Immunity:
Immunity - Specific (adaptive) Defense against infection by lymphocytes in response to antigens.
Targets specific pathogens after exposure. The immune response is altered based on the identity of the pathogen. The immune system is reactive, not proactive. That is, it reacts after exposure, not before. The immune system only comes into play after the first two lines of defense fail.
The immune system is able to tell the difference between self and nonself (foreign) cells so that, when it is functioning properly, it does not attack the body’s own cells.
Two Types of Immune Response – Brief Overview
Humoral Immunity (Antibody Mediated Immunity) – derived from the word humor referring to bodily fluids. Describes an immune response that takes place in bodily fluids effected by antibodies which recognize and bind to foreign molecules known as antigens.
Antibodies are proteins produced by a special kind of cell called a B Lymphocyte
(B cell) in lymphoid tissue. They are secreted into the circulatory system and are found in the Gamma globulin fraction of blood serum.
When a particular B cell is activated, the cell differentiates and divides, and produces a specific antibody when will then react with a specific antigen.
Cellular Immunity (Cell Mediated Immunity) – mediated by T Lymphocytes (T cells) which do not directly bind to antigens (unlike antibodies).
When T cells are activated, they divide and differentiate to produce various cell types, some of which directly destroy target cells and some of which secrete chemical messengers called cytokines that trigger other cells to perform some function.
ANTIGENS
Antigen – any substance that provokes the production of antibodies. (Antigen = antibody generator). Foreign molecules typically composed of proteins or large polysaccharides.
TYPES OF ANTIGENS:
A. Blood Antigens - glycoproteins on the surface of erythrocytes (RBCs) associated with the blood groups (A, B, AB, O) and the Rh factor.
B. Allergens - noninfectious substances such as pollen, dust, fur, dander, food and drugs that the body may become hypersensitive to resulting in an allergic (hypersensitive) reaction. Food additives such as sulfites, nitrates and nitrites, MSG, caffeine, theophylline, coca and tartrazine yellow dye 5 can also provoke allergy symptoms which may be severe in some victims.
C. Microbial antigens - components of bacterial cells (capsule, flagella, cell wall), viruses, protozoans, rickettsias and other microorganisms.
D. Vaccines - killed, attentuated or biotechnically derived components of microorganisms that are used for immunization purposes.
E. Toxoids - detoxified toxins (bacterial exotoxins or animal venoms) used to stimulate antitoxin production.
F. MHC (HLA) antigens - glycoproteins on the surfaces of cells that serve as "self markers" which assists the immune system in distinguish self vs. nonself. These MHC Class I and Class II proteins are a third set of antigen binding molecules and play an integral role in the immune response. Class II MHC proteins are found only on the surfaces of B lymphocytes, Macrophages and other APCs. MHC proteins serve as a platform on which the foreign antigen is bound and presented to immune system cells. The TCR (T cell receptor) on T cells recognizes the MHC protein as well as the antigen in the immune response.
Detection of an antigen by the immune system leads to the production of the corresponding antibodies (immunoglobulins). Typically, antibodies react not with the entire antigen but with regions on the antigen known as epitopes or antigenic determinants. A single antigen may have multiple epitopes, with each epitope have its corresponding antibody produced by the immune system. Soluble antigens usually have few sites whereas cellular antigens have multiple sites and can provoke a stronger immune response.
Valence – the number of epitopes on an antigen
Antigens vary in the number of antigenic determinants (epitopes) on their surfaces that immune effectors can bind to. The number of epitopes on an antigen is known as its valance.
ANTIBODIES/IMMUNOGLOBULINS:
Antibody – a protein which recognizes and binds to a specific antigen.
Antibody structure consists of 4 polypeptide chains linked by disulfide bonds. Each antibody consists of 2 identical heavy and 2 identical light chains forming a flexible Y-shaped molecule.
a. Fab Region - (fragment antigen binding) - region that, in each antibody, is different
due to the hypervariability of amino acids in this region. This region binds to the
antigenic determinant (epitope) and is specific for only one epitope of a specific
antigen.
b. Fc Piece (fragment crystallized) – this region is the same for all Ab of the same class.
The Fc piece functions in binding to cell membranes, phagocytes and complement. It functions in immune adherence, opsonization and complement-mediated lysis.
