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Sock's Rheumatoid Arthritis Links - RA

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The major source of TNF-alpha are the macrophages,plentiful,active cells that move around the joint tissues. These macrophages normally, recognizes  foreign  invaders such as bacteria and viruses as foreign. They alert the T cells so that the T cells will turn on or off,in opposition to the foreign invaders. What happens is that the macrophages misreads the bar code, causing the T cells to misinterpret the recognition "message" or signal. The result of which,the natural antagonist, that normally control the level of TNF  in our body is unbalanced, resulting in excessive cytokine production.
In essence,what is happening,in disesase state, is that the  macrophages, carrying these foreign fragments,called antigens,come in contact with special kind of white blood cells,the T cell. This meeting stimulates the T cells to make cytokines that attract other T cells and macrophages to the site.  Soon there is an abundant supply of TNF-alpha coming from the macrophages,whcih can transform joint cells to divide and destroy In addition,TNF alpha induces other cells in the area to make inflammatory cytokines,like interleukin-1 (IL-1) and interleukin-6 (IL-6). The resulting pannus tissue in the synovium,eats away cartridge and causes damage (erosions)  to bone .
Joint damage is caused by inflammation in the synovial membrane. This normally,thin,synovial membrane becomes inflamed with cells called lymphocytes,macrophages,polymorphs and fibroblasts (white blood cells). This,now, thick,inflamed synovial membrane is called a pannus. The cells within the pannus become activated and release enzymes and chemicals (cytokines) that both permanently damage the cartilage and bone,and also attract more cells into the inflamed tissue. In rheumatoid arthritis,this inflammatory process is like a one-way highway;the inflammation can continue indefinetly causing more and more,damage,possibly leading to joint destruction and deformity.
Ths inflammatory process is part of the body's immune system. The immune system is a natural defense against invaders such as bacteria and virses,even cancer. The cells of the immune system recognize and respon to invaders either by making antibodies to combat invaders or by attacking invaders directly.
Althugh the immune system is normally activated by a foreign  agent,it can be activated to attack normal cells. In RA,for unknown reasons,the immune system becomes activated and causes marked inflammation in the synovial membrane (linings) Many of the drugs used to fight RA have antibacterial and/or anti-immune system activity.

In the human fetus the full skeleton is fashioned first as clear,flexible cartilage. Within the core of the developing bones,the bone marrow;a soft,rich tissue; begins to form from masses of cells called stem cells,which migrate there from the young liver. These stem cells have the capacity to differentiate into each of the six kinds of blood cellls.
Most will become red blood cells that carry oxygen from the lungs to the tissues. Others follow different paths and become leukocytes,the white blood cells desogned specifically for the immune system some stem cells just make more stem cells,which remain in the bone marrow to supply populations of red and white cell's throughout our lifetime.
Of the various white blood cell types,the lymphocytes in particular need further preparation for their centrl role in the immune system. This is crucial so that not only will the lymphocytes be prepared to recognize foreign invading antigens, they also must be conditioned not to mistake as dangerous any of the cells of the body,the way they appear to do in RA.
They must be able to distinguish between self (any part of the body in which they are functioning) and nonself (anything else from outside the body). The lymphocytes must be able to recognize and fight bacterial cells,but not recognize and harm cells from the muscles or joints. This vital learning goes on in several sites.
A portion of the newly made bone marrow lymphocytes are sent off from the bone marrow through the blood stream like young students to study in the thymus gland. This gland teaches the young lymphocyte to become a specific type of mature lymphocyte,the crucially important T cell..
Cells communicate by means of chemicals. The T cells as well as other members of the immune system's cast of cells are sensitive only to very specific signals,i.e.,to specific antigens. They pick up those signals by means of protein receptors on their cell membranes.
The young T cells developing in the thymus gland in the chest will not survive unless they are exquisitively sensitive to nonself antigens.,but simply ignore self antigens. They are not supposed to recognize any of the body's own chemicals, particularily the proteins,as "enemy" but should recognize chemicals from any outside source as such.
One of the extraordinary aspects of this recognition system is that individual T cells,and also B lymphocytes (B cells) develop in such a way that each cell is capable of recognizing a different specific antigen out of all yhe literally millions of antigens that a person might be exposed to during a lifetime. We each have at least a trillion of them.
In addition to the T cell receptors (TCRs),most T cells also have co-receptors ,which assist in the recognizing of antigens. The T cells use yet another lock that requires a different key. Primed with those receptors and coreceptors,the T cells are ready to sense and attach to antigens.
The thymus now makes certain that these T cells will not react against self antigens. It must not allow the T cells to recognize the body's own tissues as dangerous and set off a damaging immune system response againt them.
