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Although we do not know the cause of rheumatoid arthritis,joint damage is caused by inflammation in the synovial membrane.
This normally thin memberane becomes inflamed and thick,filled with cells called fibroblasts,lymphocytes,polymorphs, and macrophages.
This thick,inflamed synovial membrane is called the pannus. The cells within the pannus becomes activated,and releases enzymes,and
chemicals that both permanetly damage the cartilage and the bone,and also attract more cells into the inflamed tissue. In
RA,this inflammatory process is like a one-way highway, the inflammation continue indefinitely causing more and more damage,possibly
leading to joint destruction,and deformity if not controlled.
This inflammatory process is part of the body's immune
system. The immune system is a natural defense against invaders such as bacteria, viruses,and even cancer. The cells of the
immune system recognize,and respond to invaders either by making antibodies to combat invaders or by attacking invaders directly.
Although
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 over-activated and causes marked inflammation in the synovial membrane. Many of the drugs used to fight
RA have antibacterial and/or anti-immune system activity.
The damage to the joints caused by RA is thought to be caused
by the interaction of many inflammatory cells and chemicals. Cytokines,like tumour necrosis factor,IL-ra alpha etc., are secreated
by synovial fibroblasts and other cells resulting in pain,and inflammation TNF may also be responsible for influencing other
inflammatory compounds including interleukins (IL-1), collagenase,and prostaglandins
The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune
system, which fights infection and heals wounds and injuries:
- When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as
a virus.
- The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood,
and fight any infections.
- In the process the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called
upon to repair wounds by clotting off any bleeding blood vessel and initiating fiber-like patches to the tissue.
- Under normal conditions, the immune system has other special factors that control and limit this inflammatory process.
The Infection Fighters. Two important components of the immune system that play a role in the inflammation associated
with rheumatoid arthritis are B cells and T cells, both of which belong to a family of immune cells called
lymphocytes.
When macrophages recognize foreign particles entering the bloodstream, they are programmed to ingest them, split them into
pieces, and bring specific sections of them (antigens) into contact with the surface of the T cell. These antigens are placed
within specialized proteins on the surface of the T cell that signal to a T cell and begin a process of immune system inspection.
This process involves the interaction of several proteins on B cells and T cells, which seem to signal back and forth. If
the T cell recognizes an antigen as "non-self," then it will produce chemicals (cytokines) that cause B cells to multiply
and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign
particles and triggering inflammation in order to rid the body of the invasion. T cells can be further categorized as killer
T cells or helper T cells. Killer T cells directly attack antigens, such as viruses and tumor cells. Helper T cells
recognize antigens that are presented to them by macrophages (or other specialized cells), and can stimulate B cells to mount
various kinds of attacks on the antigen. They also produce chemicals (cytokines) that can have a more direct role in
the inflammatory process.
For reasons that are still not completely understood, both the T cells and the B cells become overactive in patients with
RA. In an immune response it is normal for the antibody response to change over time, particularly if the first antibodies
that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes
in an attempt to achieve better recognition and a stronger inflammatory response against a recalcitrant invader. In RA, a
complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal
repertoire of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues
in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.
The complex and finely tuned immune system in our bodies consists of a varied array of cells and chemicals that recognizes
the invasions from microorganisms in our environment,such as,bacteria,viruses,fungi,or protoza. Those cells and chemicals
recognize these creatures when they enter our tissues and they surround,attack,and destroy them before they can do serious
harm.
Cells are living sacs of chemicals. Cells neither feel nor hear or see. They can know nothing about their immediate surroundings
or what might be happening in other parts of the body beyond what arrives at their borders as chemical signals. The
language that cells use is spelled out in molecules,the chemical messages that arrive at the cell borders are translated by
the cells into commands that alter the cell's own chemistry in some way.
Cells detect these signals when the chemicals combine with specific receptors on the cell membrane,which then relay
the information to the cell's interior. These receptors are special proteins,which can be thought of as padlocks ;they will
open up only in response to the right key.
Depending on the chemical message that the unlocked padlock lets inside,the cell may respond by switching on or off specific
genes or perhaps slowing down or accelerating their activity. Through this constant monitoring of the chemistry of its environment,a
cell acts in a way in keeping with the messages brought to it from near and far.
The reactions of our immune system require cell workers and chemical messages and also a means of carrying those messages
throughout the body. For that purpose we use two quite distinct but interconnected anatomical networks,the blood circulatory
system and the lympatic system.