CLASSES OF ANTIBODIES (IG'S):
1. IgG – accounts for about 80% of all antibodies in serum. They can readily cross the walls of blood vessels and enter tissue fluids and can cross the placenta. They protect against circulating (free) antigens, neutralize toxins, activate complement and make phagocytosis more effective.
2. IgA - found in serum and body fluids and is produced by lymphocytes in the gut, respiratory tract and glandular tissues. It is normally secreted in a dimer form (2 IgG's) with a secretory place which apparently protects it from enzymatic degradation. It is received by infants in colostrum (breast milk) and primarily protects mucosal surfaces from invasion.
3. IgD - found on the surface of B lymphocytes where they serve as the receptor site for the antigen they are destined to respond to.
4. IgE - usually found in small amounts. These antibodies respond to animal parasites. They are able to bind to mast cell surfaces and play an integral role in allergies or hypersensitivity.
5. IgM - comprise 5-10% of serum. This is the first Ig produced in an immune response and is the largest Ig consisting of 5 IgG's bound by a J chain. It has 10 antigen binding sites. B cells will eventually undergo class switching and produce IgG's rather than IgM's.
All antibodies consist of Constant Regions (in which the amino acid sequence is the same for all Ab of the same class) and Variable Regions (which are specific for the Ig and correspond to the epitope and the configuration of the Fab Region).
Antibodies have been traditionally classified according to their method of action. This classification includes: Antitoxins, Opsonins, Precipitins, Agglutinins and Complement-fixing antibodies.
HUMORAL (AMI) IMMUNITY
When appropriate “antigenic material” (bacterium, virus, etc.) enters the body, it will rapidly encounter a macrophage or other antigen presenting cell (APC) which phagocytize it and enzymatically destroy the invading organism. However, the antigenic determinants (epitopes) will be preserved and combined with the APC's MHC Class II protein and then moved to the surface of the cell. The macrophage or APC will then move to the nearest lymphoidal tissue (lymph nodes, etc.) and will present the MHC protein and processed antigen to any T helper (TH) cells residing there.
The APC will place its MHC protein and processed antigen into the receptor of the TH cell.
The TH cell has a two part receptor. The T Cell Receptor (TCR) much bind to the presented antigen, and the CD4 receptor must bind the APC’s MHC II. Both regions must bind in order for the response to be triggered.
The TH cell will be activated and will then divide and differentiate, producing large populations of two cell types. Mature TH cells will produce cytokines (signaling chemicals) that will activate the appropriate B cell. Memory TH cells will stay behind to trigger a later immune response should it be necessary.
The B cell, when activated by cytokines from the TH cell will then divide and differentiate, producing large populations of two cell types.
1. Memory B cells - these retain the memory of the antigen and will remain inactive unless
the antigen is encountered again. If the antigen is encountered again, these cells will
rapidly divide forming more memory B cells and plasma cells.
2. Plasma cells - rapidly produce and secrete their specific antibody for the antigen, at the
rate of 2,000 antibodies per second for 4 to 5 days.
Because the APC is presenting multiple epitopes, multiple TH and B cells may be activated, so there may be several different antibodies produced (polyclonal antibodies).
The first antibodies generated are usually IgMs. After a few days, however, the plasma cells undergo class switching and begin to produce IgGs instead.
Plasma cells in the lymph nodes take 1 to 6 days to develop and the detection of antibodies in blood serum in significant numbers takes 2-3 weeks. However, the number of antibodies may be sufficient to fight the infection even before they reach detectible levels. The number of plasma cells increases for several weeks and then declines.
NOTE: while most AMI responses require the assistance of TH cells, there are some antigens which are T-independent. That is, B cells can react directly to these antigens without going through the APC and TH cell. These tend to be antigens made of repeating subunits, especially polysaccharides. The bacterial capsule, for example, typically functions as a T-independent antigen.
Responses to T-independent antigens are typically weaker responses, involve only IgMs and do not generate memory cells.
Types of Immunity: All types of immunity are acquired during the life of the individual; although mechanisms are set up during embryonic development, the actual exposure to the antigen and subsequent presentation of the antigenic determinant to a B or T lymphocyte by a macrophage or antigen-presenting cell is necessary in order for the immune response to occur.
