The immune system 2: ACQUIRED IMMUNITY

This form of immunity is "learned" as you go along in life. Immunity can be "active"whereby your own immune system makes the cells and substances necessary for a response, or "passive" whereby preformed immune substances are provided for you. There are four main ways immunity can be acquired:

• Natural (active) immunity results from exposure and recovery from infection
• Natural (passive) immunity results from a transfer of antibodies from mother to infant.
• Artificial (active) immunity results from vaccination against disease
• Artificial (passive) immunity results from the administration of immune serum or cells

The specific immune system has FOUR important features:

It can tell the difference between self (you) and a bug It is important that your immune system knows 'who you are'; if it fails to recognize this it could attack the very body it is designed to protect! This sometimes happens and results in autoimmune responses. (Immunologists call a bug or parts of a bug an antigen. For our purposes we will use the term antigen when referring to a substance that causes an immune response but note that this is not always true).

Specificity: The immune system must be able to tell different bugs apart from one another. For example, it can tell the difference between influenza (a virus) from a yeast infection (a fungus).

Memory:it is critical that the immune system can remember bugs once it has met them. Once your immune system remembers meeting a bug it recognizes and reacts much quicker the second time it meets them. This is the basis of the "booster response."

Diversity: your immune system produces an almost limitless supply of cells (clones) and substances that are "designed to fit" just about any bug that comes its way.

White blood cells called B and T lymphocytes are responsible for these four important features. In a healthy adult about 25-30% of WBCs are lymphocytes.

The specific immune system has two arms:

• Humoral immune response(antibody-mediated)
• Cell-mediated immunity (CMI)

Antibody-mediated immune responses

Involves B lymphocytes which mature in the bone marrow. When B cells meet a foreign invader it is stimulated to divide and becomes a protein factory called a plasma cell. The plasma cell produces a specific antibody that binds to a specific part of the invader (antigen), marking it for destruction by macrophages or the complement system.

Some B cells become memory cells. Memory B cells divide and produce antibody rapidly upon a second encounter with the antigen. This is the basis of the booster response. Effector plasma cells are like money in your checking account; they provide a source of ready cash (antibodies) that you can use right away. Memory cells are more like a savings account that you draw on for future needs.

Antibodies: "lobsters of the immune system."

Also known as immunoglobulins, antibodies are proteins that inactivate antigens, including viruses, and flag microbes that are not inside cells for destruction. Note: once a bug is inside a cell it's really hard for an antibody to get to it. This is one reason antibodies don't work very well against HIV-infected cells.

Each antibody is a Y shaped molecule consisting of 4 protein chains held together by chemical bonds. There are two identical long heavy chains and two identical short light chains. The stem of the Y is made only of heavy chains while the arms of the Y are composed of both types of chains. The form of an antibody is like the body of a lobster. The arms of the antibody molecule act like lobster claws; they grasp hold of their food (antigen) so it can be eaten (phagocytosed by WBCs). Each antibody is specific for a given antigen. Each type of antibody is made by cells from the same clone. It is thought that each individual has between a million to a billion different types of lymphocyte clones!

Humans have five different types of antibodies which are given shorthand names. Each type of antibody serves a particular purpose.

IgA Also known as secretory antibody as it is found in tears, saliva and on the surface of mucus membranes. It is also secreted into breast milk and is very important in providing the newborn with passive immunity against gut and respiratory tract infections (see the Scientific American, August 1995 article on the importance of breast milk).

IgD Found on the surface of B cells, it assists B cells in recognizing antigens for which they are specific.

IgE Plays a role in allergic reactions. In the presence of antigens IgE triggers WBCs called basophils to release allergy-producing chemicals such as histamine. IgE also helps eosinophils recognize and kill parasites.

IgG This class of antibodies is really busy and is produced in large amounts in secondary immune responses. IgG coats microbes, including viruses, and targets them for phagocytosis by macrophages and neutrophils. IgG also activates natural killer cells. IgG is the only class of antibodies that can cross the placenta and is important in providing passive immunity to the newborn.

IgM This class of antibodies is like the sea star of the immune system . Sea stars have five arms. Likewise, IgM has five arms; each arm is an antibody unit joined by a special kind of link and each arm has two hands. Hey, five arms are better than the usual two which means that IgM can trap a whole bunch of bugs! IgM is the first class of antibodies that is produced when the immune system first meets a microbe. Many diagnostic tests that determine whether or not you are infected with something are actually measuring a rise in this kind of antibody. This rise, if significant, is called seroconversion.

Cell-mediated immunity (CMI)

Involves T lymphocytes and their products (cytokines) and not antibodies. CMI is important in immunity to intracellular microbes (bacteria, viruses, parasites) and cancer. CMI is also important in transplantation reactions.

T cells are also formed in the bone marrow but they track to the thymus gland located under the breast bone. The hormone thymosin helps educate T cells to express surface markers. These markers determine what jobs the cells will be responsible for. T cells that have been assigned jobs are called immunocompetent. The full complement of different T cells is analogous to the tiles of a scrabble game. There are set number of "p's, a set number of "q's and so on.

In the thymus cells that have a potential to react with the body and cause autoimmune damage are usually eliminated (negative selection) by apoptosis while those with little or no self-reactivity survive (positive selection).