Some of our lymphocytes,the type of white blood cells that are key players in the recognization proces,have the potential
to react against our own tissues but are usually suppressed from doing that. In fact,those that do react that way are usually
destroyed before they can do harm. The immune system normally can distiguish between "self" and "nonself".
Scientists think there may be some interruption in that mechanism for control of "self- recognizing" lymphocytes. Also,there
is evidence that there may be some alteration in certain body tissues so that they are no longer recognized as self and are
interpreted as foreign invaders and attacked.
Exactly,what causes this lack of control or tissue change is not yet known. There appears to be a mix of contributing
factors including perhaps certain microbial infections,a genetric predisposition,problems with white blood cells,environmental
factors,all of which might result in a bypassing of the normal process of recognizing self.
In order to attack and neutralize the invaders,our immune system is equipped with detectors that can recognize them as
outsiders to our bodies,as foreign ;literally,cratures that are not us. We can distinguish what is "non-self" from "self",and
set about to destroy the former.
But all living cells,whether they are bacteria,muscle cells or any other cell types,share many of the same molecules
We need to have a very efficient mechanisim within the immune system to prevent it from mistakenly detecting our own cells
as foreign invaders.
Sometimes, for reasons unknown,that very mistake happens and we experience autoimmunity,an immune response directed toward
self (toward one's own body). The result of this response manifest themselves as a wide variety of autoimmune disease.
The more than eighty types of autoimmune disease differ widely in their effects on the body. There are two major categories:
organ specific and non-organ specific. In organ-specific disease,the autoimmune attack is directed against one organ,e.g.,
insulin-dependent diabetes,mellitus-the pancreas,pernicious anemia affects the stomach,addison's disease-the adrenal gland.
Non-organ-specific diseases such as RA,SLE,and dermatomyositis have more widespread effects on many areas of the body-dependant
on patient case.
In trying to decipher exactly what goes on in RA at the level of cells and chemicals it is important to notice that RA
occurs in individuals whose immune systems are generally competent. People with RA do not necessarily catch more colds,allergys
or have more infections. As one professor of rheumatology said,"In rheumatoid arthritis the immune system has some minor character
defect". What is this "minor defect" (or perhaps there are several) that leads to RA? We don't know! It has to be yet,more
clearly defined.
The immune system is a bodywide network of cells and organs that has evolved to defend the body against attacks by "foreign"
invaders. The proper targets of the immune defenses are infectious organismsbacteria such as these streptococci; Fungi (e.g.,
one happens to be the mold from which penicillin is made); Parasites, including these worm-like microbes that cause schistosomiasis;
and Viruses such as the herpes virus.
Markers of Self: At the heart of the immune response is the ability to distinguish between self and nonself. Every body
cell carries distinctive molecules that distinguish it as "self." Normally the body's defenses do not attack tissues that
carry a self marker; rather, immune cells coexist peaceably with other body cells in a state known as self-tolerance.
Markers of Non-Self: Foreign molecules, too, carry distinctive markers, characteristic shapes called epitopes that protrude
from their surfaces.
One of the remarkable things about the immune system is its ability to recognize many millions of distinctive non-self
molecules, and to respond by producing molecules such as these antibodiesand also cellsthat can match and counteract each
one of the non-self molecules.
Any substance capable of triggering an immune response is known as an antigen. An antigen can be a bacterium or a virus,
or even a portion or product of one of these organisms. Tissues or cells from another individual also act as antigens; that's
why transplanted tissues are rejected as foreign.
Organs of the Immune System: The organs of the immune system are stationed throughout the body.: They are known as lymphoid
organs because they are concerned with the growth, development, and deployment of lymphocyteswhite blood cells that are key
operatives of the immune system.
Lymphatic System: The organs of the immune system are connected with one another and with other organs of the body by
a network of lymphatic vessels similar to blood vessels. Immune cells and foreign particles are conveyed through the lymphatics
in lymph, a clear fluid that bathes the body's tissues
Lymph Node: Lymph nodes are small, bean-shaped structures that are laced throughout the body along the lymphatic routes.
Lymph nodes contain specialized compartments where immune cells congregate, and where they can encounter antigens.
