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					The Immune System &
       Lupus


        Lyubov Korolchuk
          Bunsree Patel




  Topics in Medicine and Biology
Summer Ventures in Science & Math
    Instructor: Willson Kwok
           July 14, 2006
Abstract:

       The body has a system of defenses known as the immune system. The immune system

has many parts that work together to protect the body against viruses, bacteria, micro-organisms,

parasites, and other foreign bodies. Lymphatic organs and leukocytes each have their own role in

fighting off invaders of the body. There are two types of leukocytes: phagocytes, which ingest

and destroy foreign matter, and lymphocytes, which consist of B-cells and T-cells that regulate

the two immune responses: cellular and humoral. When problems arise with the immune system

because of non-self/self recognition breakdown, allergies, and excessive response, disorders

arise. This paper also discusses Lupus, an autoimmune disorder, which affects all parts of the

body. In Lupus, the immune system loses its ability to tell the difference between foreign

substances (antigens) and its own cells and tissues, making it a serious and life-threatening

disease.
Introduction to the System:

       The immune system is a complex and intricate network of many organs and cells that

work together in combination to defend the body against infection, disease, and foreign

substances. It can be stimulated in specific ways to fight specific health challenges, which

includes fighting off millions of bacteria, microbes, viruses, toxins, cancer cells, and parasites.

The organs of the immune system, which are spread throughout the entire body, are called the

lymphatic organs (Wikipedia Immune System, 2006).

The Human Body’s Lines of General Defense:

       There are three lines of defense for the human body. The first line of defense consists of

surface membrane barriers such as the skin. The skin, which has an acidic pH, is a passive

physical barrier to foreign materials such as bacteria and viruses. The skin glands secrete

chemicals to inhibit bacterial growth and organisms that live on the skin’s surface are unable to

penetrate through. Moreover mucous membranes in the respiratory, digestive, reproductive, and

urinary tracts secrete mucus to form an additional barrier. The mucus in the digestive and

respiratory pathways traps micro-organisms while the mucosa of the stomach produces

hydrochloric acid (HCl) and has protein-digesting enzymes (Farabee, 2001).

       The second line of defense is the inflammatory response, which is triggered when body

tissues are injured. There are four cardinal signs of inflammation: redness, heat, swelling, and

pain, which result in a chain of events that lead to defense and healing. The inflammatory

response helps prevent the spread of infectious and harmful agents, it removes cell debris and

pathogens, and helps set the stage for body repair (Marieb, 2003).

       The third line of defense is a specific response known as the immune system. It is antigen

specific, which means it recognizes and acts against particular foreign substances. In addition it
is system and is not restricted to the initial infection site, and has memory, which aids in a

stronger attack on previously encountered pathogens (Marieb, 2001).

Parts of the Immune System:

       Throughout the entire human body, the parts of the immune system each have their own

role. The bone marrow is the site of origin for all the cells of the immune system including red

blood cells, white cells (neutrophils, lymphocytes), and platelets, which are formed and then

released into circulation. These cells form through a process called hematopoiesis, where bone

marrow-derived stem cells differentiate into either mature cells or into precursors of cells that

migrate out of the bone marrow to continue their maturation elsewhere. In the thorax, the

thymus gland is responsible for the maturation of new lymphoid cells before they are released

into the bloodstream. This maturation process allows T cells to develop self tolerance and          the

white cells to develop specialized functions.



       The small bean-shaped structures known as the lymph nodes filter particulate matter and

micro-organisms, and produce antibodies to destroy invading organisms and abnormal cells. The

defense cells within the lymph nodes are macrophages, which engulf and destroy foreign

substances, and lymphocytes, which provide an immune response to antigens (Cann, 2005). The

spleen in the upper left section of the abdomen consists of two components which filter blood,

destroys worn out blood cells, forms blood cells in the fetus, acts a blood reservoir, and removes

abnormal cells from circulation: the red pulp and the white pulp. The red pulp houses a complex

system of blood vessels, designed to remove old or damage blood cells from circulation. The

white pulp, which contains T cells, B cells and accessory cells, has the role of mounting

immunological responses to antigens within the blood. Another important part of the immune
system is Gut Associated Lymphoid Tissue, which includes tonsils, adenoids (Waldeyer’s ring),

Peyer’s patches, lymphoid aggregates in the appendix and large intestine, lymphoid tissue in the

stomach, small lymphoid aggregates in the esophagus, diffusely distributed lymphoid cells and

plasma cells in the lamina propria of the gut. The tonsils are small masses of lymphoid tissue in

the back of the throat around the pharynx. They act as a filter to trap and remove bacteria and

foreign intruders that cause infection. Peyer’s patches in the walls of the small intestine capture

and destroy bacteria. They facilitate the generation of an immune response within the mucosal

membrane, where B cell precursors and memory cells are stimulated by antigens (Cann, 2005).

