II. IMMUNITY--specific resistance to disease. Immunology is the branch of science. Two important properties of immunity:
1. Specificity for particular foreign molecules such as bacteria, viruses, toxins, fungi, foreign tissues, which are recognized by the immune system as foreign and provoke immune responses. These foreign molecules are called antigens.
2. Memory for most previously encountered antigens, so that a second encounter produces a stronger and faster response.
Two types of lymphocytes are the cells responsible for the immune response--the T cells and the B cells. Both are formed in red bone marrow. B cells remain there until they develop immunocompetence (the ability to carry out immune responses). Immature T cells (pre-T cells) leave the bone marrow and go to the thymus, where they also develop immunocompetence. In the maturation process both B and T cells develop distinctive surface proteins, some of which act as antigen receptors capable of recognizing specific antigens. While in the thymus, all T cells also develop one of two special proteins, CD4 or CD8, on their plasma membranes.
Immunity consists of 2 kinds of responses, both triggered by antigens:
A. Cell-mediated (cellular) immunity—CD8 T cells proliferate into cytotoxic T cells and directly attack specific invading antigens. This type of immunity involves cells attacking cells and works best against:
1. Intracellular pathogens (fungi, parasites, viruses)
2. Some cancer cells
3. Foreign tissue transplants
B. Antibody-mediated (humoral) immunity—B cells transform into plasma cells and produce special proteins called antibodies, which bind to and inactivate a specific antigen. Antibodies work best against:
1. Antigens in body fluids
2. Extracellular pathogens, which includes most bacteria
An antigen is any substance that is recognized by the body as foreign. Antigens are large, complex molecules that are most often proteins. Occasionally other molecules such as lipoproteins, nucleic acids, glycoproteins and certain large polysaccharides may also act as antigens.
Antigens have 2 important characteristics:
1. Immunogenicity—ability to provoke an immune response
2. Reactivity—ability of antigen to react
with the antibodies or cells it provoked
Entire microbes, parts of microbes, or toxins produced by microbes may act as antigens. Pollen, egg white, incompatible blood cells, and transplanted tissues are antigenic. Antigens entering the body usually reach lymphatic tissue in one of the following ways:
1. Antigen enters bloodstream and is carried to the spleen
2. Antigen enters skin, is picked up by lymphatic vessels and carried to a lymph node
3. Antigen enters a mucous membrane and reaches the mucosa-associated lymphoid tissue (MALT)
Small, specific portions of antigens trigger immune responses—these parts are called epitopes. Sometimes small molecules called haptens enter the body and do not cause an immune response by themselves, but combine with a protein in the body and then become antigenic.
The human immune system has the ability to recognize and bind to at least one billion different antigens. Different B cells and T cells have a tremendous diversity of antigen receptors on their plasma membranes. Even before the first time we encounter a particular antigen, we have ready & waiting a few B and T cells that are programmed to recognize and respond to that antigen. If we do not have cells programmed to respond to the antigen, we cannot mount an immune response to it. If we never encounter the antigen a particular B or T cell is programmed to respond to, that cell never participates in an immune response.
Our ability to produce this tremendous number of different antigen receptors is due to genetic recombination. Several small gene segments are reshuffled over and over in developing lymphocytes and put together in different combinations to make different genes for different types of antigen receptors.
All body cells except RBC have antigens called by 2 names: major histocompatibility (MHC) antigens or human leukocyte antigens (HLAs). These are used by the immune system to distinguish self from foreign invaders.
Class I MHC (MHC-I) molecules are built into the plasma membrane of all nucleated body cells
Class II MHC (MHC-II) molecules appear only on the surface of APCs, thymic cells, and T cells that have been activated by exposure to an antigen
For an immune response to occur, B and T cells must recognize that a foreign antigen is present. B cells can directly recognize and bind to their particular antigen in extracellular fluid. T cells can recognize only antigens that have been processed and presented together with MHC proteins by antigen presenting cells. As proteins inside body cells are being broken down, some peptide fragments bind to newly synthesized MHC molecules. This stabilizes the MHC protein, aids in its folding, and allows it to be inserted into the plasma membrane.
