Lecture Notes on the Immune System
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The immune system identifies specific foreign agents, contains and attacks them. The word we use for foreign agents (anything that is non-self) is antigen. Every cell has antigens; antigens are markers on the surface of cells that the immune system can recognize. Self antigens are antigens in individual to which the immune system is tolerant (the immune system does not try to attach).
Without an immune system we cannot survive in a normal environment. The immune system is very complex and by studying genetic disorders that affect just one component of the immune system, we can develop an understanding of what that component does. Ex. studying HIV has enabled us to learn much about the immune system.
The immune system gives us Non-specific, natural protection which is inherited
(Ex. barriers, skin, protective secretions, lysosomes, properdin system), and the ability to acquired immunity.
Acquired immunity is extremely specific; the body produces antibodies that work against a specific antigen. Ex. The antibodies that kill the polio virus will not affect any other organism. You make antibodies in response to every antigen that you come into contact.
The antigen is usually of sufficient size to contain a specific marker that triggers antibody production. Small substances that can't be recognized by the immune system are called haptens; when join with a protein the immune system can recognize them. Also it is very important to remember that the immune system can distinguish between self and non-self.
SELF VERSUS NON-SELF
Cells have surface antigens that are coded by clusters of genes called Major histocompatibility Complex (MHC). Many of these genes are found on chromosome 6.
HLA stands for Human Leukocyte Antigens because they were first detected on the leukocyte on the human and also inherited and part of genetic makeup. They are the same thing as the MHC, just a different name. Another way to kook at it is the MHC refer to genes that code for the antigens which are referred to as the HLA. We have so many different tissue antigens that its virtually impossible for two people to be identical unless they are identical twins.
T cells versus B cells:
Two immune systems: The T cells and the B cells.
B cells are most effective in fighting bacteria. Major function is to produce antibody. There are memory B cells that stay in the body for long periods of time and when same antigen enters the body, they can make antibody very quickly. They start in the bone marrow as undifferentiated cells and then somehow are altered to have surface antigens that identify them as B cells. The fully mature B cell is a plasma cell that has the ability to make antibody.
Theory: We know that in birds the blast cell (immature lymphocyte) is changed to a B cell in the Bursa of Fabricus. In man it is possible that there is "bursa equivalent tissue" that lies along the intestines (maybe Pyer's patches). We do know that only 10-20% of the immature lymphocytes (blast) become B cells.
The plasma cellís main job is to make antibody and there are five classes of antibody (immunoglobulin) Gamma globulin is a specific type of antibody (IgG).
Primary versus Secondary Immune Response
The primary immune response occurs the first time that the immune system comes in contact with the antigen. During this time the immune system has to learn to recognize antigen and how to make antibody against it and eventually gain immunological memory. This primary response takes time (about two weeks) and during this time the person experiences signs of illness. IgM antibodies are the hallmark of a new infection because they are the first antibodies made when a person is exposed to an antigen for the first time. After the body learns to make IgM antibodies, it will start making IgG antibodies to the antigen.
The secondary immune response occurs the second time (3rd, 4th, etc.) the person is exposed to the same antigen. At this point immunological memory has been established and the immune system can start making antibodies immediately. The antigen usually is killed within minutes and the person is not aware that he/she was attacked. The antibodies in this response are IgG and IgA or (in the case of allergy IgE).
Titers of antibody refer to the amount of antibody you find in the blood. If the titer is high it means that you have recently been exposed to the antigen. If you have no antibody titer, it means that you have never been exposed or have been exposed so recently that the immune system hasnít started to make antibodies. You also can analyze the type of antibodies involved. If the antibodies are IgM, it mean a new infection. In order to measure for a titer, the antigen has to have already been determined. For example, before we knew what caused AIDS, we could not measure antibody titers even though the people with AIDS already had titers.
There are three major classes of lymphocytes
B-cells (10-20%) that ultimately differentiate to plasma cell
Humeral immunity is important in eliminating bacteria, neutralizing bacterial toxins, and preventing viral reinfection and hypersensitivity.
T-cells (60%) which differentiate along two lines
CD4 cells (helper cells)
CD8 cells (suppressor cells or cytotoxic T-cells)
Null cells (natural killer cells)
These cells can attack any antigen but must be directed by the T cell.
In order for a B cell to differentiate into a plasma cell, it must de introduced to the antigen by the macrophage. The macrophages are also called an antigen-presenting cell (APC). There are other APCs in the body such as the Langerhansí cells in the skin and Dendritic cells in the lymph nodes. The macrophage or (APC) first comes into contact with the antigen and phagocytizes it. The macrophage then is able to present the antigen to the B cell in a form, which the B cell can recognize. When the B cell is introduced to the antigen (by the macrophage), it starts to change so that it will become a plasma cell, which will make antibody. The altered plasma cell will only be able to make antibody against the specific antigen to which it was introduced. Every time the body comes into contact with a NEW antigen the process from immature B cell to plasma cell must start over again. Eventually we will have thousand of lines of plasma cells, which will only be able to make a very specific antibody. In the process of differentiation to a plasma cell, some mature (antigen sensitized) B-cells will become MEMORY cells. These memory cells will be able to turn into plasma cell (real fast) at a later time when the host is exposed to that specific antigen. Therefore, for every line of plasma cells you make against a specific antigen, you also make memory cells that are related.
The production of antibody is usually under the influence of T helper cells. Thus when the T cells are not working properly, antibody production is effected.
ANTIBODIES OR IMMUNOGLOBULINS
Made of four protein chains, two heavy and two light.
Heavy chains identify the class of antibody (G, A, M, E or D).
Each chain has a constant region (C) and a variable (V) region.
Antigen reacts to the variable region.
The variable region can change in response to the antigen.