1. Naturally Acquired Active Immunity -permanent or long-lasting immunity resulting from
successful recovery from certain infectious diseases.
2. Naturally Acquired Passive Immunity -temporary or transient immunity of newborn due to
breast feeding (colostrum) and placental transfer of the mother's Ig's to the fetus.
3. Artificially Acquired Active Immunity -permanent or long-lasting immunity resulting
vaccination or immunization of the individual against a particular infectious disease.
4. Artificially Acquired Passive Immunity - temporary or transient immunity of persons who
have been given immune serum (gamma globulin) when they have been exposed to certain
diseases such as infectious hepatitis (HAV).
Upon exposure to an antigen, the first time, a number of reactions may be observed that are referred to as the Primary Response. These include:
1. Lag Period-no apparent rise in antibody titer (levels) in blood serum.
2. Rapid antibody synthesis- within one to six days.
3. Peak antibody level- may be detected in blood serum in two to three weeks.
4. Rapid drop in antibody titer which eventually levels off.
Upon later exposure to the same antigen, a number of reactions may be observed that are referred to as the Secondary Response: These include.
1. No lag period.
2. A very rapid rise in antibody titer.
3. A much higher peak in antibody titer.
4. A slow decline in antibody levels, but they level off at a much higher level than at the end of the
primary response.
The rapid response of the secondary response is referred to as an Anamnestic Reaction and is the result of Memory B cells being activated. This reaction is the basis of "Booster Vaccines" to stimulate higher levels of antibody titer.
CELLULAR (CMI) IMMUNITY
Antigens which enter cells cannot be reached by antibodies. This includes viruses, some bacteria and certain parasites.
When appropriate “antigenic material” enters the body, it will rapidly encounters a macrophage or other antigen presenting cell (APC) which phagocytize it and enzymatically destroy the invading organism. However, the antigenic determinants (epitopes) will be preserved and combined with the APC's MHC Class II protein and then moved to the surface of the cell. The macrophage or APC will then move to the nearest lymphoidal tissue (lymph nodes, etc.) and will present the MHC protein and processed antigen to any T helper (TH) cells residing there.
The APC will place its MHC protein and processed antigen into the receptor of the TH cell.
The TH cell has a two part receptor. The T Cell Receptor (TCR) much bind to the presented antigen, and the CD4 receptor must bind the the APC’s MHC II. Both regions must bind in order for the response to be triggered.
The TH cell will be activated and will then divide and differentiate, producing large populations of two cell types. Mature TH cells will produce cytokines (signaling chemicals) that will activate the appropriate Cytotoxic T cell (CTL). Memory CTL cells will stay behind to trigger a later immune response should it be necessary.
The CTL then locates an infected bodily cell. This cell will be presenting new antigens combined with its own MHC I proteins.
The TH cell has a two part receptor. The T Cell Receptor (TCR) much bind to the presented antigen, and the CD8 receptor must bind the infected cell’s MHC I. Both regions must bind in order for the response to be triggered.
(Because it binds to MHC I, the CTL can attack any infected nucleated cell in the body.)
The CTL attaches to the infected cell and releases perforin followed by granzyme which then initiate programmed cell death (apoptosis).
Natural Killer (NK) Cells – not part of the CMI response. They are not specific and are not stimulated by the presence of a particular antigen, but they can distinguish between normal cells (which have MHC I) and cancer cells and infected cells (which often have no MHC I or reduced numbers of MHC I).
If they detect the absence (or low numbers of) MHC I, NK cells will then kill the target cell in a manner similar to that of CTLs.
Type of T Cells
1. T cells that have TCRs and CD4 receptors on their membranes. The two types of T cells
with these receptors are: (T4 cells)
a. Helper T cells - as previously stated, these cells help B lymphocytes to become
plasma cells and memory cells by secreting interleukin 2.
b. Delayed Hypersensitivity T cells (DHT cells) - these cells are involved in T Cell
responses but do not interact with B cells. They respond after 24 hours by
recruiting and activating nonspecific effector cells such as macrophages. They
are involved in delayed hypersensitivity responses such as organ transplant
rejections.
