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.
