These lecture notes will provide an outline of information from the lectures. They are not complete. They should be used to help follow the lecture and as a guideline for information I think is important. You will need to fill in the gaps.

These notes were updated March 11, 2001, and are ready for printing by Spring 2001 Med Micro. students.

Chapter 18

I.    Resistance to Disease A.    Nonspecific 1.    Defenses that protect against any pathogen, regardless of species a)    First line of defense is skin and mucous membranes
b)    Second line of defense is phagocytes, inflammation, fever, and antimicrobial substances B.    Specific 1.    Third line of defense II.   Nonspecific Resistance A.    Some factors are not well-defined or identifiable 1.    Species immunity
2.    Behavioral immunities
3.    Racial immunities
4.    Population immunities B.    Identifiable factors are present in the body from birth 1.    These operate against all foreign substances and organisms
2.    These are defenses that protect against any pathogen, regardless of species a)    Mechanical and Chemical Barriers
b)    Phagocytosis
c)    Inflammation
d)    Fever
e)    Natural Killer Cells
f)    Complement III.    Mechanical Barriers Involved in the First Line of Defense A.    Skin 1.    Epidermis
2.    Dermis
3.    Mucous membranes a)    Line GI, respiratory, and GU tracts B.    Lacrimal apparatus
C.    Saliva
D.    Mucus
E.    Ciliary escalator
F.    Epiglottis
G.    Urine
H.    Vaginal secretions IV.   Chemical Barriers Involved in the First Line of Defense A.    Sebum
B.    Perspiration
C.    Lysozyme
D.    Gastric juice (stomach acid)
E.    Bile
F.    Transferrins
G.    Interferon
H.    Microbial antagonism becomes competitive exclusion 1.    Normal microbiota competition
2.    Normal microbiota antibiotic production
3.    Normal microbiota metabolic control of pH and oxygen availability V.    The Second Line of Defense Includes Several Factors A.    Phagocytosis
B.    Inflammation
C.    Fever
D.    Antimicrobial Substances (Complement and Interferon) VI.    Phagocytosis, a Second Line of Defense A.    Review of Blood and the Human Circulatory System (page 559) 1.    Plasma/serum
2.    Cellular a)    Erythrocytes or red blood cells
b)    Leukocytes or white blood cells (1)   Granulocytes (a)    Neutrophils (i)    Also known as a polymorphonuclear leukocyte or segmented white blood cell ("seg")
(ii)    Highly phagocytic during early infection stage
(iii)    Highly motile (b)    Basophils (i)    Important in inflammatory and allergic responses
(ii)    Release histamine
(iii)    In tissues (outside of blood), are called "mast cells" (c)   Eosinophils (i)    Some phagocytosis
(ii)    Increased in parasitic infections and allergic reactions (2)    Agranulocytes (a)    Monocytes (i)    Not actively phagocytic in blood stream
(ii)    Once out of blood, called a macrophage (a)    Macrophages are very phagocytic
(b)    Histiocytes are fixed macrophages (b)    Lymphocytes (i)    Not phagocytic
(ii)    Important in specific immunity c)    Platelets (1)    AKA thrombocytes
(2)    Blood-clotting mechanisms 3.    CBC a)    Hemogram
b)    Differential B.    The phagocytes include the PMNs, the circulating monocytes, and the tissue monocytes 1.    The tissue monocytes are AKA as the reticuloendothelial system (RES) a)    Some are stationary ("fixed") and some wander around
b)    Those that are fixed earn special names, but their duties are still phagocytic (1)    For example, Kupffer cells of the liver
(2)    For example, alveolar macrophages of the alveoli
(3)    For example, microglial cells of the nervous system
(4)    For example, Langherhan cells of the skin 2.    PMNs arrive first, followed by monocytes a)    Microbe sticks to the neutrophil
b)    Phagocytosis begins with invagination of cell membrane
c)    Microbe is now contained within a phagosome
d)    Phagosome fuses with a lysosome
e)    Microbe is digested and waste materials are discharged from cell
f)    Note that some microbes can resist phagocytosis (1)    One example is M. tuberculosis, which actually replicates inside the macrophage
(2)    Another example is Staphylococcus species that produce toxins that kill the phagocytes g)    Chemotaxis is the chemical attraction between the microbe and the phagocyte
h)    Antibodies, a SPECIFIC DEFENSE RESPONSE, may attach to the microbe and enhance phagocytosis (1)    This is called OPSONIZATION