2. T cells that have TCRs and CD8 receptors on their membranes. The two types of T cells
with these receptors are: (T8 cells)
a. Cytotoxic (killer) T cells which interact with and directly destroys cells having
the specific antigen on their surface. These can be foreign cells, tumor cells
or virus-infected cells. They release perforins, chemicals that kill these cells.
b. Suppressor T cells serve to regulate the immune response by suppressing the
action of immune cells such as a B cells and macrophages. They tend to tone
down the immune response by preventing cells from being involved in the
"fight".
Many of the effector T cells will also respond with the secretion of soluble chemical signals called lymphokines or cytokines. These signals serve to incite local inflammatory responses as well as activate or suppress certain cells. The term lymphokine versus cytokine is currently in a state of flux as many scientists have named similarly isolated signals with different names. Within the near future agreements will be worked out as to their specific categories and names. Thus far, some of these chemical signals that have been isolated are:
1. Chemotactic factor- attracts macrophages and other phagocytic cells-causes an
influx of these cells into the area where the antigen is present.
2. Macrophage (migration) inhibition factor (MIF) - reduces the movement of
macrophages and other phagocytes away from the site of infection.
3. Macrophage Activating (arming) factor (MAF) - increases the number of
lysosomes in macrophages and turns phagocytic cells into "angry macrophages".
4. Interferons - gamma (immune) interferon acts as an immune regulator to some
cells. It is involved to some extent in fighting tumor cells.
5. Interleukins - signals between leukocytes that act on B or T lymphoctyes:
a. Interleukin 1 -is released by macrophages when they present antigen to B
and T lymphocytes-they tend to activate these cells.
b. Interleukin 2 -produced by antigen-activated T lymphocytes such as
Helper T cells stimulates B cell proliferation into plasma cells and
memory cells and rapid antibody synthesis.
c. Interleukin 3 and 4 have also been isolated but their role in the immune
response is unclear at the present time.
6. Colony Stimulating Factor (CFS) causes phagocytic white blood cells of all
types to differentiate and divide.
7. Transfer Factor -converts normal lymphocytes into antigen-sensitized cells.
8. Lymphotoxin -kills many different kinds of cells nonspecifically. These kill
normal cells and tissues as well as foreign and infected cells.
B and T lymphocytes are identical under the conventional light microscope, but differences in surface markers and Ig's on the surfaces of these cells can be noted by electron microscopy and immunoassay (serological tests). Additional differences are:
1. They occupy different regions of lymphoid tissue (B lymphocytes in germinal
centers and T lymphocytes in the medullary area).
2. They are "processed" in different areas (B lymphocytes in bone marrow and T
lymphocytes in the Thymus gland).
3. B cells are short-lived (months); T cells and long-lived (years).
4. B cells have their specific antibody on their surface and receptor; T cells have
TCR (T cell receptor) on their surface which is somewhat similar to the B cell
receptor.
5. B cells have few surface markers or antigens on their surface. T cells have more.
6. B cells comprise 20% of circulating lymphocytes whereas T cells comprise 80%
of lymphocytes.
The immune system cooperates with and enhances the nonspecific defenses. The immune defenses control infection in the later stages of the first attack and defend against second or subsequent attacks by the same agent. The two systems are both essential to the control of infectious diseases.
ORIGIN OF THE IMMUNE SYSTEM:
The human body is capable of producing 1 X 1015 different receptors for antigens, even though the human genome does not carry enough DNA to code for that many different receptors. They are created through random rearrangement of the relevant DNA.
Because antigenic receptors are generated randomly, some of them may be able to recognize and bind to some of the body’s own antigens, causing the generation of an auto-immune response.
Lymphocytes must therefore undergo clonal selection in which those which are harmful are removed (clonal deletion) before they have a chance to cause harm.
Lymphocytes arise from bone marrow stem cells. Lymphoblasts will become lymphocytes.
Lymphocytes are dispersed throughout the body in blood and lymphatic circulation and are one of the most prevalent mammalian cells. Both B and T cells are derived from cells in bone marrow. The differentiation of stem cells into mature lymphocytes is determined by the organ in which they become established. B cells mature in bone marrow and T cells mature in the thymus (these areas are designated as primary lymphoidal tissues). Later B & T cells are dispersed throughout the body via blood and lymphatic circulatory systems. Mature B & T cells come to reside in lymph nodes or the spleen (which are designated as secondary lymphoidal tissues).
