Response • Class I MHC proteins are present on the surface of every nucleated cell in animals. • When cellular proteins are degraded in the proteasome, an MHC I protein may bind a fragment and travel to the plasma membrane to present it outside on the cell’s plasma membrane surface. • TC cells have a surface protein called CD 8 that recognizes MHC I.

Figure 18. 16 The Interaction between T Cells and Antigen-Presenting Cells (Part 1)

Figure 18. 16 The Interaction between T Cells and Antigen-Presenting Cells (Part 2)

Figure 18. 16 The Interaction between T Cells and Antigen-Presenting Cells (Part 3)

18 T Cells: The Cellular Immune Response • Class II MHC proteins are found mostly on the surface of B cells, macrophages, and other antigen-presenting cells. • When an antigen is ingested by an antigenpresenting cell, it is broken down and fragments are presented at the cell surface by class II MHC proteins. • TH cells have CD 4 surface proteins that recognize MHC II.

Figure 18. 15 Macrophages Are Antigen-Presenting Cells

18 T Cells: The Cellular Immune Response • Class III MHC proteins include some of the proteins of the complement system that interact with antigen–antibody complexes to cause lysis of foreign cells.

18 T Cells: The Cellular Immune Response • T cells recognize the MHC I or II and then inspect the attached fragment. • There are three different loci for each MHC I and for each MHC II. • The six loci have as many as 100 different alleles. • This is why different individuals generally have different MHC genotypes.

18 T Cells: The Cellular Immune Response • TH cells bind to an antigen presented to it by an antigen-presenting macrophage. • The then-activated TH cell produces and secretes cytokine molecules, which attach to their own specific cell membrane receptor proteins. • The cell can then divide to produce clones capable of interacting with B cells. • These steps, called the activation phase, occur in the lymphatic tissues.

18 T Cells: The Cellular Immune Response • In the effector stage, an antigen of the same sort that was processed by the macrophage binds to a specific Ig. M receptor on the surface of a B cell. • The B cell degrades the antigen and presents a piece of processed antigen in a class II MHC protein on its cell surface. • One of the TH cells created in the activation stage recognizes the processed antigen and class II MHC protein on the surface of the B cell. • The TH cell releases cytokines, which activate B cell proliferation and differentiation into plasma cells and memory cells. • The plasma cells secrete antibodies.

Figure 18. 17 (a) Phases of the Humoral and Cellular Immune Responses (Part 1)

Figure 18. 17 (a) Phases of the Humoral and Cellular Immune Responses (Part 2)

18 T Cells: The Cellular Immune Response • Like class II MHC molecules, class I MHC molecules also present processed antigen to T cells. • Foreign protein fragments are bound by class I MHC molecules and carried to the plasma membrane, where TC cells can check them. • If a cell has been infected by a virus, or has mutated, it may present protein fragments that are not normally found in the body. • If a TC cell binds to the MHC I–antigen complex, the TC cell is activated to proliferate and differentiate.

18 T Cells: The Cellular Immune Response • In the effector stage, TC cells once again bind to the cells bearing MHC I–antigen complex and secrete molecules that lyse the cell. • TC cells can also bind to a specific target cell receptor (called Fas). • This binding initiates apoptosis in the target (for example, virus-infected) cell. • This system helps rid the body of virus-infected cells. It also helps to destroy some cancer tumors.

Figure 18. 17 (b) Phases of the Humoral and Cellular Immune Responses (Part 1)

Figure 18. 17 (b) Phases of the Humoral and Cellular Immune Responses (Part 2)

18 T Cells: The Cellular Immune Response • T cells developing in the thymus are tested to ensure that they will be functional and will not attack normal self antigens. • Each new T cell must recognize the body’s MHC proteins. If it fails to do so, it dies within about 3 days. • If the developing T cell binds to self MHC proteins and to one of the body’s own normal antigens, it undergoes apoptosis. • If these T cells were not destroyed they would be harmful or lethal to the animal. • If the T cell survives these tests, it becomes either a TC or TH cell.

18 T Cells: The Cellular Immune Response • For organ transplants to be successful, MHC molecules must match; otherwise, these same molecules will act as antigens. • The cellular immune system is responsible for rejection. • Rejection problems can be controlled somewhat by treating patients with immunosuppressing drugs such as cyclosporin.

18 The Genetic Basis of Antibody Diversity • As B cells develop, their genomes become modified until the cell can produce one specific type of antibody. • If we had a different gene for each antibody our immune systems are capable of producing, our entire genome would be taken up by antibody genes. • Instead, just a small number of genes that can recombine to generate multitudes of possibilities are responsible for the vast diversity of antibodies.