The Cells of the Immune System and their Function:

       There are many different types of cells in the immune system that work together to

protect the human body. The two main classes of lymphocytes are B cells and T cells, which

originate from the hemocytoblasts in the red bone marrow. B lymphocytes mature in the bone

marrow, while T lymphocytes mature in the thymus. B lymphocytes play a large role in the

humoral immune response and function to produce antibodies in response to foreign proteins

such as bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically

recognize and bind to one particular protein. Antibody production and binding to a foreign

substance or antigen is critical as a means of communicating with other cells to engulf, kill or

remove that substance from the body. B-cells differentiate to form plasma cells and memory

cells. The plasma cells secrete antibodies which help destroy antigens by binding to them and the

memory cells produce antibodies to provide immunity to a familiar antigen. There are three

different types of T-cells: helper T-cells, suppressor T-cells, and killer T-cells. Helper T-cells

(CD4+) activate B-cells that produce antibodies; suppressor T-cells slow down and inhibit B-

cells and T-cells from generating an immune response; and cytotoxic (CD8+) aka Killer T-cells
recognize and kill virus-infected cells without communicating with other lymphoid organs.

Helper T-cells aid the cellular and humoral immune

 responses by supplying cytokines.

 Killer T-cells that are activated by

CD4+ T-cells secretions kill their viral-infected targets more effectively. B-cells make up

10-20%, helper T-cells make up 68-75%, and killer T-cells make up

 5-10% of lymphocytes (Purves, 2001).

       In addition to B-cells and T-cells, there are monocytes, macrophages, dendritic cells, and

granulocytes. These cells are known as phagocytes because they engulf and ingest foreign bodies

and harmful micro-organisms while absorbing waste materials in the bloodstream and tissues.

Monocytes make up to 1-6% of white blood cells; their function is to circulate in the

bloodstream, migrate to other tissues, and differentiate into macrophages. Macrophages, which

are phagocytic cells, can be found in a variety of tissues. They play an important role in

regulating immune responses because they collect and ingest foreign materials and present the

antigens to B-cells and T-cells. Along with activating the immune response, they engulf and

digest micro-organisms along with releasing cytokines to activate T-cells. Another type of cells

is a dendritic cell, which can be found in the structural components of lymphoid organs i.e.

thymus, lymph nodes, and spleen. They capture antigens and transport them to the lymphoid

organs, but little is known about these cells due to the difficulty in isolating them (NIAID, 2003).

       There is another group of white blood cells known as granulocytes or polymorphonuclear

leukocytes. There are three cell types that compose granulocytes: neutrophils, eosinophils, and

basophils. Their overall role is to remove bacteria and parasites by engulfing these foreign

materials and using powerful enzymes to wear them down. Neutrophils, making up 50-70% of
white blood cells, respond to inflammation by moving from the blood to the site of

inflammation, where they phagocytize debris and pathogens. Another type of cell that makes up

1-3% of white blood cells is an eosinophil. They migrate from the blood to other tissues and kill

antibody-coated parasites. Basophils are the third and smallest group of granulocytes that make

up less than 1% of white blood cells. Basophils secrete histamine, several proteoglycans, lipid

mediators like leukotrienes, and several cytokines, all which contribute to inflammation and an

allergic response (Linnemeyer, 1993).

Types of Immunity:

       There are four different types of immunity: natural passive immunity, acquired passive

immunity, natural active immunity, and acquired active immunity. Natural passive

immunity is where antibodies produced by one individual are passed into another individual i.e.

from a mother to her baby. In this type of hereditary immunity, antibodies from a mother cross

the placenta and enter her fetus so that they can protect the baby for the first six months of its

life, until its own immune system is functional. Passive immunity can also be transferred from a

mother’s first milk because the baby’s intestines absorb antibodies. A second type of passive

immunity is acquired from vaccines i.e. rabies and tetanus, where antibodies made in one

individual are injected into another individual’s blood. It is not permanent and only lasts for a

temporary period of time.