The Clonal Selection Theory states that each antigen-reactive B or T cell has an antigen specific receptor on its surface. When presented or stimulated by a specific antigen, each cell is capable of dividing, making several copies of itself - forming a clone of cells after antigen contact.
Because of the infinite variety of antigens available, a large number of antigen-reactive cells must be available in the body and each cell is capable of forming a clone or identical cells. Ultimately the immune response has the ability to discriminate between foreign invaders (nonself) and host (self) tissue by deleting or inactivating self-antigen reactive cells. This inability to make an immune response to a specific antigen (self antigen) is known as tolerance. The development of tolerance occurs along with maturation of lymphocytes.
Remember – the TCR binds to (nonself) antigen and the CD receptor binds to self MHC.
In the first T cell maturation (Positive Selection), lymphocytes leave bone marrow and enter the thymus gland. CD receptors develop on T cells in the thymus. T cells then interact with self MHC proteins in the thymus. These T cells continue to mature and proliferate. T cells that do not interact with MHC proteins stop growing and eventually die. Thus positive selection is a sorting process that retains cells that can recognize self MHC proteins and ultimately deletes cells that cannot recognize self (and which are therefore useless because they cannot be activated).
The second stage of T cell maturation is Negative Selection. Cells which were positively selected are then exposed to self antigens. If the TCR of a cell recognizes and binds to self antigen, that cell is eliminated (Clonal Deletion) so that it will not destroy self tissue.
Those T cells in which the CD receptor reacts with MHC proteins but the TCR does not react with any self antigens continue to proliferate, leave the thymus and migrate to the spleen and lymph nodes where they can contact foreign antigens and interact with APC's and B lymphocytes.
The acquisition of immune tolerence in B cells is also necessary. The mechanisms for achieving B cell tolerance parallel those already seen in T cells. B cell tolerance includes acquisition of IgD antibody on the surface (positive selection) and destruction of those B lymphocytes that react with self antigen (negative selection).
Evidence for the two immune systems (and clonal selection) is provided via the characterization of immunodeficiences:
a. DiGeorge's Syndrome - a T cell deficiency. Abnormal embryonic
development results in a rudimentary or absent thymus. The infant is
deficient in CMI. Since they lack Helper T cells, an effective AMI
response cannot be mounted. Transplantation with fetel thymus has
been successful.
b. Bruton's Agammaglobulinanemia - this B cell deficiency is the result
of a sex-linked recessive gene and the individual lacks the ability to
fight off numerous bacterial and viral infections. They do have the
ability to resist deep-seated infections and reject transplants due to CMI.
c. Severe Combined Immunodeficiency (SCID) -In this rare condition
bone marrow stem cells (lymphoblasts) failed to develop. Victims
must be kept in a germ-free environment to survive and avoid infect-
ion. Some success has been met with bone marrow transplants.
d. HIV (AIDS) - this type of immunodeficiency is the result of HIV, a
retro-virus that attaches to CD4 receptors on Helper T cells. The virus
eventually destroys Helper T cells sharply decreasing the immune
response because Suppressor T cells do not decline in number and shut
down the immune system.
Hypersensitivity - an abnormal physiological state resulting from the combination of antigen with
an immune effector (B or T cell) at the wrong time, in the wrong place or in the wrong
proportions. The inciting agents that provoke these responses are known as allergens.
Initial exposure to an allergen sensitizes the individual to future contact with the same allergen. Various types of harmful reactions can result from such exposures. Four major types of Hypersensitivity have been noted:
Type 1 & Type 4:
1. Type I - Hypersensitivity (Classic Immediate/Anaphylaxis) include atopic allergies such as hay fever, asthma, food intolerance and hives as well as anaphylactic shock. Components are:
1. IgE antibodies which are cytotropic and bind to:
2. Mast cells - a connective tissue cell which degranulates secreting a variety of
leukotrienes (mediators of anaphylaxis) including:
3. Histamines - cause dilation of capillaries, increased permeability of capillaries
4. Eosinophil chemotactic factor - summons eosinophils into the area
5. Slow reacting substance - causes spasmotic contraction of smooth muscle
6. Platelet activating factor (PAF) - causes platelets to release clotting factors
7. Serotonin - increased vascular permeability, respiratory rate and diminished central
nervous system activity (shock).
