Inflammation+and+the+Immune+Response

= __ Week 1 - Inflammation and the Immune Response; Brought to you by Johanna..... __ =

1. Describe the major cell types involved in immune and inflammatory responses the body and their response to biochemical mediators and antigens that activate the systems (ie WBC, NK, antibodies, CD4 or T4 vs CD8 or T8 cells..) JOHANNA

First of all, we must examine the immune and inflammatory responses (and all they key players involved) as part of a bigger picture. I say this because the immune system also includes barrier defenses, such as the skin and our mucous membranes. The skin is the first line of defense against pathogenic microorganism. It is only once these organisms break through this barrier and enter the underlying tissue that the cellular defenses go to work. Let's take a look at these cellular defenses now.

__**Major Cell Types Involved in the Immune and Inflammatory Responses**__

Leukocytes, or WBCs, are the key components of the immune response. There are two different kinds of leukocytes; lymphocytes and myelocytes. Lymphocytes are the T cells, B cells, and Natural Killer cells. Myelocytes include neutrophils, basophils, eosinophils, monocytes, and macrophages. So, what exactly do each of these guys do during invasion?

**//Lymphocytes//**

Lymphocytes account for 25% of white blood cells. There are actually three different types of lymphocytes; B cells, T cells, and Natural Killer Cells. All three types have slightly different functions. B cells are responsible for making antibodies to foreign materials such as bacteria and viruses. Antibodies are little chemicals that are custom designed to attack specific chemical markers on the outside of the target. When an antibody attaches to an invading cell, it triggers a sequence of reactions that enable your body to kill the invader. T cells come in two different types, CD4 and CD8. CD4 cells can be thought of as coordinators and facilitators of an immune defense against a virus or bacteria. CD4 T cells are the troops that go in and actually make the kill. Of course, this is a gross oversimplification. The details of T cell functioning is quite complicated and well beyond the scope of this study guide. lol. Interestingly, it is the CD4 T cells that are the primary immune cell damaged in HIV/AIDS, allowing infections to successfully attack the infected person.

//T cells://

the T cells are programmed in the thymus gland and provide //cell-mediated immunity//. There are 3 different types of T cells; Effector or cytotoxic T cells, Helper T cells, and Suppressor T cells.


 * Cytotoxic T cells are found dispersed throughout the body. They are very aggressive against non-self cells, and realease a chemical called cytokine that can either directly kill the non-self cell or mark it for destruction by a phagocyte. (a cell that can engulf and then "eat" another cell) This marking of the non-self cells by cytokines can in turn elicit an inflammatory response.
 * Helper T cells are attracted to the chemicals involved in immune activity (such as the cytokines) and they work by attracting other lymphocytes to wherever they're needed.
 * Suppressor T cells are like the regulators of the system. They keep the immune and inflammatory response from getting out of control, to the point that it could cause damage to our body. The Suppressor and Helper T cells sort of keep eachother in check, and the body's defenses stay nice and balanced.


 * //CD4 and CD8 Cells - two distinct types of T cells!//**

Clusters of Differentiation T and B cells display additional membrane molecules called clusters of differentiation (CD). These molecules aid the function of immune cells and also serve to define functionally distinct subsets of cells, such as CD4+ helper T cells and CD8+ cytotoxic T cells. The many cell surface CD molecules detected on immune cells have allowed scientists to identify distinct subsets of lymphocytes and study both the normal and abnormal developmental processes displayed by these cells. (Porth, ch. 13)

The CD4+ T cells ( sometimes referred to as T4 cells) are necessary for normal immune function, which is why HIV infection is so deadly. Usually discussions of CD4 and CD8 cells (sometimes referred to as T8 cells) revolve around describing the progression of HIV/AIDS, because the virus has an affinity for these specific components of the human immune system. Among other functions, the CD4+ T cell recognizes foreign antigens and helps activate antibody-producing B cells. The CD4+ T cells also orchestrate cell-mediated immunity, in which cytotoxic CD8+ T cells and natural killer cells directly destroy virus-infected cells, tubercle bacilli, and foreign antigens. The phagocytic function of monocytes and macrophages is also influenced by CD4+ T cells. Basically, the CD4 cells present the antigen to B cells, which in turn become activated and start making antibodies, while the CD8 cells work indirectly in the actual phagocytosis of infected cells.

The normal ratio of CD4 to CD8 cells in the body is 2:1. Measuring this ratio is instrumental in tracking the progression of HIV infection.

