18 Natural Defenses against Disease

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 (aka, leukocytes).

Figure 18.1 The Human Lymphatic system

18 Animal Defense Systems White blood cells are important in defense. White blood cells (leukocytes) are clear and have a nucleus and organelles.. 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 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 and 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 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.  They shut down transcription and translation 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.

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 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.  The sites on antigens that the immune system recognizes are the antigenic determinants (or epitopes).  Each antigen typically has several different antigenic determinants.  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 different antigenic determinants.  3. Distinguishing self from nonself:  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:  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 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.  Before vaccines, tens of millions of people died each year from infectious diseases

18 Specific Defenses: The Immune System The body is self 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.

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 (T H ) must also bind the same determinant as it is presented by an antigen- presenting cell. Cellular division and differentiation of the B cell is stimulated by a signal from the activated T H cell. Activated B cells become plasma cells and memory cells.

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 Structure of Immunoglobulins (Part 1)

Figure 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.  IgG - the majority of serum antibody  IgM - first antibody made after an infection  IgA - most abundant antibody made; mucosal secretions and breast milk  IgE - parasitic infections; allergies  IgD - B cell receptor only; not secreted The constant regions of IgG antibodies are like handles that make it easier for a macrophage to grab and ingest antibody-coated antigens.

Figure IgG Antibodies Promote Phagocytosis

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 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 T C, recognize virus- infected cells and kill them by causing them to lyse.  Helper T cells, or T H cells, assist both the cellular and humoral immune systems. Activated helper T cells proliferate and stimulate both B and T C cells to divide.

18 T Cells Recognize Antigens Bound to MHC Molecules on APC

18 Helper T Cells Provide Permission to B Cells to Secrete Antibodies Through MHC:Antigen:TCR interactions