These mediators may be released in varying amounts depending upon the degree of the immune response.
Atopic allergies - the mechanism of sensitization is that IgE antibodies attach to the cell membrane of mast cells and basophils by their Fc pieces. When the allergen binds to the Fab regions of two antibodies, the Ig triggers the mast cell to degranulate releasing primarily histamines which cause the runny nose, watery, reddened, and itching eyes as well as the coughing, sneezing, wheezing and difficult breathing associated with asthma and hay fever. In food allergies, mediators cause nausea, vomiting, abdominal cramps and diarrhea. If the reaction occurs near the skin, hives may result. Most atopic allergies respond well to antihistamines. In fact, eosinophils release antihistamins and other substances that counteract the secretions released by mast cells.
Anaphylaxis- the only difference between atopic allergy and anaphylaxis is one of degree. This, the most sever kind of Type I hypersensitivity occurs when the allergen is systematically injected into the sensitized person. A bee sting or injected medication such a penicillin may provoke anaphylaxis. The capillaries dilate causing a sharp drop in blood pressure and at the same time SRS causes slow contraction of respiratory muscles. Asphyxiation and cardiac failure follow unless the patient is immediately given epinephrine (adrenalin) and CPR. Individuals that are subject to anaphylaxis may be desensitized by being given minute doses of the allergen over a period of time. This results in the production of IgG and IgM antibodies (blocking antibodies) which neutralize the antigen before it can bind to IgE antibodies. Suppressor T cells may also be stimulated by this desensitization technique.
2. Type II - Cytotoxic Hypersensitivity - results in cellular destruction and involves IgG and IGM antibodies which fix or react with complement. Examples are improper blood transfusions, the Rh baby (erythroblastosis fetalis) and certain drug caused blood loses.
3. Type III - Immune-Complex-Mediated Hypersensitivity - results from reactions involving specific allergens, Ig's and certain auto-immune states. These are partially due to the complement fragments C3 and C5a which are anaphylotoxins causing damage to joints, kidneys and skin. Examples are the Arthus reaction, serum sickness, and certain auto-immune diseases such as Lupus
(Systemic lupus erythematosus) and Glomerulonephritis. Involves IgG, IgM and complement components.
4. Type IV - Cell-Mediated (Delayed) Hypersensitivity - occurs one or two days after exposure whereas the other types occur within 12 hours. This type is due to CMI and involves infiltration into the area by Delayed Hypersensitivity (DHT) T cells. These release lymphokines which summon and activate macrophages and other phagocytic cells. One example is contact
dermatitis which is responsible for the majority of common allergic skin disorders in humans. Including those to poison ivy, cosmetics and certain drugs or chemicals. In incompatible organ transplants or skin grafts, rejection is due to DHT cells, macrophages and phagocytes affect lymphokines destroy the foreign tissue unless immunosuppressive drugs such as Cyclosporine and Orthoclone OKT3 are administered. Cyclosporine blocks the cell division of Helper T cells by blocking Interleukin 2 production. As a result T cells cannot respond. This drug has greatly enhanced transplant success. OKT3 binds to CD receptors on T cells preventing their response. Certain types of disease such as tuberculosis and systemic mycoses also provoke a DHS response. The result is an allergy to infection which can be detected by a skin test that results in a skin rash after exposure. The skin tests for Tuberculosis, the Mantoux Test and the multiple tine skin test will indicate if a person has been exposed to Mycobacterium tuberculosis.