Cells of the Immune System: Cells destined to become immune cells, like all blood cells, arise in the bone marrow from
so-called stem cells. Some develop into myeloid cells, a group typified by the large, cell- and particle- devouring white
blood cells known as phagocytes; phagocytes include monocytes, macrophages, and neutrophils. Other myeloid descendants become
granule-containing inflammatory cells such as eosinophils and basophils. Lymphoid precursors develop into the small white
blood cells called lymphocytes. The two major classes of lymphocytes are B cells and T cells.
B Cells: B cells work chiefly by secreting soluble substances known as antibodies. Each B cell is programmed to make
one specific antibody. When a B cell encounters its triggering antigen (along with various accessory cells), it gives rise
to many large plasma cells. Each plasma cell is essentially a factory for producing that one specific antibody.
Antibody: Each antibody is made up of two identical heavy chains and two identical light chains, shaped to form a Y.
The sections that make up the tips of the Y's arms vary greatly from one antibody to another; this is called the variable
region. It is these unique contours in the antigen-binding site that allow the antibody to recognize a matching antigen, much
as a lock matches a key.
The stem of the Y links the antibody to other participants in the immune defenses. This area is identical in all antibodies
of the same classfor instance, all IgEsand it's called the constant region
IgG, IgD, and IgE: Antibodies belong to a family of large protein molecules known as immunoglobulins. Scientists have
identified nine chemically distinct classes of human immunoglobulins, four kinds of IgG and two kinds of IgA, plus IgM, IgE,
and IgD.
Immunoglobulins G, D, and E are similar in appearance. IgG, the major immunoglobulin in the blood, is also able to enter
tissue spaces; it works efficiently to coat microorganisms, speeding their uptake by other cells in the immune system. IgD
is almost exclusively found inserted into the membrane of B cells, where it somehow regulates the cell's activation. IgE is
normally present in only trace amounts, but it is responsible for the symptoms of allergy.
IgA and IgM: IgAa doubletconcentrates in body fluids such as tears, saliva, and the secretions of the respiratory and
gastrointestinal tracts. It is, thus, in a position to guard the entrances to the body. IgM usually combines in star-shaped
clusters. It tends to remain in the bloodstream, where it is very effective in killing bacteria.
Antibody Genes: Scientists long wondered how all the genetic information needed to make millions of different antibodies
could fit in a limited number of genes. The answer is that antibody genes are pieced together from widely scattered bits of
DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V,
diversity-D, joining-J, and constant-C segments of this antibody molecule, a typical IgM heavy chain.
T Cells: T cells contribute to the immune defenses in two major ways. Some help regulate the complex workings of the
immune system, while others are cytotoxic and directly contact infected cells and destroy them. Chief among the regulatory
T cells are "helper/inducer" T cells. They are needed to activate many immune cells, including B cells and other T cells.
Another subset of regulatory T cells acts to turn off or suppress immune cells.
Cytotoxic T cells help rid the body of cells that have been infected by viruses as well as cells that have been transformed
by cancer. They are also responsible for the rejection of tissue and organ grafts.
Cytokines: Cytokines are diverse and potent chemical messengers secreted by the cells of the immune systemand the chief
tool of T cells. Lymphocytes, including both T cells and B cells, secrete lymphokines, while monocytes and macrophages secrete
monokines.
Binding to specific receptors on target cells, cytokines recruit many other cells and substances to the field of action.
Cytokines encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cellsincluding cancer
cells. Because they serve as a messenger between white cells, or leukocytes, many cytokines are also known as interleukins,tumour
necrosis factor etc.
Natural Killer Cells: At least two types of lymphocytes are killer cellscytotoxic T cells and natural killer cells. To
attack, cytotoxic T cells need to recognize a specific antigen, whereas natural killer or NK cells do not. Both types contain
granules filled with potent chemicals, and both types kill on contact. The killer binds to its target, aims its weapons, and
delivers a burst of lethal chemicals
Phagocytes and Granulocytes: Phagocytes are large white cells that can engulf and digest foreign invaders. They include
monocytes, which circulate in the blood, and macrophages, which are found in tissues throughout the body, as well as neutrophils,
cells that circulate in the blood but move into tissues where they are needed. Macrophages are versatile cells; they act as
scavengers, they secrete a wide variety of powerful chemicals, and they play an essential role in activating T cells.
Neutrophils are not only phagocytes but also granulocytes: they contain granules filled with potent chemicals. These
chemicals, in addition to destroying microorganisms, play a key role in acute inflammatory reactions. Other types of granulocytes
are eosinophils and basophils. Mast cells are granule-containing cells in tissue.