Within the thymus the young T cells are exposed to samples of almost all of the antigens that the body carries,such as protiens from muscles,or kidneys,or cartilage. They face a tough test. The way in which each T cell responds seals its fate. If it recognizes any self antigens,such as proteins from the body's cartilage or muscles as keys that open up its padlocks,the T cell will wither and die. This is the fate of least 90 percent of the tested T cells.
The other T cells,which do not recognize self antigens,are allowed to leave the thymus and circulate in the blood for a few days,where they undergo some further selection to make sure the T cells are healthy,functioning cells that are not harmful to self antigens.
Then they take up residence in the lymphatic tissues and recirculate between the lymph and the blood. The T cells are always on the lookout for the keys that will fit their padlocks and stimulate them into a immune system response.
Meanwhile,other lymphocytes in the bone marrow undergo maturation into B cells. Rather than head for education in the thymus,these young cells confine their studies to the marrow,where they divide repeatedly and come up with a dazzling variety of B cells. Each B cell becomes capable of making one specific type of B cell receptor (BCR),each ofwhich matches one of the millions of antigens also recognized by the T cells.
Each B cell is capable as well of synthesizing one of the millions of unique antibodies that match and lock on to specific antigens.  In addition,the B cells can recognize many other antigens beyond those perceived by the T cells. As the B cells mature they are shuttled off to the lymphatic tissues throughout the body,ever on the watch for signs of danger in the form of antigens.
The initial immune response is the one in which hungry macrophages,waiting in the tissues,engulf the offending antigens,perhaps bacteria or viruses (we don't exactly know),and digest them. Physical damage to the tissue,as might occur in a would such as a laceration or when antigens are being ingested,causes cells to release a host of chemicals,including histamine and prostglandins.
Soon,these chemicals expand the diameter of the local blood capillaries. Other powerful chemicals prod white blood cells to squeeze out through the capillary walls and then lure them towards the nearby site of inflammation. Also, a specific type of white blood cell,the natural killer cells (NK cells) join the action,swarming in from the blood.
They are specialists in killing tumour cells,virus infected cells,and bacteria, parasities and fungi. NK cells are three times as common in their joints, compared to the general population.
Meanwhile,a witches brew of chemical messengers is being released by the feeding macrophages as well as other cells in the inflamed tissues. These are cytokines. At least 24 different cytokines may play a role in RA. Cytokines are the primary chemical messengers of the immune system :the language that the cells use to talk to each other.
The cytokines play a key role in developing and sustaining the response of the immune response. The biologic response modifiers fights the antigens with other weapons such as antibodies.
Here, in the body's first reaction to an attack,cytokines have wide-ranging effects. RA includes a persistent,prolonged activation of the early immune system inflmmatory response. The person with RA may experience a wide variety of harmful cytokine effects beyond joint damage throughout the body.
These effects may include anemia,difficulty sleeping skeletal muscle shrinkage pain,and fatigue. Meanwhile,after the early response,the immune  response escalates. Urgent messages arise from the inflamed tissues where the initial reactions are taking place. The answers to those messages are both the manufacture of antibodies against the invading antigens as well as the activation of the white blood cells that attack and destroy those antigens.
B cells make the antibodies. B cells are born in the bone marrow. Each day, about one billion B cells are produced in our bodies  They each have many protein receptors on their surface,the B cell receptors,which recognize only one kind of antigen per B cell. These receptors and the antibodies are very similar in structure. Antibodies come in five forms all based on the most common one,immunoglobulin G (IgG). the latter antibodies are literally Y-shaped molecules.
In order for B cells to be activated into pumping out antibodies,several things has to happen. First the B cell must somehow come in contact with the specific antigen it can recognize among all others.
This meetimg may take place in the various tissues of the body or when the antigens trickle through the lymph nodes. The nodes are those lumps of lymephatic tissue that acts as filters through which fluid returning from the tissues passes as it returns through the blood circulating system.
The waiting B cell receptors will grab onto the antigens to initiate the process of antibody formation. Often the antigen has already been recognized as dangerous and is covered with a coating of complement,a set of proteins that are always present in our tissues,ready to assist in our defense.
Now we have B cells primed and ready for action against invading antigens. but they can't act quite yet.
Here is where the T cells come into the picture. They must physically interact with the B cells in a process known as activation,so that the B cells can finally make antibodies, But before they can be activators,the T cells also need some preparation-they themselves need to be activated.
Earlier in the thymus gland the T cells were decorated with molecules on their surfaces,the T cell receptors and co-receptors-those padlocks looking for unique antigen keys. There are specialized immune system cells designed to try the antigen keys in the T cell locks. They are called antigen presenting cells (APCs).