18 The Genetic Basis of Antibody Diversity • Each gene encoding an immunoglobin is in reality a “supergene” assembled from several clusters of smaller genes located along part of a chromosome. • During B cell development, these variable regions rearrange and join. • Pieces of DNA are deleted, and DNA segments formerly distant from one another are joined together. • Immunoglobulin genes are assembled from randomly selected pieces of DNA.

Figure 18. 18 Heavy-Chain Genes

18 The Genetic Basis of Antibody Diversity • Each B cell precursor assembles its own two specific antibody genes, one for a heavy chain, and the other for a light chain. • In both humans and mice, the DNA segments coding for immunoglobulin heavy chains are on one chromosome and those for light chains are on another.

18 The Genetic Basis of Antibody Diversity • There are multiple genes coding for each of the four kinds of segments in the polypeptide chain for the heavy chain in mice: 100 V, 30 D, 6 J, and 8 C regions. • Each B cell randomly selects one gene for each of the V, D, J, and C regions. • A similar process occurs for the light chain. • Theoretically, there are 144, 000 x 144, 000 possible combinations of light and heavy chains, i. e, 21 billion possibilities.

Figure 18. Heavy-Chain Gene Rearrangement and Splicing (Part 1)

Figure 18. Heavy-Chain Gene Rearrangement and Splicing (Part 2)

18 The Genetic Basis of Antibody Diversity • Additional diversity is possible because the recombinations do not occur at precise segments. Imprecise recombinations can create new codons at the junctions. • After DNA fragments are cut out and before they are joined, an enzyme, terminal transferase, adds some nucleotides to the free end. This adds even more variability by causing frame shifts and new codons. • Finally, the relatively high mutation rate in immunoglobulin genes leads to even more diversity.

18 The Genetic Basis of Antibody Diversity • B cells make only one class of antibody at a time, but class switching can occur. For example, the B cell can switch from Ig. M to Ig. G. • The constant region for Ig. M is coded for by the m segment. • If the cell becomes a plasma cell, another DNA splicing event positions the heavy-chain variable region next to a constant segment farther down the DNA strand, and the m segment is deleted. • Class switching is triggered and controlled by a TH cell via cytokine signals.

Figure 18. 20 Class Switching

18 Disorders of the Immune System • The human immune system can overreact to a dose of antigen and produce an inappropriate immune response. Allergies are the most familiar example. • Immediate hypersensitivity occurs when too much Ig. E is made. § If the Ig. E binds with antigens, mast cells and basophils are triggered to release histamine. • Delayed hypersensitivity does not begin until hours after exposure to an antigen and involves antigen-presenting cells and T cells. § The response can activate macrophages and cause tissue damage.

18 Disorders of the Immune System • If clonal deletion fails, “forbidden clones” of B and T cells directed against self-antigens are sometimes made. • Examples of autoimmune diseases include: § Systemic lupus erythematosis § Rheumatoid arthritis § Multiple sclerosis § Insulin-dependent (juvenile-onset) diabetes mellitus

18 Disorders of the Immune System • HIV (human immunodeficiency virus), which leads to AIDS (acquired immune deficiency syndrome), causes a depletion of TH cells. • It can be transmitted through blood or by exposure of broken skin or an open wound to the body fluids of an infected person.

Figure 18. 21 The Course of an HIV Infection

18 Disorders of the Immune System • HIV uses RNA as its genetic molecule. • The core of the virus contains two identical molecules of RNA and the enzymes reverse transcriptase, integrase, and a protease. • The envelope is derived from the plasma membrane of the cell in which the virus grew. • The envelope has glycoproteins gp 120 and gp 41 protruding. These proteins are necessary for the targeting of TH cells. • The virus enters the cell via CD 4 membrane proteins on TH cells. The gp 120 protein binds to CD 4.

18 Disorders of the Immune System • Once in the cell, reverse transcriptase makes a DNA copy (c. DNA) of the viral RNA, and cellular DNA polymerase makes the complementary strand. • Reverse transcriptase is error prone; this elevates the mutation rate and adds to the adaptability of the virus. • The c. DNA integrates into the host DNA.

18 Disorders of the Immune System • Viruses are made when the TH cell is activated. • Transcription of the viral DNA requires host transcription factors and a viral protein, Tat. • The RNA is either spliced and translated or unspliced to become the genetic molecule of a new virus. • A viral protease is needed to cleave large viral precursor proteins into smaller functional units. • Viral membrane proteins are synthesized on rough ER, and glycosylation occurs within the ER and Golgi complex.

18 Disorders of the Immune System • Highly active antiretroviral therapy (HAART) was developed in the late 1990 s. • A protease inhibitor obstructs the active site of the HIV protease. • Two reverse transcriptase inhibitors that terminate the c. DNA molecules prematurely are used. • Unfortunately, 80 percent of patients taking HAART develop mutant strains of HIV that are resistant.

Figure 18. 22 Relationship Between TH Cell Count and Opportunistic Infections