Phagocytes in the Body: Specialized phagocytes are found in organs throughout the body.
Complement: The complement system consists of a series of proteins that work to "complement" the work of antibodies in
destroying bacteria.
Complement proteins circulate in the blood in an inactive form. The so-called "complement cascade" is set off when the
first complement molecule, C1, encounters antibody bound to antigen in an antigen-antibody complex. Each of the complement
proteins performs its specialized job in turn, acting on the molecule next in line. The end product is a cylinder that punctures
the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell.
Mounting an Immune Response: Microbes attempting to get into the body must first get past the skin and mucous membranes,
which not only pose a physical barrier but are rich in scavenger cells and IgA antibodies.
Next, they must elude a series of nonspecific defensescells and substances that attack all invaders regardless of the
epitopes they carry. These include patrolling scavenger cells, complement, and various other enzymes and chemicals. Infectious
agents that get past the nonspecific barriers must confront specific weapons tailored just for them. These include both antibodies
and cells. Almost all antigens trigger both nonspecific and specific responses.
Antigen Receptors: Both B cells and T cells carry customized receptor molecules that allow them to recognize and respond
to their specific targets. The B cell's antigen-specific receptor is a sample of the antibody it is prepared to manufacture;
it recognizes antigen in its natural state.
The T cell receptor system is more complex. A T cell can recognize an antigen only after the antigen is processed and
presented to it by a so-called antigen-presenting cell, in combination with a special type of cell marker.
The T4 T cell's receptor looks for an antigen that has been broken down by an immune system cell such as a macrophage
or a B cell and combined with a marker, known as a class II protein, carried by immune cells. The T8 T cell's receptor recognizes
an antigen fragment produced within the cell, combined with a class I protein; class I proteins are found on virtually all
body cells. This complicated arrangement assures that T cells act only on precise targets and at close range.
Activation of B Cells to Make Antibody: The B cell uses its receptor to bind a matching antigen, which it proceeds to
engulf and process. Then it combines a fragment of antigen with its special marker, the class II protein. This combination
of antigen and marker is recognized and bound by a T cell carrying a matching receptor. The binding activates the T cell,
which then releases lymphokinesinterleukins,TNFs etc.that transform the B cell into an antibody- secreting plasma cell.
Activation of T Cells: Helper and Cytotoxic: After an antigen-presenting cell such as a macrophage has ingested and processed
an antigen, it presents the antigen fragment, along with a class II marker protein, to a matching helper T cell with a T4
receptor. The binding prompts the macrophage to release interleukins ,TNF etc. that allow the T cell to mature.
A cytotoxic T cell recognizes antigens such as virus proteins,which are produced within a cell, in combination with a
class I self-marker protein. With the cooperation of a helper T cell, the cytotoxic T cell matures. Then, when the mature
cytotoxic T cell encounters its specific target antigen combined with a class I marker proteinfor instance, on a body cell
that has been infected with a virusit is ready to attack and kill the target cell.
Immunity: Short- and Long-Term Cell Memory: Whenever T cells and B cells are activated, some become "memory" cells. The
next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. Long-term immunity
can be stimulated not only by infection but also by vaccines made from infectious agents that have been inactivated or, more
commonly, from minute portions of the microbe.
Short-term immunity can be transferred passively from one individual to another via antibody-containing serum; similarly,
infants are protected by antibodies they receive from their mothers (primarily before birth).
Disorders of the Immune System: Allergy ;When the immune system malfunctions, it can unleash a torrent of disorders and
diseases.
One of the most familiar examples is allergy. Allergies such as hay fever and hives are related to the antibody known
as IgE. The first time an allergy-prone person is exposed to an allergenfor instance, grass pollenthe individual's B cells
make large amounts of grass pollen IgE antibody. These IgE molecules attach to granule-containing cells known as mast cells,
which are plentiful in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract. The next time that person
encounters grass pollen, the IgE-primed mast cell releases powerful chemicals that cause the wheezing, sneezing, and other
symptoms of allergy.
Disorders of the Immune System: Autoimmune Disease: Sometimes the immune system's recognition apparatus breaks down,
and the body begins to manufacture antibodies and T cells directed against the body's own cells and organs. Such cells and
autoantibodies, as they are known, contribute to many diseases. For instance, T cells that attack pancreas cells contribute
to diabetes, while an autoantibody known as rheumatoid factor is common in persons with rheumatoid arthritis.