(2)    Opsonins are the antibodies that do this VII.    Inflammation, a Second Line of Defense A.    Bodily response to cell damage 1.    Is nonspecific
2.    Thus ANY type of cell damage results in inflammation B.    Redness, pain, heat, swelling, loss of function 1.    Dilation of blood vessles increases flow of blood through the area, causing skin to turn red a)    More blood in the area also causes temperature to increase 2.    Dilation of vessels increases vascular permeability (blood vessels get leaky) a)    Leaky blood vessels lose fluid into the surrounding area, leading to swelling (edema) (1)    Swelling causes pain
(2)    Swelling may also lead to loss of function b)    Diapedesis also occurs, as neutrophils adhere to the vessel walls and then migrate into the surrounding tissues 3.    Pus is the accumulation of plasma, dead tissue cells, WBCs, and bacteria a)    Abscesses (AKA boils) result if the pus is enclosed in fibrin, forming a sac
b)    Carbuncles are the accumulation of several abscesses VIII.    Fever is a Second Line of Defense A.    Abnormally high body temperature produced in response to bacterial/viral infection
B.    Induced by bacterial endotoxins/interleukin-1 IX.    Natural Killer (NK) cells are a Second Line of Defense A.    Nonspecific
B.    Lymphocytes that form complexes with foreign cells 1.    Once it is determined that the cell IS foreign, the cell's cell membrane is damaged, and lysis of the cell leads to its death X.    Antimicrobial Substances (Complement and Interferon) are a Second Line of Defense A.    Complement 1.    May work nonspecifically or specifically
2.    Consists of 20 plasma proteins
3.    Defensive system that mediates a series of biologic reactions a)    Increases vascular permeability
b)    Chemotaxis
c)    Opsonization prior to phagocytosis
d)    Lysis of target organisms 4.    Must be activated to work a)    Classical pathway (1)    Is fast, efficient, and SPECIFIC
(2)    It is initiated by antigen-antibody complexes (a)    More about Ag-Ab complexes soon b)    Alternate pathway is slower to begin (1)    It is NONSPECIFIC and is initiated by nonimmunologic stimuli (a)    Examples are bacterial endotoxins (lipid A), complex polysaccharides (bacterial/fungal cell walls), and cobra venom
(b)    C3 is activated directly c)    Both pathways must activate the C3 component of the "cascade" in order for the end results to be achieved
d)    The Classical and Alternate pathways merge into one pathway at the C3 juncture B.    Interferon 1.    Group of antiviral proteins produced by specific animal cells AFTER viral stimulation
2.    Classed as CYTOKINES
3.    Interfere with viral multiplication
4.    Are host-cell-specific, but not virus-specific a)    That is, human cell interferon only protects human cells AND
b)    Interferons of a species work against many different viruses XI.    Specific Resistance to Disease A.    Antigens (AKA Immunogens) 1.    Are proteins (usually) or large polysaccharides that are capable of mobilizing the immune system to respond immunologically a)    May be lipids or nucleic acids IF combined with proteins or large polysaccharides
b)    Will often be a component of an invading microbe (capsule, cell wall, flagella, fibriae, or a toxin)
c)    Can also be nonmicrobial (pollen, egg white, blood cell surface molecules, serum proteins from other individuals/species, etc.) 2.    Antigens are immunogenic a)    It is the EPITOPE that actually stimulates the immune system (1)    The epitope is also called the antigenic determinant
(2)    One antigen may have many epitopes
(3)    Epitopes are very unique
(4)    The epitope (or antigenic determinant) is what is recognized by the antibody b)    Small compounds, called HAPTENS, are not capable of stimulating the immune system (1)    HOWEVER, if they are attached to carrier molecules, an immune response occurs as a result of this combination
(2)    Once an immune response has occurred, subsequent exposures only require the hapten's presence to react with the antibody 3.    Antigens are reactive a)    This means that antigens are able to combine with the products of the immune system cells or even with the cells themselves 4.    There are three main types of antigens a)    Autoantigens
b)    Alloantigens
