Immunology Primer, Part 1, Text THIS IS A DRAFT ONLY. Part II: An Immunology Primer Immunology is the study of the body's natural defenses against invaders like bacteria, fungi, viruses and cancers (when your body's wn cells stop functioning normally and start to make many, nonfunctional copies of themselves). Immunity to a parasite of some kind is most effective when the body first recognizes that there is something attacking bodily tissues and then, without causing life threatening damage in the process, can eliminate the parasite. Sometimes, the body settles for next best and tries to control the offender, leading to chronic (ongoing) disease which may be very damaging or even deadly after many years. HIV is an example of this as is, say, an uncleared infection by the hepatitis B virus. In many ways, this is a very new science with an explosion of information and deeper understanding occurring over the last 10-20 years. Still, there is much, much more to learn. Every day brings new insights. Organs of the Immune System There are many organs in the immune system. The first is your skin (the body's largest organ). This is a natural, protective barrier to many critters that might like to make a meal out of you or use your body as an orgy site to reproduce like crazy. The sites where "bugs" get in most readily are all the orifices: your mouth, nose, ears, eyes, genitals and anus (or cuts in the skin). At these entry points, there are a variety of different cells that act as defenders. The lymphatic system is a major immune system component. One of the early signs of HIV (and other) infections is swollen lymph nodes. The nodes become swollen when the body is trying to fight the infection. These nodes are masses found where many of the vessels that make up the lymphatic system converge. They are found throughout the body but are particularly noticeable in the neck and groin area. The lymphatic system, like blood vessels, carries lymphatic fluids around the body. Lymph fluid is a clear liquid composed of cells called lymphocytes (T and B cells) and other molecules like proteins (albumin for examples), salts, water and other substances. The system spreads throughout the body, much like the veins and arteries that carry blood. Lymph vessels found around the intestines sometimes takes on a milky color due to the fats that wind up in it. Other organs of the immune system include the thymus, tonsils, adenoids, bone marrow, the spleen and Peyer's patches (found in the intestines). The thymus is a gland found in your upper chest. This gland is where T-cells are guided into becoming either CD4+ cells ("T cells") or CD8+ cells. The spleen is a blood storage and filtering organ. It serves as a source for the formation of new cells if the bone marrow isn't up to par. The intestines are filled with Peyer's patches (collections of lymph nodes) and lymph vessels. In fact, what is known as Gut-Associated Lymphoid Tissue (GALT) is thought to be an important site for HIV activity, resulting in damage to the tissue. GALT is a system that includes the Peyer's patches and the lymphoid-tissue-packed appendix. (Some immunologists include the tonsils and lymph nodes as a part of GALT). This may be part of the reason nutritional deficiencies begin early. Finally, the bone marrow produces a great deal of brand new cells that will evolve into the many different cells types your body needs for its overall structure and its many functions. Cells of the Immune System The various immune system cells are all derived from the marrow of your bones. Bone marrow is an active factory of "stem cells" that then evolve into a variety of types. Stem cells are identified by a marker known as CD34. The cells then follow one of three developmental pathways and become: red (erythrocytes) and white (leukocytes or everything else). Platelets--the cells that help blood coagulate--are the third. Platelets are derived from cells called megakaryocytes. White blood cells are sometimes divided into two categories: those that contain little granules inside them (granulocytes) and those that don't. Granulocytes are then differentiated between neutrophils, eosinophils and basophils. The non-granulated cells include monocytes/macrophages and lymphocytes (which include T- and B-cells). Each of these cells has its own particular function(s). (See the Table of Cell Types at the end of this section). A very important immune system cell type is the natural killer cells (NK cells), which usually express CD16 and/or CD56 (see the discussion below on the meaning of the CD designations). These cells are poorly understood but play an important role in controlling neoplasms and bacterial infections (of particular note, mycobacteria). CD16 is expressed on cell types besides NK cells whereas CD56 is restricted to NK cells. They are not MHC-restricted and usually are CD3- (i.e., they have no T-cell receptor). How they identify and kill target cells is still unknown. This is why they are known as part of the non-specific immune system. Circulating NK