Disorders of the Immune System: Immune Complex Disease ;Immune complexes are clusters of interlocking antigens and antibodies.
Normally they are rapidly removed from the bloodstream. In some circumstances, however, they continue to circulate, and
eventually they become trapped in and damage the tissues of the kidneys, as seen here, or in the lungs, skin, joints, or blood
vessels.
Disorders of the Immune System: AIDS: When the immune system is lacking one or more of its components, the result is
an immunodeficiency disorder. These can be inherited, acquired through infection, or produced as an inadvertent side effect
of drugs such as those used to treat cancer or transplant patients.
AIDS is an immunodeficiency disorder caused by a virus that destroys helper T cells and that is harbored in macrophages
as well as helper (T4) T cells. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter
directed to churn out new viruses.
Human Tissue Typing for Organ Transplants: For an organ transplant to "take," it is necessary to minimize the body's
drive to rid itself of foreign tissue.
One way is to make sure that the markers of self on the donor's tissue are as similar as possible to those of the recipient.
Because tissue typing is usually done on white blood cells, or leukocytes, the markers are referred to as human leukocyte
antigens, or HLA.
Each cell has a double set of six major antigens, HLA-A, B, and C, and three types of HLA-D. Since each of the
antigens exists, in different individuals, in as many as 20 varieties, the number of possible HLA types is about 10,000. The
genes that encode the HLA antigens, located on chromosome 6, are the subject of intense research.
"Privileged" Immunity: A child in the womb carries foreign antigens from the father as well as immunologically compatible
self antigens from the mother. One might expect this condition to trigger a graft rejection,but it does not because the uterus
is an "immunologically privileged" site where immune responses are subdued.
Immunity and Cancer: When normal cells turn into cancer cells, some of the antigens on their surface change. These new
or altered antigens flag immune defenders, including cytotoxic T cells, natural killer cells, and macrophages.
According to one theory, patrolling cells of the immune system provide continuing bodywide surveillance, spying out and
eliminating cells that undergo malignant transformation. Tumors develop when the surveillance system breaks down or is overwhelmed.
Immunotherapy: A new approach to cancer therapy uses antibodies that have been specially made to recognize specific cancer.
When coupled with natural toxins, drugs, or radioactive substances, the antibodies seek out their target cancer cells and
deliver their lethal load. Alternatively, toxins can be linked to a lymphokine and routed to cells equipped with receptors
for the lymphokine.
The Immune System and the Nervous System: Biological links between the immune system and the central nervous system exist
at several levels.
Hormones and other chemicals such as neuropeptides, which convey messages among nerve cells, have been found also to
"speak" to cells of the immune systemand some immune cells even manufacture typical neuropeptides. In addition, networks of
nerve fibers have been found to connect directly to the lymphoid organs.
The picture that is emerging is of closely interlocked systems facilitating a two-way flow of information. Immune cells,
it has been suggested, may function in a sensory capacity, detecting the arrival of foreign invaders and relaying chemical
signals to alert the brain. The brain, for its part, may send signals that guide the traffic of cells through the lymphoid
organs.
Hybridoma Technology: Thanks to a technique known as hybridoma technology, scientists are now able to make quantities
of specific antibodies. A hybridoma can be produced by injecting a specific antigen into a mouse, collecting antibody-producing
cells from the mouse's spleen, and fusing them with long-lived cancerous immune cells.
Individual hybridoma cells are cloned and tested to find those that produce the desired antibody. Their many identical
daughter clones will secrete, over a long period of time, the made-to-order "monoclonal" antibody.
Genetic Engineering: Genetic engineering allows scientists to pluck genessegments of DNAfrom one type of organism and
combine them with genes of a second organism.
In this way relatively simple organisms such as bacteria or yeast can be induced to make quantities of human proteins,
including interferons and interleukins. They can also manufacture proteins from infectious agents such as the hepatitis virus
or the AIDS virus, for use in vaccines.
The SCID-hu Mouse: The SCID mouse, which lacks a functioning immune system
of its own, is helpless to fight infection or reject transplanted tissue. By transplanting immature human immune tissues and/or
immune cells into these mice, scientists have created an in vivo model that promises to be of immense value in advancing our
understanding of the immune system.