c)    Heterophile antigens 5.    Antigens may also be classified as T-dependent, T-independent, and superantigens B.    Origin of the Immune System 1.    Composition of Lymphatic System (page 562) a)    Lymph (not to be confused with the lymphocyte) (1)    Is a fluid that results from blood plasma that has moved from the blood capillaries into the spaces between the tissue cells and is subsequently filtered (a)    This fluid is the "lymph"
(b)    It is also known as interstitial fluid b)    Lymph vessels (1)    Lymph capillaries around tissue cells absorb the interstitial fluid (or lymph)
(2)    Lymph capillaries become larger lymph vessels called lymphatics
(3)    Lymphatics, like veins, contain valves that keep fluid moving toward heart c)    Lymph nodes (1)    Lymph move from lymphatics through lymph nodes (a)    Fixed macrophages and T and B lymphocyte cells are here (2)    All lymph is dumped back into blood at juncture of vena cava and thoracic duct d)    Lymphoid organs (1)    Tonsils
(2)    Appendix
(3)    Spleen
(4)    Thymus 2.    Lymphocyte is the cornerstone a)    Lymphocytes originate from stem cells in the fetal yolk sac and bone marrow (1)    Stem cells either become erythromyelopoietic or lymphopoietic cells
(2)    Lymphopoietic cells either move through the thymus, where they become immunocompetent, OR
(3)    Lymphopoietic cells move through other lymphatic organs (such as the bone marrow), where they become immunocompetent b)    During the above maturation processes, SURFACE RECEPTOR PROTEINS are inserted throughout the lymphocytes' cell membranes (1)    These proteins are what make the lymphocyte immunocompetent and enable it to recognize epitopes on antigens
(2)    Once an epitope is recognized and the lymphocyte is bound to it, the lymphocyte is said to be COMMITTED c)    The recognition between epitopes and lymphocytes is dependent upon the MAJOR HISTOCOMPATIBILITY COMPLEX PROTEINS (MHC) (1)    MHC proteins are embedded in the membranes of almost every cell of the body
(2)    The MHC proteins are very unique to their individual
(3)    MHC proteins are either Class I (found on almost all cells) or Class II (found only on B-lymphocytes and macrophages)
(4)    It is the Class II MHC proteins that are important in the immune response d)    There are two types of lymphocytes, B-lymphocytes and T-lymphocytes (1)    B-lymphocytes are mostly responsible for antibody-mediated immunity, AKA HUMORAL IMMUNITY
(2)    T-lymphocytes are mostly responsible for cell-mediated immunity, AKA CELLULAR IMMUNITY 3.    A brief overview of the actual immune response a)    Antigen enters into the body and pentrates the lymphatic or cardiovascular system
b)    Here, macrophages phagocytize the antigen
c)    Antigen is broken down, releasing its epitopes
d)    The macrophages display the epitopes on the surface of their cell membrane, while transporting the epitopes to the lymphoid organs
e)    At the lymphoid organs, T and B lymphocytes are waiting
f)    Either an antibody-mediated immune response (AKA humoral immunity) or a cell-mediated immune response will be implemented at this point C.    Cellular Immunity 1.    Cell-mediated T lymphocytes ("killer" cells) a)    These cells regulate the activation and proliferation of other immune system cells, such as macrophages, B cells, and other T cells 2.    Most effective against fungi, protozoa, and helminths, and viruses and bacteria INSIDE of cells a)    Examples include the rickettsiae and M. tuberculosis 3.    Primary, major responder to transplanted tissue
4.    Important factor in fight against cancer
5.    Two kinds of T cells (encompassing four types) a)    Effector T-lymphocytes cause cell-mediated immune responses to happen (1)    Include cytotoxic (T_C) (Some of these are CD8 cells) and delayed hypersensitivity T-lymphocytes (T_D) b)    Regulator T-lymphocytes oversee the immune response (1)    Include Helper (T_H) (CD4 cells are mainly this type) and suppressor T-lymphocytes (T_S) (Some of these are also CD8 cells) 6.    Summary of the Cell-Mediated Immune Response a)    Infected tissue
b)    Macrophages engulf the microbe
c)    Microbe is digested and epitope(s) is(are) released
d)    Epitopes are displayed on the macrophage's surface, nestled within the Class II MHC proteins
e)    The macrophage is now an ANTIGEN-PRESENTING CELL (APC)