If the peptide fragment comes from a self protein, T cells ignore it. If the peptide is from a foreign protein, certain T cells recognize it as an intruder and this triggers an immune response. The process is described as processing and presenting the antigen. It occurs in two different ways, depending on whether the antigen comes from inside or outside body cells.
Exogenous antigens are antigens present in fluids outside body cells. This would include:
Bacteria (most)
Bacterial toxins
Worm parasites
Inhaled pollen and dust
Viruses that have not yet entered a cell
Special cells that begin as macrophages, B cells, or dendritic cells are located in places where antigens are likely to enter the body. They encounter the exogenous antigen and proceed as follows:
1. Antigen is taken in either by:
a. Phagocytosis by a macrophage or dendritic cell (which need not be specific to that antigen)
b. Occasionally by endocytosis by a B cell (which would have to be specific to only that antigen)
2. Inside the cell, the antigen is partially broken down into peptide fragments by lysosome enzymes. At the same time, the cell is synthesizing MHC-II proteins.
3. Vesicles containing the peptide fragments of the antigen fuse with vesicles containing MHC-II proteins.
4. Antigen peptide fragments bind to MHC-II molecules.
5. Antigen-MHC-II complexes leave by exocytosis but remain stuck onto the outside surface of the plasma membrane of the cell. The cell is now an antigen-presenting cell (APC).
6. APC migrates to lymphatic tissue to present the antigen to B cells and T cells
which were programmed to respond specifically to that antigen.
These are foreign antigens that are synthesized inside body cells. They may be viral proteins or abnormal proteins produced by a cancerous cell. Fragments of these antigens combine with MHC-I molecules inside the cell. The antigen-MHC-I complex is then displayed on the outer surface of the cell. This is a signal that the cell have been infected and needs help. It will be recognized by B and T cells programmed for that antigen.
Now the immune response, both cell-mediated and antibody-mediated, really begins. Both types of response often occur, even though one of the types would probably work better against a particular of invader.
In general, this branch of the immune response involves activation of the small number of T cells specific to the antigen. Activated T cells undergo proliferation and differentiation into a clone of effector cells recognize the antigen and participate in an immune attack against it.
These steps occur in secondary lymphatic tissue:
1. T-cell receptors (antigen receptors) on the surface of those T cells preprogrammed to recognize the antigen as presented by an APC bind to it. There will only be a few of these specific T cells at first. Some of them will be CD4 T cells and some will be CD8 T cells. Antigen recognition is the first signal in activation of a T cell.
2. A second signal, called a costimulator, is required for full activation of a T cell. This costimulator is often a cytokine, such as interleukin-1 or interleukin-2. With this second signal, T cell become activated.
3. Activated T cells enlarge. They proliferate (divide) and differentiate (specialize), forming thousands of T cells that recognize this antigen and are specific to it. This group of cells is called a clone and they all recognize the same antigen.
Differentiation produces several types of T cells (all specific to the antigen that started the whole process):
1. Helper T cells—t hese develop from T cells that were CD4 T cells specific to the antigen. They are activated by their antigen-MHC-II complex and interaction between molecules on their surface and the surface of the APC. Following activation, different subsets of T cells secrete different cytokines. One of the most important is interleukin-2 (IL-2), which is needed for either type of immune response to proceed any further. IL-2 acts as a costimulator for other T cells as well as the T cells that secrete it. It also enhances activation and proliferation of B cells and NK cells. Helper T cells are often described as the regulators of immunity.
