Specific Defenses of the Host - Immune Response

Specific Defenses of the Host - Immune Response (Ch. 17)

Specific Defenses

• Specific resistance is the third line of defense, effective against particular pathogens.
• Immunity involves a specific defensive response to an invasion by foreign organisms or foreign substances.
• Antigens are organisms or substances that provoke an immune response.
• The immune response involves antibodies and specialized lymphocytes.
• Immune response may be triggered by:
  • Pathogenic microorganisms
  • Foreign materials such as pollen, insect venom, or transplanted tissue
  • Cancerous body cells (but not effective against them once a solid tumor is established).

Types of Acquired Immunity

• Acquired immunity: the protection an animal develops against certain types of microbes or foreign substances; develops over the lifetime of the individual.
• Four kinds of acquired immunity:
  • Naturally acquired active immunity
  • Naturally acquired passive immunity
  • Artificially acquired active immunity
  • Artificially acquired passive immunity

Naturally Acquired Immunity

• Active: obtained when exposed to antigens in the course of daily life.
  • Lifelong immunity to some diseases, such as measles or chickenpox.
  • For others, only short term (a few years), as in the case of some intestinal diseases.
  • Subclinical infections (produce no noticeable signs of illness) can also give immunity.
• Passive: involves the natural transfer of antibodies from a mother to her infant.
  • Transplacental transfer occurs across the placenta: infant is temporarily immune to certain diseases if antibodies are passed from the mother (who was immune to the disease).
  • Certain antibodies are also passed in the first breast secretions called colostrum.

Artificially Acquired Immunity

• Active: results from vaccination.
  • Vaccination (also called immunization) introduces specially prepared antigens called vaccines into the body.
  • Vaccines may be:
    • Inactivated bacterial toxins (toxoids)
    • Killed microorganisms
    • Living but attenuated microorganisms
    • Parts of microorganisms (such as capsules)
  • These substances no longer cause disease, but can stimulate an immune response.
• Passive: from the introduction of antibodies into the body (come from an animal or person who is immune).

Adaptive Immunity Types

• A table illustrates the types of immunity:
  • Innate Immunity
  • Adaptive Immunity:
    • Active:
      • Natural (Infection)
      • Artificial (immunization)
    • Passive (antibody transfer):
      • Natural (maternal)
      • Artificial

Duality of the Immune System

• Humoral (antibody-mediated) immune system: involves the production of antibodies against foreign organisms or substances found in extracellular fluids (blood plasma, lymph, mucus secretions).
  • B cells (B lymphocytes) produce antibodies.
  • This defense system is primarily against bacteria, bacterial toxins, and viruses that are circulating freely in the body’s fluids.
  • Also involved in some reactions against transplanted tissue.
  • B cells recognize antigens by antibodies on their surfaces.
• Cell-mediated immune system: involves special lymphocytes called T cells (T lymphocytes) that act against foreign organisms or tissues.
  • T cells also regulate activation and proliferation of other immune system cells (such as macrophages).
  • Effective against bacteria or viruses located within phagocytic or infected host cells, and also against fungi, protozoa, and helminths.
  • Primary responder against transplanted tissue: mounts a response to reject foreign tissue.
  • Also an important factor in defense against cancer.

Development of T and B Cells

• Stem cells develop in bone marrow or in fetal liver.
• Stem cell diverges into two cell lines:
  • B cells: Differentiate to B cells in adult red bone marrow; Migrate to lymphoid tissue such as spleen, but especially lymph nodes.
  • T cells: Differentiate to T cells in thymus; Migrate to lymphoid tissue such as spleen, but especially lymph nodes.