f)    The APC travels to an organ of the lymphoid system (1)    Once there, a hunt begins g)    The macrophage mingles among the many groups of inactive effector T-lymphocytes, searching for the cluster having the surface receptor proteins that correspond to its epitope (1)    There will only be one such cluster h)    Once this cluster is found, another recognition must occur between the Class II MHC proteins on the APC and the Class II MHC receptors on the T-lymphocyte
i)    Once THIS recognition occurs, the inactive T-lymphocyte becomes an activated cytotoxic T-lymphocyte
j)    The macrophages also locate regulator T-lymphocytes called helper T-lymphocytes (1)    These lymphocytes have a special surface receptor protein called the CD4 receptor k)    The CD4 receptor enhances the binding of the helper cell to the macrophage (1)    CD4 receptor sites are also where HIV binds l)    Once the helper T cell is bound to the macrophage, it is activated to form a clone of helper T-lymphocytes (1)    This clone secretes lymphokines (one example of a cytokine), such as interleukin-2 m)    Lymphokines cause helper cells to be even more active and also cause the cytotoxic T-lympphocytes to become killer cells
n)    Under the influence of the lymphokines, the cytotoxic T-lymphocytes enlarge and divide, forming a clone of cytotoxic T-lymphocytes that are able to kill the infected cells
o)    These cytotoxic T-lymphocytes leave the lymphoid tissue through the lymphatics and blood vessels
p)    They circulate until they find their target cells (infected cells displaying epitopes on their surface)
q)    Cytotoxic T-lymphocytes join their receptor proteins to the epitopes (1)    This requires a surface receptor protein called CD8 to bind to CLASS I MHC protein on the infected cell surface
(2)    Once this happens, the cytotoxic T-lymphocyte releases various substances, including PERFORIN r)    Perforin punches holes in the target cell's membrane, bringing about lysis and cell death
s)    Once the infected cells are dead, a special clone of T-lymphocytes forms
t)    This clone is composed of the memory T-lymphocytes (1)    These will provide resistance any time the antigen reenters the body instantaneously D.    Humoral Immunity 1.    Antibody-mediated a)    Antibodies are produced (secreted) by the B lymphocytes 2.    Defends primarily against bacteria, bacterial toxins, and viruses outside of cells
3.    Is a factor in some reactions against transplanted tissue
4.    Stimulus: presence of free/EXTRAcellular antigen
5.    It binds to the antigen receptor on the B lymphocyte a)    This binding occurs as a result of a macrophage displaying the epitope making its way to the appropriate B-lymphocyte 6.    Once the epitope has bound with its corresponding surface receptor protein on the B-lymphocyte, the B-lymphocyte takes the complex into its cytoplasm and displays the epitope on ITS surface
7.    In the meantime, helper T-lymphocytes have been involved and are activated, forming a clone of helper T-lymphocytes specific to this epitope
8.    Lymphokines such as interleukin 2 are produced by the helper cells, causing them to bind to the B-lymphocytes
9.    This is an immunologic copperative effort among the macrophage, the B-lymphocyte, and the helper T-lymphocyte that is encouraged by interleukin-2
10.    Once the above happens, the antibody-mediated immune response has been initiated, and B-lymphocytes bearing receptors specific to the epitopes are selected (activated) a)    Note that B lymphocytes can be activated either by a T-dependent Ag or a T-independent Ag (1)    The difference is that some antigens do not require the intervention of helper T-lymphocytes and are able to bind directly onto the B-lymphocyte surface
(2)    However, this will result in a weaker immune response and does not cause memory cells to be produced b)    There is also a special group of antigens, the SUPERANTIGENS, that are able to bind directly to the MHC proteins without internal process (1)    This superantigen is then displayed on the macrophage's surface and causes a massive immune response that results in an abnormally high secretion of lymphokines that is quite destructive to the host 11.    Once activated by helper T-lymphocytes and lymphokines, the B-lymphocytes multiply, dividing AND differentiating into a clone of many effector cells (Ag-stimulated cells) called PLASMA cells a)    This is called CLONAL SELECTION
b)    Because the ANTIGEN selects the lymphocyte that will multiply to form a clone of cells with the same immunological specificity 12.    These plasma cells produce antibodies (AKA as immunoglobulins) that are directed against the specific antigen that activated the original B lymphocyte and that ALSO activate cell-mediated immunity a)    The antibodies saturate the blood, lymph, saliva, sweat, and all other body secretions