These are either the hungry macrophages that have picked up antigens in the tissues,or B cells that have grabbed onto antigens in the tissues,or B cells that have grabbed onto antigens,or a thrid category of APCs,the dendritic cells.
The dendritic cells are abundant throughout the body. These flexible,starfish-shaped cells eagerly grab arriving antigens. Only these APCs bear the keys (antigens) that will unlock the padlocks on the T cells,and turn on the T cells to really get the immune system ractions going.
T cells that have particular types of co-receptors on their membranes,known as CD4 co-receptors,are the T helper cells (Th cells). HIV,the virus that causes AIDS,specifically seeks out and kills T cells bearing the CD4 co-receptors,in effect destroying the immune system.
The T helper cells are major players in the immune system. In the lymph node,when T helper cells recognize and accept the antigen keys that are attached to the special antigen presenting cells described,things really heat up. The activated T cells (influenced by certain cytokines) divide rapidly and build up a population of identical Th cells.
A single activated T cell won't be much help against an antigen attack. Now other cytokines come in contact with these Th cells and the result is the formation of two distinct sets of Th cells,Th1 and Th2 cells,each with different functions.
These Th1 and Th2 cells start pumping out their own unique sets of chemical messages. Meanwhile other cells in the area are putting out cytokines as well. the directions that the Th cells travel toward becoming either Th1 or Th2 cells is determined by the particular mix of messages sensed by the T cells.
Once the choice has been made,the two Th cell types engage in different functions.
The Th1 cells are most interested in stimulating cells like macrophages and are therefore considered to be proinflammatory. In rheumatoid joints the balance seems to be swung toward Th1 cell activity,although the Th2 cells are also present as well.
B cells are primed to make antibodies under the influence of Th2 cells. These activated B cells then have two choices. Some act as the plasma cells. These cells churn out antibodies ;about two thousand per second,and die off after  few days. the others become memory cells,which do not release antibodies,but live much longer than the plasma cells.
They or their descendants remain in the lymphatic tissues,acutely sensitive to the particular antigen that triggered this whole process. Should that antigen show up again in the body some of the memory cells will become plasma cells and mount a swift antibody response. Most (but not all people with RA have B cells that make antibodies that recognize some of the body's very own anti bodies as foreign,i.e., antigens.
Whether or not these antiself antibodies,rheumatoid factor (RF),actually enhance the development of RA is unknown.

What might scientists do to help us in RA treatment?
I) B cells,because they make certain antibodies that attack joints and tissues in RA might be somehow removed or destroyed,in hopes that the new population of B cells that the immune system would make to replace the troublemakers would not make these destructive antibodies
II) Chemical messages come from the tissues where RA is beginning and move to the local blood vessels. There,those chemicals help to fashion proteins along the vessel lining as well as proteins on the outer membranes of the white blood cells that stream by. All this helps the cells exit to carry out inflammation.
These chemical messages cause the vessels to become "leaky" and the cells to slow down,lock on to the vessel lining,and then move quickly through the wall into the nearby tissue Interference with those messages could prevent those cellular reinforcements from answering the call for help.
III) The hungry macrophages,some of which are already in the tissues and the many others that are recruited from the blood,are central players in RA. They excite T cells,they pour out inflammatory chemicals (cytokines),and even assist in cartilage and bone destruction. Anything that could reduce their numbers would be helpful.
IV) T cells are in the mainstream of immune system reactions. They recognize substances (antigens) presented to them by specialized cells such as macrophages. The T cells become "activated" and go on to perpetuate inflammation and damage to the joints. The T cells communicate with other cells by literal physical contact. with them.
They recognize other compatible cells by sensing specific chemicals on the cell surfaces. Why not block those chemical identifiers,or plug up the sensors on the T cells? That would prevent interaction of the T cells with other cells and block the damaging aftereffects of those meetings.
Because certain types of T cells,the Th1 cells,predominate in RA,suppression of their numbers and a increase of the anttinflammatory Th2 types might help.
V) Each of the cytokines,those chemical messengers that literally run the operation of the immune system reactions are prime targets. Central among them,at least as we now understand it,are TNF-alpha and IL-1. These two have a hand in so many of the operations of immunity that some control over either one could be a very powerful weapon against RA.
VI) Apoptosis,the process that the body uses to carefully delete unneeded cells,seems to be defective in RA, It would be useful to stimulate apoptosis to get rid of particular cell types that are perpetuating destructive inflammation.
VII) In the destruction of cartilage and bone,powerful enzymes that dissolve those precious tissues are secreted by cells that have been excited by cytokines. A way to reduce or eliminate that flood of corrosive chemicals would reduce or prevent the painful damage.
Scientists in universities,medical centers and biotechnology companies around the world are already making progress,in varying degrees,in every one of these approaches