Antigens

• Most antigens are proteins or large polysaccharides.
• Lipids and nucleic acids usually only antigenic if with proteins or polysaccharides.
• Foreign to the body.
• Often components of invading microbes: capsules, cell walls, flagella, fimbriae, or toxins of bacteria; viral coats; surfaces of other microbes.
• Non-microbial antigens: pollen, egg white, blood cell surface molecules, serum proteins from other individuals or species, surface molecules of transplanted tissues.
• Antibodies recognize specific regions called antigenic determinants or epitopes. Must have at least two sites.
• Low molecular weight molecules (haptens) generally not antigenic unless attached to a carrier molecule (e.g., penicillin).
• Once an antibody has formed, it interacts with the hapten even when no longer bound to the carrier.

Antigenic Determinants

• Antibodies recognize and react with antigenic determinants or epitopes.
• Antigens: components of cell wall.

Antibodies

• Proteins made in response to an antigen.
• Can recognize and bind to that antigen.
• Very specific in recognizing the antigen that stimulated their formation.
• Each antibody has two identical sites for binding the antigen; these are called antigen-binding sites.
• Since most human antibodies have two sites, they are said to be bivalent (valence is the number of antigen binding sites on the antibody).
• Antibodies are members of the group of soluble proteins collectively known as immunoglobulins (Igs).

Antibody Structure

• A single bivalent antibody is known as a monomer, and a typical antibody monomer has four protein chains.
• Two identical light (L) chains and two identical heavy (H) chains joined by disulfide links and other bonds to form Y-shaped, flexible molecules.
• Two sections near the ends of the Y’s arms are called variable (V) regions; these are the antigen-binding regions.
• The variable regions of each arm of the Y are identical in amino acid sequence.
• The stem and lower part of the Y arms are called constant (C) regions (5 major kinds).
• Fc region in stem is important, can bind between antibodies bound to a bacterium and lead to destruction of the bacterium.

Immunoglobulin Classes

• The five classes designated: IgG, IgM, IgA, IgD, and IgE.
• IgG, IgD, and IgE resemble the Y-structure.
• IgM and IgA usually consist of two or more monomers joined by disulfide bonds.

IgG Antibodies

• Monomer.
• 80% of serum Abs.
• Fix complement.
• In blood, lymph, and intestine.
• Easily cross walls of blood vessels and enter tissue fluids, maternal IgG can cross the placenta and confer passive immunity.
• Protect against circulating bacteria and viruses, neutralize bacterial toxins, trigger complement system, and when bound to antigens, enhance the effectiveness of phagocytic cells.
• Protects fetus and newborn.
• Half-life = 23 days.

IgM Antibodies

• “m” is for macro (large).
• Make up 5-10% of antibodies in serum.
• Has a pentamer structure: 5 monomers held together by a polypeptide called a J (joining) chain.
• Remain in blood vessels (too large to diffuse out).
• Predominant antibody type in response to ABO blood group antigens.
• Enhance phagocytosis
• First antibodies to appear in response to antigen exposure.
• Relatively short lived, but important in diagnosis (detection of IgM for an antigen makes it likely the disease is caused by that pathogen). Tells if a disease is chronic.
• Half-life = 5 days.

IgA Antibodies

• Only 10-15% of antibodies in serum, but most abundant for most in mucous membranes and body secretions (the most abundant Ab in body, but IgG is most abundant in serum).
• Serum IgA in the serum, mostly as monomer.
• Secretory IgA is the most effective form: dimer of two monomers joined by a J chain; this form produced by plasma cells in mucous membranes).
• Passes through a mucosal cell where a polypeptide called a secretory component is added to protect it from enzymatic digestion.
• Helps prevent attachment of pathogens to mucosal surfaces.
• Presence in colostrum probably protects infants from gastrointestinal infections.
• Half-life = 6 days.