2. Cytotoxic T cells—these are the big ones in cell-mediated immunity. They develop from CD8 T cells and recognize their antigen-MHC-I complex. These cells, also known as killer T cells, directly attack and kill cells infected by a microbe, certain tumor cells, and foreign tissues such as transplants. Interleukin-2 from helper T cells is required for these to become able to function. They then leave the lymphatic tissue and are carried to the cells bearing their particular antigen by the blood. When they reach these cells, they attach to them and deliver a “lethal hit” to kill the cell by:
a. Releasing granzymes, which are protein-digesting enzymes that trigger apoptosis (“cell suicide”) in the target cell
b. Releasing a protein called perforin, which inserts into the plasma membrane of the target cell and creates openings called channels, resulting in cytolysis (bursting of the cell)
c. Releasing granulysin, which enters through the perforin channels and creates holes in the plasma membranes of microbes inside the cell
d. Releasing lymphotoxin, a toxic molecule that activates enzymes in the cell that break up its DNA
e. Secreting gamma-interferon, which increases the activity of phagocytic cells
3. Memory T cells remain in lymphoid tissue and recognize the same antigen if it invades again, even years later. The second and all subsequent responses will be faster and stronger than the first.
In the presence of a foreign antigen, specific B cells located in lymph nodes, the spleen, or the MALT become activated. They differentiate into plasma cells and secrete antibodies specific to that antigen. The B cells stay put in lymphatic tissue but their antibodies are carried throughout the body by the blood. Steps:
1. B cells can be activated in these ways:
a. Intact and unprocessed antigen in lymph or interstitial fluid binds to a B cell specific to it
b. B cell takes in the antigen by receptor-mediated endocytosis and processes it—this produces a much stronger response
1) Inside the B cell the antigen is broken down into peptide fragments and combined with MHC-II proteins
2) Antigen-MHC-II complex is moved to the B cell plasma membrane
3) Helper T cells which have already been activated by the same antigen recognize the complex
4) Helper Ts bind to the B cell and secrete interleukin-2, which causes the B cell to proliferate and differentiate into a clone of plasma cells. Interleukin-4 and interleukin-6, also produced by helper T cells, enhance B cell proliferation, differentiation, and secretion of antibodies
5) Most of the activated B cells differentiate into a clone of plasma cells. Plasma cells can secrete 2000 antibody molecules per second for 4-5 days. This will be one kind of antibody, specific to the antigen that provoked it. These antibodies are carried by the blood to wherever in the body the antigens are located.
A few activated B cells do not differentiate into plasma cells but remain as memory B cells, ready to respond to the same antigen in the future.
Antibodies are proteins which are also known as immunoglobulins (Ig’s). They enter circulation and combine with the same antigen that initiated their production. In the process, the antigen is usually inactivated or destroyed. Most antibodies contain 4 polypeptide chains:
2 heavy (H) chains, which are identical to each other
2 light (L) chains, which are also identical to each other
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5 classes of antibodies:
IgG—most abundant (80% of circulating antibodies)--found in blood, lymph and intestines, cross the placenta before birth to protect the newborn
IgA—provide localized protection associated with mucous membranes--levels drop during stress--these are the main antibodies in secretions, including breast milk
IgM—first antibodies secreted after initial exposure to an antigen, include ABO
Antibodies. Some are found on the surface of B cells, where they act as antigen receptors.
Ig-D—mostly found on the surface of B cells where they act as antigen receptors. Also involved in activation of B cells.
Ig-E—located on mast cells and basophils and are involved in allergic reactions, but also give protection against parasitic worms
Antibodies bring about their effects in several ways:
1. Neutralizing bacterial toxins
2. Preventing attachment of viruses to cells
3. Immobilizing bacteria
4. Agglutination—sticks a mass of invaders plus antibodies together
5. Precipitation—original antigen is water soluble & dissolved but the combination of antigen plus antibody is no longer water-soluble, so it settles out of whatever body fluid it is in and is phagocytized by an eosinophil
6. Activation of the complement system
7. Enhancing phagocytosis (opsonization)
This is a group of over 30 proteins in blood plasma and plasma membranes. They are always present in an inactive form. They can be activated in a series (cascade) of reactions to aid in defense of the body. The proteins include:
C1 - C9
Factor B
Factor D
Factor P (properdin)
Inactive forms are larger. Activation involves splitting them into smaller pieces, each of which has a separate functionl. They can be activated in 3 ways, all of which activate C3. Once C3 is activated, the remaining steps proceed the same no matter how activation began.