The macrophage introduces antigen to the variable region.
TYPES OF ANTIBODY
First immunoglobulin to appear after exposure to antigen.
Indicates new infection.
Big, can not cross placenta
Naturally occurring IgMs against A and B blood antigens
Small in molecular weight
Only produced in large amount during the secondary immune response.
(The secondary immune response is after immunological memory has taken place)
The more exposure to antigen, the more IgG.
Crosses the placenta.
Acts as an opsin (coats the bacteria so it is easily phagocytized.
Found in secretions (mucous, milk, eyes, sweat, etc.).
Offers primary protection
Is protected from digestive enzymes.
Is proceeded by IgM.
Only a small amount in serum.
Usually found in tissue attached to Mast cells.
Mediates allergic reactions.
Important in fighting parasites.
Systemic release can cause anaphylactic shock.
Not released into serum or body fluids.
Found on B-cell.
Helps the B cell become antigentically active.
Also known as thymus derived lymphocytes or cellular immunity.
In the blood, T-cells make up 60-70% of peripheral lymphocytes.
Also found in lymph nodes and spleen.
Each T-cell is programmed to recognize a specific cell-bound antigen by means of an antigen-specific receptor site on the T-cell. It is like antibody that is attached to a cell Vs antibody that circulates freely (as in humeral immunity).
All T-cells have CD3 sites. CD3 sites do not bind antigen, but they send a signal into the nucleus of the cell after antigen is bound to the cell. The CD3 cite is just one of many T-cell receptor cites (TCR).
T-cells have a number of other receptor sites that enable scientist to distinguish different types of T-cell with different functions. The two you have heard the most about are CD4 and CD8, but there are many more TRCs.
CD4 (helper, the conductor of the orchestra, the master regulator) is expressed on about 60% of mature CD3 T-cells. When antigen if presented to the CD4 cell, the CD4 site binds to the antigen presenting cell (class II major histocompatibility complex (MHC)), often a macrophage. CD4 cells secrete cytokines that influence every type of cell in the immune system (other T-cell, B-cell, macrophages, and natural killer cells). There are two major subsets of CD4 cells that secrete different types of cytokines.
T1-facilitaes delayed hypersensitivity, macrophage activation, and IgG antibodies.
T2-facilitaes other classes of antibodies
CD8 (cytotoxic) expressed on about 30% of T-cells. CD8 T-cells bind to class I MHC molecules.
Secrete cytokines similar to the T1 type but they mostly act as cytotoxic cells.
T-cells need two signals for activation. Signal 1 occurs when TCR comes together with MHC bound antigen. Coreceptors CD4 and CD8 enhance the signal.
Signal 2 occurs when another site (CD28) on the T-cell is activated.
When there is NO signal 2, T cells undergo apoptosis.
NATURAL KILLER CELLS (NK)
10-15% of blood lymphocytes. Do not have T-cell receptors or surface immunoglobulin. Have the ability to lyse many tumor cells, virally infected cells without previous sensitization. CD16 and CD56 are surface markers that are used to identify NK cells. NK cells have the ability to lyse antigen coated target cells (antibody-dependent cell-mediated cytotoxicity). NK cells do not kill normal cells because all nucleated normal cells express class I MHC and these cells send inhibitory impulses to the NK. If the cells in changed by a virus or a tumor, the inhibitory signals are blocked and the NK cells begin the attack.
CYTOKINES (messenger molecules) also called lymphokines
Can be produced by different types of cells.
Wide spectrum of effects
Many different types
Cytokines that mediate natural immunity, protect against viruses
Cytokines that regulate lymphocyte growth, activation and differentiation.
Cytokines that activate inflammatory cells.
Cytokines that effect lymphocyte movement. Also called chemokines.
Cytokines that stimulate hematopoiesis. Colony-stimulating factors.
In general, cytokines act as autocrines, paracrines and endocrines. Several cell types can produce the same cytokines. The effects of cytokines are pleiotropic (they can act of many different cells and do a variety of different things. They mediate their effect by binding to receptor sites on target cells.
Today we use cytokines therapeutically. For example anti-tumor necrosis factor (TNF) is used to treat some autoimmune diseases, and interferon is used to treat cancer.
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) In humans also known as HUMAN LYMPHOCYTE ANTIGEN (HLA). MHC is really a group of genes that code for antigens. All cells contain antigens. Because the antigens on your cells are slightly different from the antigens on someone elseís cells, you are distinctly different from everyone else in the world. The immune system has to be able to determine between you and someone else; it has to recognize self from non-self. In order to understand graft rejection and autoimmune diseases, you have to know something about the MHC.
There are three classes of genes in the MHC. Class I and II genes code for antigens (proteins) that are displayed "present" on the surface of cells. In the immune response, the very first thing that has to be done is to present the antigen to cells of the immune system. Remember that cells can not recognize an antigen unless it is presented to them properly. Class III MHC codes for proteins important in inflammation and will not be discussed here.
MHC class I
Found on all nucleated cell types.
These are usually endogenous antigens; intracellular antigens. Normal cells display samples of their intracellular proteins on their surface for surveillance by immune cells. When a cell changes (cancer) it will display different proteins on its surface to be hopefully recognized by immune cells. Viral antigens are a common source of foreign MHC classes I antigens. Cytotoxic T-cells can only recognize an antigen if it is physically bound to a MHC class I molecule. (Cytotoxic T-cells are class I restricted).
MHC Class II
MHC class II is used to present antigens obtained from extracellular sources. These cells (class II MHC) have to have the ability to engulf the antigen. Therefore such cells would be macrophages, dendritic cells and B-cells. CD4 cells (helper cells) are class II restricted because they can only recognize antigens in the contents of class II molecules. Therefore the helper T-cell doesnít go around attacking your own cells.
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