IgD and IgE Antibodies

• IgD
  • Only 0.2% of total serum antibodies.
  • Resemble IgG in structure.
  • Found in blood, lymph, and on the surface of B cells.
  • Act as antigen receptors for B cells (Functions mainly as an antigen receptor on B cells that have not been exposed to antigens).
  • Half-life = 3 days.
• IgE
  • Only 0.002% of total serum antibodies.
  • Slightly larger than IgG molecules.
  • Bind tightly by their Fc regions to receptors on mast cells and basophils.
  • Cells responsible for allergic reactions.
  • Antigen (such as pollen) bound IgE antibodies attach to the cell and induce releases of histamine and other chemicals.
  • Can trigger an allergic response as well as be protective by attracting IgG, complement, and phagocytic cells.
  • Especially useful against parasitic worms.

B Cells and Humoral Immunity

• Activated B cells produce antibodies.
• Process begins when B cells are exposed to free (extracellular) antigens.
• The B cell becomes activated, divides, and differentiates into a clone of many effector cells -- called plasma cells.
• The process is associated with assistance from T cells (covered later).
• B cells mature in the bone marrow.
• Apoptosis: programmed cell death.
• $100$ million new lymphocytes are formed each day, and an equivalent number die (to keep balance, otherwise leads to leukemia).
• Cells are programmed to die at a certain time; for B cells, those that are not activated within a certain time will die.

B Cells: Activation by Clonal Selection

• A person’s B cell population can produce many different antibodies, but each B cell can produce only one kind.
• IgM and IgD antibodies on the surface of the B cell allow it to recognize the specific antigen.
• Clonal selection occurs when the appropriate antigen binds the cell.
• The cell proliferates into a large clone of cells.
• Some become memory cells (for long-term immunity), others plasma cells.
• All the clones have the same specificity.
• Plasma cells secrete the appropriate antibodies.

Clonal Selection

• Diagram illustrating clonal selection of B cells, leading to plasma cells and memory cells, and subsequent antibody production.

Activation of B Cells

• Diagram illustrating activation of B Cells.

Antigen-Antibody Binding

• Antigen-antibody complex rapidly forms when the antibody encounters the specific antigen.
• Binding of antibody to antigen protects the host by tagging foreign cells and molecules for destruction by phagocytes and complement. Does not directly damage the antigen.
• Mechanisms for making the foreign organisms or toxin harmless:
  • agglutination
  • opsonization
  • neutralization
  • antibody-dependent cell-mediated cytotoxicity
  • inflammation
  • activation of complement

The Results of Ag-Ab Binding

• Agglutination: Reduces the number of infectious units to be dealt with.
• Opsonization: Coating antigen with antibody enhances phagocytosis.
• Neutralization: Blocks adhesion of bacteria and viruses to mucosa; Blocks attachment of toxin.
• Activation of complement: Causes inflammation and cell lysis.
• Antibody-dependent cell-mediated cytotoxicity: Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells.

Immunological Memory

• Antibody titer: the amount of antibody in the serum.
• Reflects the humoral response.
• After initial exposure to the antigen, there are no detectable antibodies in the serum for several days, then there is a slow rise in antibody titer.
• First, IgM antibodies are produced, then IgG.
• Finally, there is a gradual decline of titer.
• This is called the primary response.
• On second exposure, the response intensifies.
• Secondary response is also called memory or anamnestic response.
• Caused by the B lymphocytes that became memory cells.
• Rapidly differentiate into antibody-producing plasma cells.

Primary and Secondary Immune Responses

• A graph illustrates the primary and secondary immune responses to an antigen, showing antibody titer (IgM and IgG) over time after initial and second exposures.

Monoclonal Antibodies

• Antibodies can be used for diagnostic purposes, but should be pure.
• Animals have a mixture of many antibodies.
• Ideally, antibody-producing B cells could be cultured in cell culture.
• Unfortunately, B cells only reproduce a few times in culture.
• In 1984, Jerne, Kohler, and Milstein received the Nobel Prize for discovering a way to prolong B cell cultures.
• Fuse a cancerous B cell (myelomas) with an antibody-producing B cell to make a hybridoma.
• The hybridoma can be grown indefinitely.
• Since all the antibodies produced from a hybridoma clone are the same, they are called monoclonal antibodies.

