BIO372 : Immunology : Defenses : Lesson

I. Threats to health from the external environment

1. Virus
2. Bacterium
3. Fungus
4. Protozoan

II. Cells of the immune system recognize invaders

1. Innate immune system
   • Complement: blood proteins
     • Binds to protein on surface of bacterial cell
     • Triggers other complement molecules
     • Attracts phagocytes
     • Kill cells and bacteria by punching holes in cell membrane: bacterial meningitis and gonorrhea
     • Recognizes self
   • Bacterial defense: capsule of polysaccharides which coats the bacterium: pneumonia and streptococcus
     • Macrophages bind to polysaccharide coat
     • Ingest the bacterium
     • Secrete interleukin-6 which stimulates liver to secrete a protein which binds to mannose on the surface of the bacterium

2. Adaptive immune system
   • Clonal selection
     • B cells carry antibodies on the cell surface
     • When the cell surface antibody binds to a foreign molecule (antigen), the B cell is stimulated to begin mitosis and produce a clone of identical offspring that also bind that antigen; produce free antibodies
     • Antigens with bound antibodies are attacked by complement and phagocytes
     • Takes several days to respond to a new antigen: primary immune response

3. Antibody
   • Y-shaped molecule composed of two heavy chains and two light chains
   • Antigen-binding sites are located at the tip of each arm of the Y
   • Tail region determines the function of the antibody, e.g., activate complement or bind to phagocytes
   • Variable combination of gene segments (gene rearrangement) assembles a highly variable sequence of amino acids at the antigen-binding site
   • The three-dimensional structure of the antigen-binding site varies from antibody to antibody but both sites on the same antibody are identical

4. Immunologic memory
   • Some B cells (and T cells) become memory cells
   • On later exposure to the same antigen, response is faster and greater resulting in no disease: secondary immune response

5. Infected cells
   • Foreign antigen inside a cell is hidden from antibodies that circulate in the body fluids
   • Infected cell breaks foreign antigen into fragments
   • Each fragment combines with a class I MHC molecule
   • Antigen-MHC combination moves to cell surface and is attached to cell membrane
   • Killer T cells recognize the antigen-MHC combination
     • T cell receptor, similar to antibody antigen-binding site, matches the antigen-MHC combination
     • CD8 protein on the surface of the killer T cell binds to the constant part of the MHC molecule, strengthens recognition of the antigen and activates the killer T cell
     • Killer T cell releases a pore-forming protein which makes holes in the infected cell
     • Killer T cell activates a receptor on the surface of the infected cell causing it to undergo programmed cell death (apoptosis)
     • Infected cell is destroyed before new viral particles can be released

6. Antigen-presenting cells
   • Macrophages engulf invading bacteria and digest it into fragments
   • Each fragment combines with a class II MHC molecule
   • Antigen-MHC combination moves to cell surface and is attached to cell membrane
   • Helper T cells recognize the antigen-MHC combination
     • T cell receptor, similar to antibody antigen-binding site, matches the antigen-MHC combination
     • CD4 protein on the surface of the helper T cell binds to the constant part of the MHC molecule, strengthens recognition of the antigen and activates the helper T cell
     • Helper T cells stimulate themselves, nearby killer T cells, and B cells that have recognized the same antigen
     • Costimulating signals are required to activate T cells and B cells: CD7, CD40, interleukins

7. Agammaglobulinemia
   • Genetic deficiency in which antibodies are not made
   • A defective kinase results in no production of light chains
   • Treatment now with injections of antibodies, possibly later with gene therapy

III. Improving HIV therapy

1. HIV infection
   • HIV enters the body through contaminated body fluids
   • HIV particle binds to CD4 protein and a coreceptor on surface of helper T cell
   • Viral particle fuses with membrane of helper T cell and releases its contents into the cell
   • DNA is made from the RNA in the virus
     • A viral enzyme, reverse transcriptase, uses the information in RNA to make a matching DNA molecule: HIV is a retrovirus
     • Another viral enzyme, integrase, splices the viral DNA into the DNA of the host cell
   • Activated T helper cells now make viral particles instead of their own proteins
   • Normal immune response
     • Antibodies bind to HIV particles
     • B cells and T cells are activated
     • Virus slips inside helper T cells and makes more viral particles: fever, aches, etc.
     • Killer T cells eliminate many infected helper T cells, antibodies remove viral particles from the blood, but some infected T cells escape detection
   • AIDS
     • Population of helper T cells declines
     • HIV particles infect more and more helper T cells, cripling immune response to other pathogens
     • Pathogens that are normally kept under control cause opportunistic infections, e.g., Pneumocystis carinii pneumonia, and kill the person

2. Viral growth
   • HIV activity
     • HIV replicates prolifically from the time it enters the body
     • Strong response of killer T cells (CD8) supresses viral replication by eliminating infected helper T cells
     • Strong immune response when first infected preserves body's ability to produce helper T cells (CD4) that specifically react to HIV
     • Viral load in blood is directly related to progress of disease
     • HIV proviral particles can survive in a latent state in resting helper T cells for years without detection by the immune system
   • Blocking viral replication
     • Inhibit reverse transcriptase: nucleoside analog substitutes for A,T,C, or G and prevents completion of the DNA strand, e.g., AZT
     • Inhibit protease: stops production of viral protein
     • Drugs have side effects: interfering with viral replication also interferes with some normal body functions
   • Continued viral replication may lead to viral strains resistant to drugs
     • Mutations are produced in new viral particles
     • Some mutations change viral enzymes so drugs don't block them well, i.e., mutant viral enzymes become resistant to those drugs
     • Mutant viral particles leave more offspring than original viral particles do: natural selection

3. Other possible therapies
   • Block integrase enzyme from inserting HIV DNA into cell's chromosomes
   • Eliminate zinc from an enzyme needed to put RNA into new viral particles
   • Inactivate genes that produce proteins needed to make viral proteins
   • Prevent binding of HIV particle to coreceptor on helper T cells
   • Culturing a patient's T cells, protecting them against HIV, and reinjecting them into the patient
   • Develop viral bullets against infected T cells

When you have completed this lesson, go on to Review Questions