The Immune System And RA:
The immune system is a complex of organs--highly specialized cells and even a circulatory system separate from blood
vessels--all of which work together to clear infection from the body. The organs of the immune system, positioned throughout
the body, are called lymphoid organs. The word "lymph" in Greek means a pure, clear stream--an appropriate description considering
its appearance and purpose.
Lymphatic vessels and lymph nodes are the parts of the special circulatory system that carries lymph, a transparent fluid
containing white blood cells, chiefly lymphocytes. Lymphatic vessels form a circulatory system that operates in close partnership
with blood circulation.
Lymph bathes the tissues of the body, and the lymphatic vessels collect and move it eventually back into the blood circulation.
Lymph nodes dot the network of lymphatic vessels and provide meeting grounds for the immune system cells that defend against
invaders. The spleen, at the upper left of the abdomen, is also a staging ground and a place where immune system cells confront
foreign microbes.
Organs and tissues of the immune system dot the body in a protective network of barriers to infection. Pockets of lymphoid
tissue are in many other locations throughout the body, such as the bone marrow and thymus. Tonsils, adenoids, Peyer's patches,
and the appendix are also lymphoid tissues.
Both immune cells and foreign molecules enter the lymph nodes via blood vessels or lymphatic vessels. All immune cells
exit the lymphatic system and eventually return to the bloodstream. Once in the bloodstream, lymphocytes are transported to
tissues throughout the body, where they act as sentries on the lookout for foreign antigens.
How the Immune System Works: Cells that will grow into the many types of more specialized cells that circulate throughout
the immune system are produced in the bone marrow. This nutrient-rich, spongy tissue is found in the center shafts of certain
long, flat bones of the body, such as the bones of the pelvis. The cells most relevant for understanding vaccines are the
lymphocytes, numbering close to one trillion.
The two major classes of lymphocytes are B cells, which grow to maturity in the bone marrow, and T cells, which mature
in the thymus, high in the chest behind the breastbone.
B cells produce antibodies that circulate in the blood and lymph streams and attach to foreign antigens to mark them
for destruction by other immune cells. B cells are part of what is known as antibody-mediated or humoral immunity, so called
because the antibodies circulate in blood and lymph, which the ancient Greeks called, the body's "humors." B cells become
plasma cells, which produce antibodies when a foreign antigen triggers the immune response.
Certain T
cells, which also patrol the blood and lymph for foreign invaders, can do more than mark the antigens; they attack and destroy
diseased cells they recognize as foreign. T lymphocytes are responsible for cell-mediated immunity (or cellular immunity).
T cells also orchestrate, regulate and coordinate the overall immune response. T cells depend on unique cell surface molecules
called the major histocompatibility complex (MHC) to help them recognize antigen fragments.
Antibodies produced by cells of the immune system recognize foreign antigens and mark them for destruction. The
antibodies that B cells produce are basic templates with a special region that is highly specific to target a given antigen.
Much like a car coming off a production line, the antibody's frame remains constant, but through chemical and cellular
messages, the immune system selects a green sedan, a red convertible or a white truck to combat this particular invader.
However, in contrast to cars, the variety of antibodies is very large. Different antibodies are destined for different purposes.
Some coat the foreign invaders to make them attractive to the circulating scavenger cells, phagocytes, that will engulf an
unwelcome microbe.
When some antibodies combine with antigens, they activate a cascade of nine proteins, known as complement, that have
been circulating in inactive form in the blood. Complement forms a partnership with antibodies, once they have reacted with
antigen, to help destroy foreign invaders and remove them from the body. Still other types of antibodies block viruses from
entering cells.
T cells have two major roles in immune defense. Regulatory T cells are essential for orchestrating the response of an
elaborate system of different types of immune cells. Helper T cells, for example, also known as CD4 positive T cells
(CD4+ T cells), alert B cells to start making antibodies; they also can activate other T cells and immune system scavenger
cells called macrophages and influence which type of antibody is produced.
Certain T cells, called CD8 positive T cells (CD8+ T cells), can become killer cells that attack and destroy infected
cells. The killer T cells are also called cytotoxic T cells or CTLs (cytotoxic lymphocytes).
T lymphocytes
become CD4+ or helper T cells, or they can become CD8+ cells, which in turn can become killer T cells, also called cytotoxic
T cells.
Immune system process ;Activation of helper T cells ;After it engulfs and processes an antigen,
the macrophage displays the antigen fragments combined with a Class II MHC protein on the macrophage cell surface. The antigen-protein
combination attracts a helper T cell, and promotes its activation.