1. Classical pathway—antibody binds to antigen and this activates C1. Inactive components are then split into smaller active fragments.
2. Alternative pathway—polysaccharides on the surface of a microbe interact with B, D, and P—this activates C3
3. Lectin pathway—macrophages digest microbes & release chemicals that cause the liver to synthesize proteins called lectins. Some of the lectins bind to carbohydrates on the surface of the microbe and C3is activated.
The results of activation include;
1. Activation of inflammatory process
2. Opsonization—makes microbes more susceptible to phagocytosis
3. Cytolysis—complement proteins come together and form a membrane-attack complex (MAC) that inserts into the microbe’s plasma membrane and forms a channel that allows inflow of extracellular fluid and causes the microbial cell to burst.
A second exposure to an antigen brings about an immune response that is both stronger and faster than the first. This is true for both cellular and humoral immunity. The first response may take several days to a week to become effective and several weeks to peak, while the second develops within hours.
The amount of antibody to a particular antigen (antibody titer) can be measured in the blood.
Primary response (first exposure)--no antibody for several days, then a slow rise (first IgM, then IgG), a peak and a gradual decline
Secondary response (all subsequent exposures)--rapid response of high levels of mostly IgG antibodies that are very effective in disposing of the antigen
Immunologic memory is the reason we can have vaccines. The vaccine contains an antigenic portion of a pathogen that has been changed so that it cannot actually cause disease but can still trigger a primary response. Memory B and T cells are produced that remain and respond if the real pathogen later enters the body.
TYPES OF
IMMUNITY
1. ACTIVE IMMUNITY involves active production of antibodies by your own plasma cells
a. Naturally acquired active immunity comes from exposure to the pathogen
b. Artificially acquired active immunity comes from a vaccine
2. PASSIVE IMMUNITY results from the transfer of IgG antibodies from one person to another. These antibodies die after a period of weeks to months and no protection remains. No memory cells are formed.
a. Naturally acquired passive immunity comes from transfer of mother's antibodies across the placenta or by breast feeding
b. Artificially acquired passive immunity comes from the IV injection of IgG antibodies (gamma globulin)
The body has a series of steps to insure that the only B and T cells that are allowed to reach maturity are those that are able to:
1. RECOGNIZE self (in the form of the major histocompatibility complex antigens).This is done by a process described as positive selection. T cells that are able to interact with MHC proteins on cells of the thymic cortex are allowed to survive, others are not.
2. NOT RESPOND to self—the second step is described as negative selection. Dendritic cells located at the junction of cortex & medulla in the thymus sort out the T cells. Those with receptors for self-peptides are handled in one of 2 ways:
a. Deletion—caused to undergo apoptosis and die
b. Anergy—permanently inactivated but not dead
B cells undergo similar processes in the bone marrow and bloodstream.
If this selection of B and T cells somehow fails, an autoimmune disease may result. Common autoimmune diseases include rheumatoid arthritis, lupus, multiple sclerosis, type I diabetes mellitus, and many others.
When a cell transforms into a cancer cell, it may display tumor antigens on its surface. In many cases the immune system recognizes that the tumor cells are nonself and attacks and destroys them. It is hoped that this may be enhanced and provide a future treatment for cancer.
AIDS--Acquired Immune Deficiency Syndrome--caused by a virus (HIV, human immunodeficiency virus). Initial infection produces a brief flu-like illness but usually 2-10 years pass before true AIDS develops. Once infected, a person can spread the virus. Six weeks to 6 months after infection HIV antibodies appear, but there is a period of time when the person would be HIV negative but able to spread the virus. A few individuals never develop the antibodies at all.
The virus slowly destroys the T4 cells, which would become helper T cells. This cripples the immune system. Lowered resistance frequently results in development of a wide variety of diseases, some of which are caused by organisms that are usually harmless. 2 conditions which are seldom seen except in AIDS patients are:
1. Pneumocystis carinii pneumonia
2. Kaposi's sarcoma (form of skin cancer)
Tuberculosis is also common in AIDS patients.
In the
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the rest of the AIDS material and also hypersensitivity (allergy).