       Just as there are two types of passive immunities, there are two active forms. The

 first is natural active immunity, in which a person who has suffered a disease and its symptoms

becomes immune to it. It is also known as a secondary response, where B-Cells fire off

antibodies to combat a recognized antigen. The body makes its own antibodies the first time it is

exposed to the infectious agent, and the memory cells that were formed the first time are able to
manufacture mass amounts of antibodies when the same antigen presents itself again. An

example of this is chicken pox, because after the infectious antigen presents itself once, the body

is immune to it, and it generally persists for life. The last type of immunity is acquired active

immunity, where a vaccine i.e. polio (small amounts of antigen) is injected in an individual. This

small dose guarantees that the individual will not contract that disease and will produce

antibodies against the antigen.

The Immune Responses:

       There are two types of immune responses in the human body: cellular (controlled by

T-cells) and humoral (regulated by B cells and their antibodies). The cellular or cell-mediated

response does not involve antibodies, and instead involves the activation of macrophages and

killer T-cells, the production of antigen-specific cytotoxic T-cells, and the release of various

cytokines in response to an antigen. In this immune response antigens must be presented to an




immunocompetent T- cell by macrophages. The T- cell must recognize if it is non-self or self,

an important function of the immune system. After antigen binding, clones form as with B cells,

but different classes of cells are produced. The cytotoxic T-cells specialize in killing infected

cells by inserting a toxic chemical called perforin. The helper T-cells recruit other cells to fight

the invaders and interact directly with B cells. The suppressor T-cells release chemicals to

suppress T-cell and B-cell activity, and are like the off switch for the immune response in order

to prevent uncontrolled activity (Marieb, 2003).

       The humoral immune response is regulated by B-cells and the antibodies they produce.

Some of the digested antigens are displayed on the surfaces of the macrophages and provide
other cells of the immune system with an opportunity to recognize the invader and become

activated. In this process known as antigen presentation, the macrophage selects helper T-cells

and B-cells which have membrane receptors that are complementary in shape to the antigens

exposed. This selection process is known as clonal selection (Millar, 2003). The humoral

response pathway diagram (Figure 5) shows that in the humoral immune response, B

lymphocytes with specific receptors bind to a specific antigen. This binding activates the

lymphocyte to undergo clonal selection, where a large number of clones are produced (primary

humoral response). Most B cells become plasma cells, which produce antibodies to destroy

antigens, although some B cells become long-lived memory cells (secondary humoral response).




       The following chart on the next page shows the two types immunities and the process

B-cells and T-cells undergo to emit an immune response (Millar, 2003).
Disorders:
   In many cases, the immune system fails. An impaired immune system is called

immunocompromise and can leave the body vulnerable to various viral, bacterial, or fungal

opportunistic infections. Causes of immune deficiency can include various illnesses such as

viruses, chronic illness, or immune system illnesses i.e. AIDS. Other types of immune disorders

involve an over-active immune response. There are several different classes of diseases from an

excessive response by the immune system:


   1. Allergies - a true allergy to a substance or food is caused by the immune response.


   2. Asthma - caused by an allergic reaction affecting the airway passages.


   3. Anaphylaxis - an extremely dangerous over-reaction that can lead to shock


   4. Autoimmune diseases - a group of more than 100 diseases where the body's own immune

       system gets confused and starts to attack good body cells.

In the case of autoimmune diseases like multiple sclerosis, systemic lupus erythematosus, and

some forms of arthritis and diabetes, the process of self/non-self recognition breaks down, and

the immune system attacks its own cells (Wikipedia Immune System, 2006).

