Immune System - Action Overview

Lecture 15A [Notes]

All cells, except sperm or eggs, contain the same complement of genetic 
information. Recall that sperm or eggs contain only one-half the genetic 
complement. Some of that genetic information codes for glycoprotein receptors 
embedded in and projecting from the surface of the cell membrane surface. 	

Some of these receptors serve as identification codes for tissue or cell 
type. Some serve as general identification codes to indicate that the cells 
belong to the host (the concept of "self").

Whether or not certain receptors show up on the surface of the membrane 
(are expressed) and when they are expressed, depends on the presence of and 
interaction with various molecules such as enzymes or hormones. Thus the 
cell must receive a variety of chemical messages in order for some of the 
receptors to be expressed or be suppressed. 

The immune system functions through a series of interactions between various 
cell types and various chemicals. Sequentially, the first step in the 
development of an immune response involves RECOGNITION. Various immune 
system cells must recognize the presence of free or bound antigens. This 
recognition involves the binding of antigen to membrane surface receptors 
on the immune system cells. The second phase involves COMMUNICATION. Immune 
system cells that have bound antigens send chemical messages to the other 
immune system cells. These chemical messages bring about the last phase 
which is ACTION. The chemical messages may cause the other cells to 
(1) differentiate and divide (2) cause them to release additional chemicals 
that may destroy the antigen bearing substrate, or (3) release antibodies 
that bind to free antigen and make it easier to recognize and phagocytize. 

     I. Recognition (by membrane surface receptors)
        A. Macrophages (modified monocytes that bear multiple
           receptors for a variety of antigens). Macrophages 
	   ingest (phagocytize) - digest - release and transport
           digested antigens (endocytosis) to their cell membrane
           receptor sites where they are displayed (presentation). 
           At this point the macrophages have become activated and 
           are sometimes called "antigen presenting cells - APC".
        B. B lymphocyte cells (lymphocytes that during their
           embryonic development have been exposed to and
           influenced by secretions from lymphatic tissue regions
           such as the Peyers Patches. These regions are sometimes 
           identified as GALT or MALT regions. These B-cells will give
           rise to the cells that produce and release antibodies
           [Ab]). B-cells contain receptors for only one type of
           Ag. This commitment to producing only one type of
           antigen recognizing receptor, and thus only one type
           of Ab, occurs during their differentiation in the bone
           marrow. This means that the genetic information to
           make other types of protein receptors has been
           suppressed early in their development.

        C. T lymphocyte cells (lymphocytes that during their
           embryonic development have been exposed to and
           influenced by hormones of the thymus gland called 
           thymosins. These cells also contain receptors for 
           only one type of Ag. T-cells respond only to antigen 
           bound to the membrane of body cells, not free or unbound 

    II. Communication (involves the binding or docking of
        receptors between immune system cells and the subsequent
        release of chemicals known as lymphokines or cytokines).
        A. Macrophages (activated) release Interleukin-1 (IL-1).
           (Interleukins are a type of lymphokine) This chemical
           causes one type of T-cell called the helper T cell
           (TH, T-4, CD-4) to do two things. The helper T cell
           produces (expresses) receptors for a second
           Interleukin (IL-2) and produces and releases IL-2. 
        B. B lymphocyte cells follow two possible courses. The
           majority of B-cells are stimulated by IL-2 to divide
           and differentiate into Ab producing cells called
           Plasma cells. Some of the B-cells divide into a group
           of cells called Memory cells that are available as a
           reserve source of cells and converted to Plasma cells
           the next time the same type of Ag enters the body. 
           Usually the Helper T-cells bind to the B-cells to help
           the B-cells make the conversion (activate them) into
           plasma cells.
        C. T lymphocyte cells (TH) bind with macrophages 
           and B-cells. Interleukin 2 released by these cells binds
           with the IL-2 receptors now expressed on their surface
           and causes them to divide into a clone of active cells
           and a clone of memory cells. The IL-2 also causes the
           other types of T-cells to divide and differentiate
           into active and memory cells. Remember that IL-2 also
           caused the B-cells to divide and differentiate. Thus
           you can see the significance of helper T-cells to
           proper functioning of the immune system and why HIV
           can lead to AIDS.

   III. Action 
        Most of the action involves the differentiation and
        division of B- and T-cells into active and memory cells.
Plasma cells produce copious quantities of a single type of Ab. The price they pay for this action is a lifespan of only a few days, loss of membrane receptors, and inability to divide. Virtually all of their activity is the production of secretory immunoglobulins (Ab). Antibodies produced by the plasma cells bind with free Ag and make them (the Ag) easier to recognize and phagocytize by macrophages. The cooperative action between T- and B-cells is called T-dependent Ag and, because of the production of memory cells, leads to long term immunity. Some B-cells are not bound by TH cells but are able to bind various types of antigens such as long chain molecules, capsules and flagella. This type of action is called T-independent Ag and leads to a weaker reaction and usually no long term immunity. This may be one reason why there is no long term immunity to Neisseria gonorrhoeae since receptors on B-cells bind to the capsule. Most immature B-cells express receptors for and produce antibodies that belong to the IgM and IgD classes of immunoglobulins. IgM provides Ab action against first time antigen invasion. Long term immunity requires a switch from the IgM to the IgG class of antibodies. Conversion to IgG, IgE, and IgA classes of Ab is the result of a chemically induced genetic rearrangement. Genetic information for production of the various Ig groups is arranged on three chromosomes 2, 14, and 22. The genetic information for the constant region of each Ab molecule is arranged sequentially as M, D, G, E, and A. The switch from IgM to IgG requires that the M and D regions of chromosome 14 are looped out, excised, and lost. This action is sometimes called Ab Class Switching.
Lecture 15B [Notes]