b)    They bind to the antigens and mark them for destruction 13.    These plasma cells will live for just a few days
14.    The activated B lymphocyte also causes the production of MEMORY CELLS a)    Memory cells, if ever again stimulated by that same type of antigen, are capable of rapidly differentiating into plasma cells XII.    Immunoglobulins A.    Five Classes 1.    IgG
2.    IgM
3.    IgA
4.    IgD
5.    IgE B.    Four protein chains 1.    Shaped like a "Y"
2.    2 identical light chains
3.    2 identical heavy chains
4.    Stem of the "Y" is the "constant" region
5.    2 sections at ends of "Y's" arms are the "variable" region C.    IgG 1.    Most abundant of all immunoglobulins (80%)
2.    Monomer
3.    Crosses the placenta
4.    Activates complement
5.    Acts as an opsonin (increases phagocytic action)
6.    Protects against circulating microbes
7.    Only Ab that protects against toxins
8.    In a primary response to an immune stimulus, is not produced until later (after IgM)
9.    But in the secondary (anamnestic) response, is immediately released in great quantities D.    IgM 1.    Pentamer
2.    J chain holds five Abs together: 10 binding sites
3.    Never leaves the circulation, unlike IgG a)    Thus, cannot cross the placenta 4.    In a primary response to an immune stimulus, is the first Ab to be produced a)    This makes it diagnostically important in distinguishing a recent v.s. a past infection 5.    Activates complement the best of all the Abs
6.    Good opsonin
7.    Short half-life, as opposed to IgG E.    IgA 1.    Dimer (valence of 4)
2.    Called the secretory Ab
3.    Found in mucus, saliva, tears, breast milk a)    When taking the above into consideration, is the most abundant Ab in the body (but, since we are only able to measure blood levels, IgG has the greatest levels) 4.    In serum, circulates as a monomer
5.    J chain joins the 2 monomers to form "secretory IgA"
6.    When the dimer enters and passes through a mucosal cell, it acquires the secretory component that protects it from enzymatic breakdown
7.    Main function is to prevent pathogens from attaching to mucosal surfaces F.    IgD 1.    Monomer
2.    Looks like IgG
3.    Almost always cell-associated on B lymphocytes' surfaces
4.    Not free in serum like IgG
5.    Thought to be involved in the maturation of B lymphocytes G.    IgE 1.    Monomer
2.    Responsible for allergies
3.    Not found free in blood a)    Found attached to the mast cells and basophils
b)    Attaches by Fc, stem region
c)    When it interacts with antigen, it causes mast cell to release histamine (inflammatory mediator) 4.    Found in high numbers in upper respiratory tract and skin
5.    Attracts IgG and phagocytic cells
6.    Very effective against parasitic worms H.    Primary and Secondary Antibody Responses 1.    After an initial antigenic stimulus, a primary antibody response occurs
2.    IgM is the first antibody to appear in the circulation
3.    IgM is the principal component of the primary antibody response
4.    Much later, IgG will supplement IgM
5.    In a secondary antibody response, IgG is rapidly produced in extremely high concentrations
6.    Thus, IgG antibody is the principal componenet of the secondary antibody response XIII.    Antigen-Antibody Interactions A.    There are six mechanisms 1.    Viral Inhibition a)    Antibodies react with molecules at the surface of the virus, preventing the virus from attaching to the cells 2.    Neutralization a)    Antibodies called antitoxins combine with the toxin, thereby neutralizing it
b)    Only IgG can do this 3.    Agglutination a)    Antibodies called agglutinins combine with antigens on the cell surface, causing the cells to become clumped 4.    Precipitation a)    Antibodies called precipitins combine with dissolved antigens to form latticelike arrangements that precipitate out of solution 5.    Phagocytosis a)    Antibodies called opsonins enhance phagocytosis by forming a bridge between the parasite and the receptor site on the phagocyte 6.    Complement activation a)    The classical pathway for complement activation is activated by the interaction of an antigen and antibody

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