Background:

       Lupus is an autoimmune disease that affects your immune system. Autoimmune

diseases are illnesses which occur when the body’s tissues are attacked by its own immune

system. It may also be called Systemic Lupus Erythematosus or (SLE). Usually your immune

system tries to fight off infections by killing germs, but in Lupus it makes the mistake of

attacking its healthy cells instead. Lupus can affect any part of an individual’s body from their
joints, kidneys, skin, all the way to their heart and lungs. The body’s immune system normally

makes proteins called antibodies to protect

        the body against viruses, bacteria and other foreign materials. These foreign materials

are called antigens. In an autoimmune disorder such as lupus, the immune system loses its ability

to tell the difference between foreign substances (antigens) and its own cells and tissues. The

immune system then makes antibodies directed against “self.” These antibodies, called

“auto-antibodies,” react with the “self” antigens to form immune complexes. The immune

complexes build up in the tissues and cause inflammation, injury to tissues, and pain. In some

people, Lupus’s effects are not as prevalent as it is in others. A few will only be affected in the

joints and skin, but others will be affected in the heart and lungs. Lupus is usually a slow

processing disease that has symptoms, which just come and go, but sometimes it becomes life

threatening and can become very dangerous about deadly. Lupus can be thought of as a self

allergy that attacks its own cells and tissues, which causes inflammation, pain, swelling, and

possible organ damage. Patients with lupus produce abnormal antibodies in their blood that

target tissues within their own body rather than foreign infectious agents. Lupus can cause

disease of the skin, heart, lungs, kidneys, joints, and nervous system. When only the skin is

involved, the condition is called systemic lupus erythematosus (SLE).

                                                                     Lupus is one of America’s

                                                             least recognized diseases but is one

                                                             of its major diseases. More people

                                                             in America have lupus than any other

                                                             disease like anemia, multiple

                                                             sclerosis, or even cystic fibrosis. It
                                                             is one of the most prevailing diseases

                                                             in America, but it is very

                                                             unnoticeable. However, while lupus

                                                             is widespread, awareness and

                                                             accurate knowledge about it lags

                                                             behind many other illnesses.



Statistics:

          Lupus is on the rise, and scientists don't know exactly why. A recent report from the

Centers for Disease Control and Prevention (CDC) revealed a 60 to 70 percent rise in lupus

deaths between the years of 1979 and 1998. Each year during the study phase, death rates were

more than five times higher for women than for men, and more than three times higher for

African Americans than for Caucasians. The LFA market research data show that between

1,400,000 and 2,000,000 people reported to have been diagnosed with lupus. Lupus is more

common in women especially in Latino, Asian, and Native American. Women take over 90

percent of the lupus disease population. Lupus is the leading cause of kidney disease, stroke,

and premature cardiovascular disease in women of childbearing years. Regrettably, statistics

show that 5 percent of children born to lupus-diagnosed mothers will eventually develop the

disease themselves.

 Types:

       There are several forms of lupus. The first one, which is also the most common type of

lupus is Systemic Lupus Erythematosus (SLE).

SLE can affect a magnificent amount of parts of the body like joints, skin, kidneys, blood
vessels, nervous system, heart, blood, brain, and the lungs. This type of lupus is found in teens

and adults from the ages ranging from 15 to 44.



Even though SLE happens between these ages it could show early or late symptoms as well.

SLE is an elaborate disorder affecting a diminutive young population and shares resemblances

with the HIV infection. The etiology of SLE is not known. It can occur at all ages, but is more

common in young women. It is also a disease with many manifestations. The immune

complex deposition in many tissues leads to the manifestations of the disease. Immune

complexes can be deposited in glomeruli, skin, lungs, synovium, mesothelium, and other places.

Many SLE patients develop renal complications (Eustice, 2006).

Discoid lupus erythematosus (DLE) is a second type of lupus which affects just the skin.

Patients with DLE could also get sores in the mouth and throat. Discoid lupus erythematosus is

a chronic skin condition characterized by inflammation and scarring type skin lesions which

occur on the ears, face, scalp and sometimes on other parts of the body. These lesions develop

as a swollen growth with, scaling and a warty like form. The center areas may appear lighter in

color encircled by an area darker than the normal skin. When wounds occur in hairy areas such

as the scalp, permanent scarring and hair loss can occur. A small percentage of patients with

discoid lupus can develop disease of the internal organs which can make the person sick. Not

many but a few people with DLE get SLE. It is not known for sure if a DLE person will get

SLE. DLE does not affect the organs as SLE does, even though there are a small percentage of

people who get DLE have organ failure. The cause of this type is unknown and it is said that

this condition tends to run in families; females outnumber males with this condition 3 to 1. In

some patients with discoid lupus erythematosus, sunlight may make the lesions come out
(Eustice, 2006).