cell count is higher in the early morning and lower at night. This holds true for asymptomatics, while people with AIDS tend to show a somewhat decreased rhythmicity. These alterations are not as severe as those seen in the rhythms of circulating T and B cells. (Bourin, 1993). Neutrophils are another cell type that often express CD16. People with AIDS have a substantial reduction in numbers of cells that do express it compared to controls. This may partly explain some of the altered functions that can lead to bacterial infections. (Unkeless, 1990). (Neutropenia--a reduction in circulating neutrophil numbers--is a hallmark adverse event associated with use of some drugs like AZT.) The Different Types of Immunity There a number of different interlocking ways the body has to respond to pathogens (things like bacteria, viruses or fungi that may cause disease). The front-line defense is known as innate immunity. This involves natural killer cells as well as the "big eater" cells or macrophages (or the cells that become macrophages, monocytes) which gobble up uninvited guests. It is not very specific but is the first to recognize things aren't quite right. Collectively known as professional phagocytes (or "cells that eat"), these include cells like neutrophils and eosinophils. The mechanism that these cells use to ingest foreigners is known as phagocytosis. This includes a more general, nonspecific response. This response doesn't require antibodies or other identifying marks. Along with this, these cells also release molecules called complement which is a sort of relay race that winds up punching holes in enemy organisms. This initial fast and deadly response is highly variable and NK cell function is marked as much by the local milieu of hormones as the conditions of the host. As Jan Klein puts it in Immunology (Blackwell Scientific Publications, 1990:406): The NK cell response is influenced by a wide variety of factors such as steroids, stress-related neuropeptides, exercise, smoking, alcoholism, diet, and the pre-existing disease state. The NK cell response therefore depends to some degree on the emotional or the physiological state of the patient at the time of infection. After this first line of defense, a set of responses that are able to identify specifically the particular trouble makers, whether it is a foreign infection or the body's own cells misbehaving (e.g., cancer). This type of immunity is known as acquired immunity. The cells that accomplish the elimination of infection or correction in the body's functioning fall into two categories, humoral and cell-mediated types of immunity. The cells that perform these activities are further divided into naïve, effector and memory cells. Naïve cells don't quite know what to expect but are ready to go into action if they find themselves recognizing danger. When danger is seen, they rapidly make many copies of themselves (known as clonal expansion) and become effector cells. These either help the body to clear pathogens or do the dirty work themselves of killing infected or aberrant (misbehaving) cells. Once the danger is past, most will commit suicide. The rest will kick back into a semi-retirement, old hands known as memory cells. These will remain vigilant for a possible reintroduction by the offending pathogen. One of the first specific responses starts with the antigen-presenting cell (APC). Such cells as macrophages, neutrophils or dendritic cells engulf and cut up an invading bacteria, virus etc. Sometimes, the pathogen is processed (chewed up inside the cell) and a little piece (or antigen) is displayed on the cell's surface. The antigen is embedded in a molecule called the major histocompatibility complex (MHC). The MHC transports the antigen to the cell's surface where it is "presented" to T-cells. Then T cells come along and hook up with the MHC which is sticking out on the APC's surface. At this point, the T cells are then activated to look for pathogens. The hooking up process to the MHC is done by a complex of proteins called a T-cell receptor (TCR). The TCR is associated with either the CD4 or CD8 molecules. Class I MHC activates T cells that have a TCR working in conjunction with the CD8 protein; MHC class II join up with a TCR associated with CD4. Note that MHC is the broader word for human leukocyte antigen (HLA). Mice have their own MHC; the human form is specifically referred to as HLA. This is the same molecule referred to when people have a bone marrow transplant, say, and they have to have a "matching" tissue type. (PICTURE NOT YET AVAILABLE ON INTERNET VERSION) Of course, not all infections are created equal. Some stay outside cells (extracellular). Some bacteria and fungi hang out in the spaces between cells, eating and replicating in tissues. Others, like viruses and other bacteria, get inside cells (intracellular). Viruses hijack your cell's genetic machinery to make more of themselves. The immune system has, broadly, two different arms to deal with these. One is called humoral immunity and the other cell-mediated