Cell-mediated Immunity

• Based on the activity of certain specialized lymphocytes, primarily T cells.
• Chemical messengers of immune cells regulate many other cells of the immune system; these factors are known as cytokines.
• Interleukins are cytokines which serve as communicators between leukocytes.
• Other cytokines: interferons, tumor necrosis factor, colony-stimulating factor, chemokines (chemotaxis of leukocytes to infected area).

Activation of B Cells (T-dependent vs. T-independent)

• T-dependent antigens: Ag presented with (self) MHC to $T<em>H$ cell. $T</em>H$ cell produces cytokines that activate the B cell.
• T-independent antigens: Stimulate the B cell to make Abs.

T Cells

• Develop from stem cells in bone marrow.
• Differentiate into mature cells in the thymus gland.
• Migrate to the lymphoid organs where they may encounter antigens.
• Similar response as B cells to antigens (each T cell is specific, clones proliferate in response to antigen, some memory cells produced).
• Four main functional types:
  • Helper T cells ($T_H$)
  • Cytotoxic T cells ($T_C$)
  • Delayed hypersensitivity T cells ($T_D$)
  • Suppressor T cells ($T_S$)
• Also classified by cell-surface receptor CD for clusters of differentiation.

T Cells (Continued)

• Helper T cells ($T_H$):
  • Play a central role in the immune response.
  • Induce formation of cytotoxic T cells and macrophages.
• Cytotoxic T cells ($T_C$):
  • Destroy target cells on contact.
• Delayed hypersensitivity T cells:
  • Mostly $T<em>H$ and some $T</em>C$ cells.
  • Associated with certain allergic reactions (including poison ivy, transplant rejection).
• Suppressor T cells:
  • Not well understood.
  • Appear to regulate immune response by turning it off when an antigen is no longer present.

T Cells (Continued): Nonspecific Cellular Components

• Activated macrophages: phagocytic capabilities are greatly increased when stimulated to become activated.
  • Can be activated either by ingesting antigens or by cytokines from T cells.
  • Have an enhanced ability to eliminate certain virally-infected cells or those with intracellular bacteria.
  • Can also function as antigen-presenting cells.
• Natural killer cells: can destroy other cells, especially virus-infected and tumor cells.
  • Unlike cytotoxic T cells, do not need to be stimulated by an antigen.
  • Are not phagocytic, but must contact the cell to lyse.

Dual Nature of the Adaptive Immune System

• Humoral (antibody-mediated) immune system: Control of freely circulating pathogens; Extracellular antigens.
• Cellular (cell-mediated) immune system: Control of intracellular pathogens; Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite.
• The adaptive immune system is divided into two parts, each responsible for dealing with pathogens in different ways. These two systems function interdependently to keep the body free of pathogens.
• Humoral immunity, also called antibody-mediated immunity, is directed at freely circulating pathogens and depends on B cells.
• Cellular immunity, also called cell-mediated immunity, depends on T cells to eliminate intracellular pathogens, reject foreign tissue recognized as nonself, and destroy tumor cells.

The Roles of Antigen-Presenting Cells, Helper T Cells, and Cytotoxic T Cells

1. An antigen-presenting cell (APC) encounters and ingests a microorganism. Antigen fragments (short peptides) from the microorganism combine internally with MHC (self molecules) and the complex of MHC molecules and antigen fragments is presented on the surface of the APC.
2. A helper T ($T_H$) cell receptor binds to the complex, stimulating the APC to secrete interleukin-1.
3. This interleukin-1 stimulates the helper T cell to produce interleukin-2, which then stimulates that helper T cell to form a clone of helper T cells.
4. The cells of this clone in turn produce cytokines, stimulating cells of both immune systems: Humoral immunity (secretion of antibodies by plasma cells) and Cell-mediated immunity (attack on infected cells) .