I. Non-specific responses - general mechanisms for discouraging pathogens which do not require the identity of the pathogen's antigenic nature. These are the first line of defense against invasion by pathogens.
[See Immune Responses diagram]
A. Surface membrane barriers
1. Skin
a. acidic pH
b. keratinization protects unbroken skin against acids and bases of bacterial enzymes and toxins.
2. Mucous membranes
a. HCl in the stomach kills many pathogens, denatures proteins
b. saliva contains lysozyme, a bactericide
c. lacrimal fluid contains lysozyme
d. mucus traps organisms
B. Cellular and chemical defenses
1. Phagocytes - engulf particulates, including microorganisms, which pass through the external barriers.
Examples: histiocytes in the lungs, Langerhans cells in the skin, Kupffer cells in the liver, microglia in the nervous system, macrophages in other tissues.
2. Natural killer cells - these large lymphocytes lyse and kill tumor and virus-infected cells before activation of a specific immune response.
3. Inflammation (See Figure 22.2)
a. reduces spread of damaging agents to nearby tissues
b. increases disposal of cell debris and pathogens
c. facilitates repair processes
d. caused by histamine and prostaglandins released by basophils and other cells.
4. Anti-microbial proteins
a. non-specific complement activation
b. interferons - block tumor and viral reproduction (See Figure 22.5)
c. interleukin I - stimulates the immune response
5. Fever
a. due to pyrogens secreted by leucocytes
b. increased body temperature disrupts metabolism of pathogens
6. Cellular processes
a. amoeboid movement - "crawling" movement along vascular surface
b. diapedesis - movement through vascular wall
c. chemotaxis - chemical attraction to infection site
II. Specific Responses - These second line of defense responses are activated by, and directed against, a specific antigen.
Antigen - a protein or other substance which elicits immune system activation in a "foreign" host.
A. Humoral Immunity - the B-cell response
1. Antigen challenge - "non-self" antigen binds to antigen-specific surface receptors on generic B-cell. (For receptor/antibody structure see Figure 22.12)
2. Clonal selection - multiplication of B-cells produces cells which all contain the same antigen-specific surface receptor. (For clonal selection and responses see Figure 22.9)
a. primary response - plasma cells secrete free antibodies of the same structure as the antigen-specific surface receptor. The primary response takes 7 to 10 days to reach maximum antibody levels.
b. secondary response - memory cells which retain the ability to quickly clone to produce more plasma cells should the antigen be encountered again. The secondary response takes from 1 to 2 days to reach maximum antibody levels.
It should be noted that few pathogens are capable of stimulating the humoral response by themselves. For most the co-stimulation of helper T-cells and interleukins is necessary. (See below)
3. Antibodies form antigen-antibody complexes which have the following affects: (See Figure 22.14)
a. opsonization - labeling of antigens or foreign cells (This term should be added to Fig. 22.14)
b. neutralization - inactivation of bacterial toxins
c. agglutination - clumping of cell-bound antigens
d. precipitation - removes soluble antigen from solution
e. complement fixation (See Figure 22.4) - includes a. through d. above, plus inflammation and the membrane attack complex which causes cell lysis. Complement protein binds to a site on the constant (Fc) portion of the antibody.
4. Classes of antibodies: (See Figure 22.19)
IgD - (monomer) antigen receptor on B-cell
IgM - (pentamer) first antibody released by plasma cells during primary response
IgG - (monomer) comprises most circulating antibodies, both 1o and 2o responses
IgA - (dimer) antibody found in secretions
IgE - (monomer) secreted in mucosae, mediates inflammation in allergic reaction.
(See Figure 22.19 and Type I Hypersensitivity below)
B. Cell Mediated Immunity - the T-cell response - requires an intermediary cell to be stimulated. These intermediary cells can be infected body cells or macrophages as below. Identification of these cells and their antigens is by means of MHC proteins. MHC (Major Histocompatibility Complex) antigens are recognition proteins which identify a cell as being "self". They are displayed together with part of the antigen from invading viruses to be recognized by T-cell lymphocytes. There are two classes of MHC antigens: Class I is present on all body cells; Class II is present only on cells of the immune system.
There are several types of T cells.
1. generic cytotoxic T-cells (See Figure 22.15)
a. respond to antigens complexed by MHC I proteins from infected body cells.
b. attack and kill virus or bacteria-infected cells and tumor cells
c. maintain immunologic surveillance
d. clone to produce mature cytotoxic cells and cytotoxic memory cells
2. Helper T-cells (See Figure 22.16)
a. respond to antigens complexed with MHC II proteins on antigen presenting cells
b. act as costimulator cells for B-cells and other T-cells and . Activated Helper cells release interleukin II and act as a costimulator for an effective B-cell response.
c. release interleukin I which acts as a costimulator for T-cell production.
3. Suppressor T-cells - regulatory cells which tend to shut down B and T-cell responses.
4. Cytokines - chemical mediators involved in cellular immunity.
a. interleukin I - costimulator for activated T-cells
b. interleukin II - stimulates both B and T-cell proliferation
c. MAF - macrophage activating factor
d. MIF - macrophage migration inhibiting factor
e. perforin - causes cell lysis
f. lymphotoxin - kills cells by fragmenting their DNA
g. tumor necrosis factor - specialized destruction of tumors.
C. Immunocompetence: (See Figure 22.7) (often called immune tolerance because it is the tolerance of your own cells) is the ability of your immune system to recognize self vs. non-self (anti-self, foreign) antigens. This ability is conferred during childhood. For T cells the site for this is the thymus gland which ceases this activity after puberty. The site for the B cells is unknown. The name B cell comes from the Bursa of Fabricus, a gut-associated site which is the site of immunocompetence in chickens. Humans don't have a Bursa, so a "Bursa Equivalent" confers immunocompetence, possibly the marrow, but recent evidence suggests an area analogous to the bursa in the distal GI tract. During childhood, immature or pre-lymphocytes originate in the marrow, travel to the thymus (or other area) for immuno-competence, then travel to the lymph nodes where they proliferate in response to antigenic stimulation.
D. Hypersensitivity
1. Type I Hypersensitivity - this is the basis for allergic reactions. Usually this occurs when you have been exposed to non-pathogenic foreign antigen and built up memory cells. Subsequent exposure causes these cells to become plasma cells which release large amounts of IgE antibodies. IgE antibodies bind to basophils and mast cells causing them to release granules containing histamine and other inflammatory chemicals. This is the basis for the vascular changes seen in allergy and anaphylaxis.
2. Type II Hypersensitivity - this is a type of autoimmunity. Autoimmune disorders can result when host antigens are similar to invading antigens and cross reactions occur, or from mutations of antigens, or by antigens which are masked or not present during the period of immunocompetence, or which are altered by environmental or disease factors and cease to be recognized as "self", or by lack of immune tolerance (another term for immunocompetence). Among diseases which have been classified as autoimmune are: multiple sclerosis, myasthenia gravis, Graves disease, andsome forms of Type 1 diabetes mellitus.
3. Type III Hypersensitivity occurs when the antigen-antibody complexes produced by normal immune system reactions are not removed and lodge in the basement membrane of endothelial cells and in other connective tissues. Their presence induces massive inflammation by triggering the complement pathway with resulting cell lysis, hemorrhage, and tissue destruction. Examples include: systemic lupus erythematosus (SLE), rheumatoid arthritis and acute glomerulonephritis.
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