After birth the thymus decreases in size and significantly so at puberty. After puberty the largest reservoir of lymphocytes is in the peripheral (secondary) lymphoid organs which include the lymph nodes, spleen and lymphoid tissue of the gut, respiratory , reproductive and urinary tracts. In these sites immune cells come in contact with various antigens.

How T cells carry out an immune response:

T cells need 2 signals to become activated

• T cells identify "self" by means of a cell surface protein (a "dog tag") called a major histocompatability complex (MHC) marker.
• T cells possess T-cell receptors (TCRs), rather than antibodies, on their surface which function in antigen recognition. T cells can only respond to foreign antigens exposed on the surface of an antigen-presenting cell (typically a macrophage) in that are in close proximity to an MHC marker.
• Upon contact with antigen T cells become activated and stimulated to divide and some form memory T cells . Formation of memory cells following the first exposure to an antigen increases the size of the original clone (clonal expansion). Memory cells act much more quickly if the antigen is re-encountered and their response lasts longer. The most effective vaccines take advantage of this memory response and "boost" the immune system.
• In addition to T-cell receptors, T cells have additional proteins on their cell surface which are grouped into clusters of differentiation markers (CD markers). These proteins bind to specific sites on target cells and are critical in regulating immune responses. The CD4 marker on T helper cells and macrophages is used by HIV to gain access to these cells.

Effector T cells release chemical regulators called cytokines.

Cytokines are proteins produced by immune cells affect the behavior of other cells. Cytokines are the chemical language and messengers of the immune system; they act on specific receptors on target cells, stimulating and suppressing immune responses as needed.

Cytokines can be grouped into three main families:

• Interleukins: These chemicals signal "between white blood cells or leukocytes". Up to 18 distinct interleukins have been identified to date, probably more are on the way!
• Interferons: These chemicals are released by certain immune cells in response to cancer, parasitic and viral infections. Interferon that is released by virus-infected cells diffuses to uninfected cells. Uninfected cells are stimulated to make antiviral proteins that prevent viral replication. Humans make three major forms of interferon. Gamma interferon also stimulates macrophages to carry out phagocytosis.
• Chemokines: These are small cytokines that control the migration and activation of other cells, especially phagocytic cells and lymphocytes. They play a central role in inflammatory responses. Chemokines called MIP-1a, MIP-1B and RANTES act to keep white blood cells at the site of an infection and may also help prevent entry of HIV into cells. The receptor for these chemokines is found on the surface of macrophages. This receptor, known as Chemokine receptor-5, is the co-receptor used by HIV to gain entry into macrophages. Chemokine receptor-4 is the co-receptor used by HIV to gain entry into T cells. Other chemokine receptors used by HIV have since been identified on other cells.

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There are numerous subsets of T cells

• T helper cells 1 (Th1 subset): Th1 cells carry the CD4+ surface marker. Th1 cells secrete cytokines that regulate cell-mediated responses such as IL-2 and gamma interferon. IL-2 is a particularly important interleukin and used to be called T-cell growth factor as it stimulates production of more T cells. IL-2 is given therapuetically to some people with HIV disease in an attempt to restore depleted T cells.

Macrophages can not destroy microbes that they have eaten unless they are activated by a Th1 cell. Th1 cells recognize foreign antigens on the surface of a macrophage and in turn the CD4+ marker of the T cell binds to the MHC class II marker of the macrophage. This binding activates the T cell. Newly formed T cells release gamma interferon which in turn activates the macrophage so that it can kill the microbes within.

By the production of IL2, Th1 cells also activate killer T cells to destroy virus-infected cells and tumor cells.

• T helper cells 2 (Th2 subset): These cells also carry the CD4+ marker. Th2 cells secrete cytokines that regulate antibody responses such as IL-4, IL-5 and IL-6. These cytokines cause B cells to differentiate into antibody-producing plasma cells and memory B cells. Th2 cells also take part in inflammation. In general the functions of Th1 and Th2 functions are antagonistic, i.e., one type of cytokine suppresses the function of the other type.

In general B cells can respond to a microbe only if instructed to do so by Th2 cells. The Th2 cell recognizes the antigen-MHC II complex on the B cell via its T cell receptor and CD4 marker. The activated T cell releases the cytokines mentioned above and also binds to the CD40 marker on the B cell. Binding to CD40 allows the helper T cell to activate the B cell and, B cells differentiate into antibody-producing plasma cells and memory B cells.

• Cytotoxic T cells (CTLs): Also known as killer T cells, these cells carry the CD8 surface marker. These cells function similarly to NK cells in that they directly destroy some virus and cancer-infected cells upon contact. However, CTLs must recognize antigen on the surface of an antigen presenting cell via an MHC class I marker, they must mature in the thymus and they act specifically on their targets.

As mentioned, Thelper 1 cells can activate CTLs and cause them to divide. Activated killer T cells then attach to their targets and like NK cells, release perforins and fragmentins. The fragmentins act on the cells proteins and genetic material and drive the cell to commit suicide (see the Scientific American Article on programmed cell death)

• Suppressor T cells: These T cells carry the CD8 marker and suppress the responses other T and B cells.

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