//B cells://

B cells are responsible for providing //humoral immunity//. Basically this means that when the B cell comes into contact with a specific antigen (bad guy protein) it morphs into a plasma cell. This plasma cell is like a little factory that makes antibodies against that specific antigen. These antibodies float around in the blood and react with their enemy antigen whenever it's encountered. When the antibody comes into contact with the antigen, it produces what is called the antigen-antibody complex. Once this occurs, the antibody suddenly presents a new receptor site that initiates a series of plasma proteins in the body known as the //complement//. The complement proteins are bad-ass. They form a ring around the antigen-antibody complex and basically punch holes in the cell membrane, which makes it burst and die. Not only do they destroy the infected cell, but they also attract phagocytes and release histamine. Histamine causes vasodilation, and this brings lots and lots of additional bloodflow to the area. Along with all this blood comes the components of inflammation.



//Natural Killer Cells://

Natural killer cells are large granular lymphocytes that are activated by the cytokines released from T cells. Basically, these guys are effective against tumor cells and cells that have been infected by viruses. (Individuals who are deficient in natural killer cells are very susceptible to viral infections like Herpes.) They're full of these little granules that contain chemicals called perforin and granzyme. These chemicals destroy the cell membrane causing apoptosis. (cell destruction and demise!)


 * //Myelocytes//**

So, what about the myelocytes? Myelocytes are not all the same. In fact, there are five different types of these white blood cells, each of which has a slightly different role to play in your immune defense. The five types of myelocytes are split in to two major categories, granulocytes and agranulocytes. The three types of granulocytes are: neutrophils, basophils and eosinophils. They are named granulocytes because they contain small vessels of enzymes in membrane-bound "packets". The enzymes contained in these packets are used by the cells to digest bacteria and other foreign materials. Under a microscope, the packets resemble grains of sand, hence the name granulocyte. NEUTROPHILS Neutrophils are the most common type of white blood cell. They account for about 65% of all white blood cells, and are also known aspolymorphonuclear leukocytes or a PMN for short. They are the primary defenders against bacterial and fungal infections. Neutrophils can be thought of as the "first responders" in an invasion of foreign bacteria or fungi. Infections are often diagnosed by looking at a total PMN count as it is commonly the first of the white blood cells to become more abundant in an infection. They are the major component in pus and are seen in any process that involves inflammation. BASOPHILS Basophil s are the least common type of white blood cell. They make up only about 1% of your white blood cells. The primary function of abasophil is to release a chemical known as histamine in response an infection. Histamine is a chemical that has many functions, but it is primarily responsible for initiating an inflammatory reaction. EOSINOPHILS The last type of granulocyte is called an eosinophil. They account for about 4% of your leukocytes. These white blood cells are used for two purposes. They are the primary defense against parasitic infections. They are also commonly elevated in cases of allergic reactions, such as hives, or even asthma related to allergies. MONOCYTES Monocytes make up about 6% of white blood cells and have a somewhat unique and interesting role to play in your immune system. Monocytes are rather long lived compared to other white blood cells. They travel around in your blood, looking for bacteria, viruses and other "waste" that needs removal. When they find something that needs cleaning up, they swallow the offending particle in a process known as "phagocytosis". After swallowing these bits, the monocyte will break the invader in to smaller pieces and present them on its cell surface so that passing T cells can "learn" more about the chemical make-up of the invader and make it easier to kill more of them. MACROPHAGES The last type of white blood cell is actually a modified monocyte. Some monocytes travel in to the tissues of your body, outside the bloodstream. When they do this, they transform slightly and become macrophages. The function of a macrophage is similar to that of a monocyte.




 * NORMAL ADULT WBC DIFFERENTIAL COUNT **


 * Cell Type || Percentage and Count ||
 * Neutrophils || 56% or 1800-7800 cells/mm>3 ||
 * Bands || 3% or 0-700 cells/mm>3 ||
 * Eosinophils || 2.7% or 0-450 cells/mm>3 ||
 * Basophils || .3% or 0-200 cells/mm>3 ||
 * Lymphocytes || 34% or 1000-4800 cells/mm>3 ||
 * Monocytes || 4% or 0-800 cells/mm>3 ||


 * __How the Inflammatory Process Works__**

When a cell is injured, a chemical called the Hageman factor is activated. The hageman factor activates three different systems; the kinin system, the clotting system, and the plasminogen system. Bradykinin was the first kinin to be discovered and is it remains the one which is best understood. Bradykinin causes local vasodilation which allows increased blood flow to the injured area, allowing white blood cells to escape into the injured tissues, leading to inflammation. It also stimulates the nerve endings to cause pain, which alerts the person that they have been injured. Additionally, bradykinin is a precursor to some other cool substances that cause an inflammatory effect on the injured area. These substances include prostaglandins, leukotrienes, and thromboxanes. Prostaglandins and leukotrienes both have a vasodilating effect and enhance the inflammatory reaction, while thromboxane is actualy a vasoconstrictor that facilitates platelet aggregation (clotting).