immunity. Humoral immunity is mobilized to arrest extracellular infections mostly. The antibodies secreted by B-cells attack these extracellular infections. Cell-mediated immunity (CMI), by and large, is conducted by cytotoxic T-cells that identify and destroy infected cells. While B-cells get their name from being derived from bone marrow, precursor cells that eventually become T cells also arise in the bone marrow. However, T-cells must pass through an organ in the chest called the thymus to mature. The T and B cells constitute what is known as the specific immune response. There are billions of different clones of T and B cells. Each clone has a slightly different configuration of proteins on its surface, and has the ability to respond to one unique pathogen (unwanted invader). This very specific and flexible response makes this a very powerful system. The first time an enemy is encountered, the response is called the primary immune response. Then, should the offending invader try to crash the party again, the body is ready to quickly respond with the booster or secondary immune response. These different arms of the immune system allow us to recognize and to eliminate, or at least control, infectious microorganisms that live within differing body compartments. Antibodies are produced by B-cells (possibly found on your lab work under the classification of CD19 or CD20). Antibodies are effective against certain soluble toxins released by pathogens, as well as against some types of bacteria which live outside cells, or that in some phases of the infection are spread in the bloodstream. Likewise, parasites like various worms, which are much more complex, also induce an antibody response against their secreted byproducts. These are activated by the MHC-II/CD4 interactions. Once the rather small B-cell is activated in this way, it begins to transform into a larger cell called a plasma cell. With the stimulation of the cytokine IL-6, it begins to secrete antibodies. There are five different classes of antibodies (or immunoglobulins), including IgA, IgD, IgE, IgG and IgM. Many microbes, by hiding inside cells, are impossible for antibodies to reach. Hepatitis, herpes viruses, Mycobacteria and HIV for example, once inside cells, can only be eliminated by killing the infected cell. When pieces of the microorganism (antigens) are moved from the interior of the infected cell and presented on the cell surface for recognition by other immune cells. This leads to the stimulation of cytotoxic (cell-killing) CD8+ T helper (Th) lymphocytes known as CTLs. Thus, some believe the increase in CD8 counts in HIV is at least partially a good thing. It may be indicating the body's attempt to compensate, killing infected cells. To the extent that infected cells are thus killed (and not uninfected ones), this is probably a good thing. This immune response, the cellular or cell mediated immunity (CMI), is induced by MHC class I interactions with CD8 cells. The problems are when either uninfected T cells are targeted for killing and/or if there are too many infected cells to keep up (as work by various researchers suggests). Natural killer (NK) cells are involved in another type of immune response called antibody-dependent, cellular cytotoxicity (ADCC). In ADCC, effector cells recognize a foreign body that's been opsonized (or "buttered" with antibodies), whereupon they kill the target cell. While some have discredited ADCC as a role player in killing HIV-infected cells, one lab remarked on a common epitope that was "recognized" (in a non-MHC-restricted fashion) by CD16+ NK cells. (Kurth, 1990). An epitope is the specific piece of an antigen that is recognized by the T-cell receptor. (A paratope is the site on an antibody where the antigen binds). The experiment was in the test tube using laboratory strains of HIV, which sometimes bare little resemblance in their activity to the HIV found in people (also known as primary isolates). In this experiment, the lab isolates used were IIIB and RF. Another lab (Rinaldo, 1990) showed a similar CD16+ mediated ADCC that was suppressed with progression. And further still, Dr. Luc Montagnier's lab also found evidence that ADCC play a role specifically targeting cells that have HIV envelope proteins (gp120 and gp41) associated with them. (Montagnier, 1990). Still other researchers have had similar observations. (Bolognesi, 1989). Finally, there is yet one more way the immune system responds. This is called delayed-type hypersensitivity (DTH). This is the kind of immunity seen when one rolls around in poison ivy. Nothing happens right off the bat. But with several hours, places where your skin came into contact with the leaves responds with a red, itchy rash. Tests for TB use this idea to see if your body has already been exposed to it. Anergy panels are the tests used to assess the body's ability to respond to a variety of different infections. See the comments at the very end of How To Monitor Your Bloodwork.

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