Miscellaneous Notes on Immunology
DEFINITION Immunology is the study of the physiological mechanisms which allow the body to recognize substances as foreign or abnormal and to neutralize or eliminate those substances. GENERAL PRINCIPLES A. Recognition of Self vs. Non-Self 1. MHC (Major Histocompatibility Complex) - a section of chromosome 6 containing a group of genes that code for and produce glycoprotein molecules marking a cell as Self; histocompatibility testing, or tissue typing involves identifying specific markers on body tissues (on cell membrane surface); because the typing is usually performed on WBC's, or Leukocytes, the markers are referred to as Human Leukocyte Antigens (HLA); each cell has a double set of six major antigens designated as HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DP, HLA-DQ. In addition, the HLA markers are essential for immune function. they not only determine which antigens (foreign or self) an individual responds to, they also determine how strongly the immune system will respond. They also allow the immune system cells to recognize and communicate with each other. a. HLA antigens are found in urine and sweat and may serve as human pheromones b. HLA Class I ABC Group (HLA-A, HLA-B, HLA-C) are found on all cells except red blood cells (erythrocytes) c. HLA Class I D Group (HLA-DR, HLA-DP, HLA-DQ) are found only on cells of the immune system d. HLA-DR is related to autoimmune diseases such as juvenile onset diabetes 1. Juvenile Onset Diabetes - about 90% of those having the disease are white, blond haired and blue-eyed 2. HLA-DR3 have a 5x higher risk for JOD 3. HLA-DR4 have a 7x higher risk 4. HLA-DR3,4 have a 20x higher risk 5 Latest research suggests that the trigger may be a virus or bovine albumin protein B. Specificity The ability to recognize millions of distinctive non-self molecules and to produce substances to counteract each one (selectivity) C. Memory (Secondary Response) 1. Once having met a substance, it will rarely ever forget it, and it will prevent you from getting the disease twice 2. Testing for Memory a. Humoral - determine through Ab titer (concentration), should be good for 60-65 years b. CMI (Cell Mediated Immunity) - skin tests THE SPECIFIC IMMUNE RESPONSE A. Functions of Interleukin-1 (IL-1) -[about 15 different types of IL] 1. Stimulates prostaglandin production in the anterior hypothalamus - increases temperature setpoint; works best between 101-103o (benefit of elevated temperature) Various drugs (ASA, NSAID's [non-steroidal], acetaminophen) are inhibitors of prostaglandin synthesis in the anterior hypothalamus - thus, anti-pyretics 2. Increases serotonin in the brainstem (sleepy) 3. Increases serotonin release in the GI tract (causes nausea - duodenum is organ of nausea) 4. Alters pain threshold (everything hurts) B. The Effector Cells of the Immune System B lymphocytes, T lymphocytes, NK (Natural Killer) Cells 1. B lymphocytes - bone marrow derived; when activated by an antigen or IL-2 released by the T4 lymphocytes, the B lymphocyte changes into a plasma cell that produces Ab specific for that antigen. There are five classes or types of Antibodies (Immunoglobulins) a. IgG - all purpose Ab; major one in serum; crosses the placenta; is Ab of memory; lasts 60-65 years in adult; last 15-18 months in newborn (maternal Ab) b. IgM - first Ab formed in response to a new Ag; causes agglutination reactions c. IgA (secretory) - found in secretions; saliva, breast milk, GI, prostate; 3x as much in serum d. IgD - not much known e. IgE - causes release of histamine from mast cells and is responsible for the allergic response; allergic rhinitis; hay fever (seasonal allergies); anaphylaxis - the systemic release of histamine in response to IgE. Common allergens causing anaphylaxis - bee stings, food (e.g. roach parts in chocolate), drugs, latex, husbands semen 2. T lymphocytes - thymus-derived; two major sets are responsible for cellular immunity; cellular immunity is the arm of the immune system that neutralizes or destroys viruses, fungi, parasites, protozoa, TB, cancer, and foreign tissues a. Helper T lymphocytes (T4 or CD4) - vital to orchestrating the specific immune response; T4s release IL-2 (Interleukin-2) which in turn activates B lymphocytes, killer T cells, phagocytic cells (PMNs and macrophages),stimulates the bone marrow and activates suppressor T cells (T8 or CD8) b. Clinical correlation - clinical use of IL-2 with LAK (Lymphokine Activated Killer) cells; IL-2 and TILs (Tumor Infiltrating Lymphocytes); Cyclosporine and FK 506 are immunosuppressant drugs - work by inhibiting IL-2 Normal number of T4 cells in the adult - 800-1200; HIV infects and kills the T4 cells, count falls as disease progresses c. Suppressor T cells (T8 or CD8) - turn off immune system d. NK cells - natural killer cells fight viruses and cancer cells; represent about 4% of T cells and last 10-60 years; no prior sensitization required; cancer immune surveillance cells
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