Activation of cytotoxic T cells: After a macrophage engulfs and processes an antigen, the macrophage displays the antigen
fragments combined with a Class I MHC protein on the macrophage cell surface. A receptor on a circulating, resting cytotoxic
T cell recognizes the antigen-protein complex and binds to it.
The binding process and a helper T cell activate the cytotoxic T cell so that it can attack and destroy the diseased
cell.
Activation of B cells to make antibody: A B cell uses one of its receptors to bind to its matching antigen, which the
B cell engulfs and processes. The B cell then displays a piece of the antigen, bound to a Class II MHC protein, on the cell
surface. This whole complex then binds to an activated helper T cell. This binding process stimulates the transformation of
the B cell into an antibody-secreting plasma cell.
Simplified Version Of What's Going On:
One research-scientist has called macrophages the "messenger" of the immune system. They sound an alert and wait for the
immune system troops to arrive. It is a war going on in our bodies. Immune system sentries known as helper T cells are the
first to respond. They assess the situation and decide what type of immune system soldier should be called to the scene. At
this stage there are no symptoms.
The immune response escalates: Now that the immune system has recognized a foreign invader,it initiates a cascade of events
meant to ensure that the invader is destroyed.
The helper T cells call for the soldiers. There are two broad categories of soldiers in the immune system:killer T cells,which
can attack an enemy head-on,and B lymphocytes, which manufacture and release antibodies specifically designed to home in on
and destroy the foreign invader. Meanwhile,other changes take place to enable additional immune system cells to reach the
area.
The macrophages(white blood cells) which originally helped sound the alert about the invader,now help new blood vessels
to form. They are assisted by hormonelike substances called cytokines (they have a good part and a bad side),which enhance
and amplify the process of inflammation that has now begun.
Other immune system cells (billions) that are circulating elsewhere in the body home in on the joint, attracted by all
the commotion. These cells start to accumulate in the synovial membrane surrounding the joint.
Meanwhile,other immune system cells known as neutrophils, another type of white blood cell,begin to accumulate in the synovial
fluid that fills the joint cavity. Neutrophils exist as a type of cleanup mechanism at the site of infection,they consume
the debris of an immune system assault and any other unwanted particles or bacteria. They do this by releasing digestive substances
known as lysosomal enzymes that break down and dissolve their targets.
At the same time another component of the immune system known as the complement system is activated. this unleashes proteins
that further speed the destruction of foreign particles by antibodies.
In some ways it sounds like a war is going on. In RA for reasons that is still unclear,the attack not only continues beyond
the original goal of destroying virus and bacteria but also escalates. As many as a billion neutrophils may be circulating
in the synovial fluid of the knee that is moderately inflamed. The enzymes they release,once directed at a foreign invader,start
to attack healthy cartilage and ligaments.
By this time,you are quite aware, that something is wrong in your body. You might feel stiff upon awakening,and it may
take as much as an hour or more to limber up (some patients claim it never eases up),for some people,increased fatigue.
If it continues without treatment.--loss of mobility, visible swelling of the joint. Unchecked joints may become deformed,
or even become disabled.
Immune cells initiate and control the inflammatory process in part by releasing messenger proteins called cytokines (e.g.,interleukins
and tumor necrosis factor), which act like distress signals to all relevant immune cells.
Specifically, cytokines tells other immune cells to initiate "cascade" reactions that yield hormone-like chemicals called
inflammatory mediators.
In RA,the inflammatory mediators that immune cells release in response to cytokine "messengers" include histamine,leukotrienes,and
certain prostaglandins.These inflammatory mediators make small capillaries wider and "leakier",permitting more immune cells
to flood the area,where they release enzymes that dissolve connective tissues.
Normally,inflammation is an appropiate immune response to injury or infection. But RA is charachterized by a ungovernable,ongoing
inflammation. We also know that when synovial fluid contains high levels of cytokines,collagen damage and the risk of
arthritis is increased-and the cells that send the first inflammatory messages,via release of cytokines,may be distant from
joint tissue.
We also know that damage to the synovial capsule corresponds to abnormally low levels of antioxidant molecules,including
certain enzymes. Furthermore, damage to collagen correlates with high level os inflammatory messenger molecules in synovial
fluid (e.g., tumor necrosis factor-alpha,interleukin-1 etc. )
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