Autoimmune Diseases - even with recognition of self during embryonic development, some immune system cells capable of mounting an immune response against self do survive. This may be due to the fact that some cells or tissues were sequestered or not available at the time of this event or that some B and T lympocytes become reactivated later in life. This resurgence of self reactive clones leads to immunological disorders referred to as autoimmune diseases. Most are slow, progressive disorders in which the function of some specific organ or set of tissues becomes increasingly poorer with time. Evidence is accumulating that heredity has an important influence on the incidence, type, and severity of autoimmune diseases. An inherited tendency to develop certain autoimmune diseases is known to exist. Many autoimmune diseases have a strong correlation with the presence or absence of certain MHC (HLA) antigens. Some of the determined autoimmune diseases are Juvenile Onset Diabetes (pancreas), Myasthenia Gravis (acetyl choline receptors on skeletal muscle), Goodpasture's syndrome (Kidney), Rheumatoid arthritis (cartilage at joints), Hashimoto's disease (hypothyroidism), Lupus (DNA), Pernicious anemia (intrinsic factor), Addison's disease (Adrenal cortex) and Multiple sclerosis (myelin sheath).
Histocompatibility-Tissue grafts and organ transplants have a greater chance of "taking" if closely related individuals serve as donors. It has been determined that self markers on the cell membrane are under genetic control. These genes are associated with chromosome #17 in mice and chromosome #6 in humans.
Barju Benacerraf, Jean Dausset and George Snell won the 1980 Nobel Prize in Medicine or Physiology for their work on the Major Histocompatibility Complex (MHC). The genes analogous to the MHC on mice was subsequently discovered in humans and was labeled the HLA system (Hjman Locus/Leukocyte Antigen system). The MHC/HLA system are both still used. This group
of genes is involved with:
1. The production of surface markers (self antigens) which are found on all nucleated cells and
erythrocytes.=MHC Class I, MHC Class II antigens
2. Immune Response Genes - code for our ability to respond to non-self antigens; both AMI and
CMI immune responses.
3. Antigens that demonstrate a propensity for certain diseases such as Mysthenia gravis, Lupus,
Arthritis, diabetes and other disease states.
With the isolation of an individual's HLA antigens, better success will be forthcoming in successful organ transplants and well as preventative medicine for those individuals that show a propensity for certain autoimmune diseases or certain other disease states. A technique that has been used to identify HLA antigens and determining histocompatibility is through the production of Monoclonal Antibodies by the Hybridoma technique.
Hybridoma-an immortal cell produced by the fusion of a "normal" B lymphocyte with a malignant B lymphocyte. This hybrid cell takes on the function of the normal cell but is immortal and can be grown on tissue culture indefinitely. The technique was developed by Kohler and Milstein in 1975. They have since been awarded a Nobel Prize in Medicine or Physiology. The original technique involved cell fusion by the use of poly ethylene glycol although electro-fusion procedures now exist. This technique is to immunology what the recombinant DNA technique has been to genetics.
When an immune response is made by B cells, any B cell capable of making an immune response will do so by differentiating into plasma cells and producing and secreting antibodies. Therefore in the serum of the individual they may be many antibodies in response to different antigenic determinants of the antigen. These antibodies in blood serum will therefore be polyclonal antibodies. Through the hybridoma technique, cells can be tailor-made to produce a single antibody specific for the antigenic determinant, that is, a Monoclonal Antibody. As a result of this technique of fusing an sensitized B lymphocyte with a Myeloma cell, Monoclonal Antibodies have been produced that:
1. Recognize many serological types of rabies viruses'
2. Recognize many serological types of influenza viruses
3. Recognize human melanoma, colorectal and breast carcinomas-specific human cancer
antigens.
4. Recognize HLA antigens
5. Fight specific diseases-they have been used in cancer therapy
6. Detect low levels of substances in blood-many metabolic intermediates of drugs such as
cocaine, etc can now be detected in urine or blood by MCA's.
7. Recognize commonly sexually transmitted diseases (STD's)
a. Gonozyme-allows for rapid detection of Neisseria gonorrhoea (gonorrhea)
b. Chlamydiozyme-allows rapid detection for Chlamydia trachomatis which is
responsible for the majority of cases of NGU-Non Gonococcal Urethritis-the most
commonly transmitted STD.
8. Rapid Strep test for Streptoccal Sore throat caused by Streptococcus pyogenes (Beta
Hemolytic) Group A.
9. Early Pregnancy Tests-involve MCA's against HCG (Human Chorionic Gonadotropin)
produced by the placenta and found in the urine of pregnant females.
The possibilities of the usages of monoclonal antibodies appear to be able to challenge researchers for decades to come.