Injury to a cell membrane also causes the release of histamine. Histamine also causes vasodilation, which aides WBCs in getting to the injured area in order to incite the immune response.

The clinical manifestations of inflammation are pain, swelling, redness, and heat.


 * __Drugs Related to the Immune and Inflammatory Responses__**

i. Rituximab For some reaosn my palm pilot lists this as a less commonly used drug. It is a monoclonal antibody, the usual indication to treat "relapsed follicular B-cell non-Hodgkins lymphoma. It works by inducing the killing (apoptosis) of B-cells, either malignant or not. The usual adult dosage is 375 mg. via IV once weekly for four weeks. ii. Celebrex Celebrex is an NSAID and non-opioid analgesic. It is also classified as a COX 2 enzyme blocker. It's typically used to treat rheumatoid and osteo arthritis, but I've personally found it to also be great for hangovers. :) The COX 2 enzyme is activated during inflammation and causes all of the clinical inflammatory manifestations listed above. The usual adult dosage is 100-200 mg PO bid.

iii. Cyclosporin This is an immunosuppressant. It's used as a prophylaxis for organ rejection in kidney, liver, and heart transplants. However, it can also be used to treat severe rheumatoid arthritis and psoriasis. It works by inhibiting immunocompetent lymphocytes, specifically T-helper and T-supressor cells. The dosage varies greatly dependent upon the indication. iv. Aspirin Aspirin is a salicylate. It treats mild to moderate pain or fever and is also an anti-inflammatory. It inhibits the production of prostglandins, which is how it reduces inflammation. It also blocks the effects of pyrogens at the hypothalamus, reducing fever, and inhibits platelet aggregation. It can be given orally or rectally. Usual dosage for adults is 325-650 mg.

v. Ibuprofen Ibuprofen is an NSAID. It can be used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, to relief mild to moderate pain, and to reduce fever. It works by inhibiting prostaglandin synthesis, and is an oral medication. Usual adult dosage is 400 mg q4-6hrs. vi. Acetaminophen Acetaminophen (Tylenol) reduces pain and fever, but not inflammation. So, I don't really know why it's on this list, but I regress. It can be used to treat the pain associated with arthritis or rheumatic disorders, so I guess that's why. Anyway, it works on the hypothalamus to cause vasodilation and sweating which in turn reduces fever. It's pain relief mechanisms are not fully understood. This is an oral or rectal drug and the usual adult dosage is 325-650 mg q4-6hrs. DO NOT EXCEED 4G/DAY! vii. colchicine I found this online; this drug wasn't listed in my palm pilot. This seems like a pretty decent explanation of how the drug works, though.

In gout, uric acid crystals are deposited in the joints. Immune cells called leukocytes try to engulf the uric acid crystals, which they recognize as foreign. The leukocytes then become hyperactivated, and they release inflammatory agents that cause the characteristic joint damage (and pain) associated with gout. In order for the phagocytosis to occur, the leukocyte cell has to drastically change its shape to be able to engulf the uric acid crystals. Cytoskeletal elements called microtubules must dissemble and reorganize to allow the leukocytes to do this. Colchicine inhibits this reorganization of the microtubules, and thus prevents phagocytosis of the uric acid crystals by leukocytes. To sum it up... Colchicine = no microtubule reorginization = no phagocytic immune response to uric acid crystals = no inflammatory agents released in the joints = no joint pain. Note that colchicine only relieves pain, and does not actually CURE gout. vii. benadryl-first generation antihistamine Benadryl is the classic and most widely used antihistamine. It works by competitively blocking the effects of histamine and the H1 receptor sites. It also has sedative-like effects. Benedryl and LOTS of uses, most of which are associated with mediating the allergic response, such as with allergic rhinitis, conjunctivits (itchy eyes), and puritic skin conditions caused by allergens. It can also be used as a mild sleep aid. The usual adult dosage is 25-50 mg q4-8hrs.