       The next type of lupus is Neonatal Lupus Erythematosus (NLE). Neonatal lupus occurs in

babies. If a woman gets pregnant and she has SLE or any other immune system disorders then

the baby could be born with neonatal lupus. Neonatal is a rare type of lupus. In most of the

cases neonatal lupus does not need to be treated. In those cases neonatal lupus disappears

impulsively in a few weeks, leaving nothing behind. With a simple blood test you will be able

to tell which women will deliver a child with neonatal lupus. Many of the children born with

neonatal lupus are born to mothers who don’t have SLE. Some of the babies who are born with

this disease could have a serious or even sometimes minor heart defect, though most of the time

it is serious. Once a baby is born with this heart defect it stays permanent and cannot be cured

but treated with a pacemaker (Eustice, 2006).

       The very last type of lupus is the Drug-Induced Lupus Erythematosus (DILE); it is

related to drug prescriptions. This type of lupus is related to a reaction from some sort of

prescription medications. This type of lupus will not show right away after you had a reaction

to medicine it would have to take months or even years before the first symptoms show and then

when you quit taking those medications it would take days, weeks, months, or even years for the

symptoms to go away. Lupus-inducing drugs are normally those used to treat chronic diseases.

The list includes medicines used to treat: Heart disease, Thyroid disease, Hypertension,

Neuropsychiatric disorders, and certain anti-inflammatory agents and antibiotics. At least 38

drugs recently used can cause DILE. However, most cases have been associated with these

three drugs: Procainamide (Pronestyl), Hydralazine (Apresoline), Quinidine (Quinaglute). The

risk for developing lupus-like disease from any of the other 35 drugs is very low; with some

drugs only one or two cases have been reported. For the high-risk drugs such as procainamide
and hydralazine, only 5 to 20 percent of people treated for one to two years at currently used

doses will develop drug-induced lupus. With most of the other drugs, the risk is less than 1

percent that those taking the medication will develop DILE. Some studies show that Caucasians

are more likely to develop this than African Americans. Usually DILE occurs in males over the

age of 50, because they have a higher chance of developing chronic diseases that require this

type of continuous medication procainamide or quinidine is prescribed for cardiac arrhythmias,

and hydralazine is prescribed for hypertension. Obviously men over 50 have both or one of

these (Eustice, 2006).



Causes:

       Lupus is a disease whose cause is still unknown, even if it is starting to become one of

the major diseases in Americans. It is thought that there is no single cause for any type of lupus

but a combination of many things. These include genetic, environmental, and maybe hormonal

factors that work together to make this immune disorder come alive. People cannot catch lupus

from a person when they sneeze or even when they breath on you because lupus is not

contagious, but is known to run in the family. Some of the environmental factors that may

trigger the disease are: infections, antibiotics (especially those in the sulfa and penicillin groups),

ultraviolet light, extreme stress, and certain drugs (What causes lupus?, 1996).

People Affected:

       Lupus is often called a "woman's disease" despite the fact that many men are affected.

Lupus can occur at any age, and in either sex, although it occurs 10 to15 times more frequently

among adult females than among adult males. The symptoms of the disease are the same in

men and women. People of African, American Indian, and Asian origin are thought to develop
the disease more frequently than Caucasian women, but the studies that led to this result are

small and need validation. Hormonal factors may explain why lupus occurs more frequently in

females than in males. The increase of disease symptoms before menstrual periods and/or

during pregnancy support the belief that hormones, particularly estrogen, may be involved.

However, the exact hormonal reason for the greater prevalence of lupus in women, and the cyclic

increase in symptoms, is unknown.

Symptoms:

       Although lupus can affect any part of the body, most people experience symptoms in

only a few organs. Since there is more than one type of lupus each type has its own symptoms.

Percentage        Symptoms
95%               Achy joints (arthralgia)
90%               Fever over 100 degrees F (38
                  degrees C)
81%               Prolonged or extreme fatigue
90%               Arthritis (swollen joints)
74%               Skin Rashes
71%               Anemia
50%               Kidney Involvement
45%               Pain in the chest on deep
                  breathing (pleurisy)
42%               Butterfly-shaped rash across the
                  cheeks and nose
27%               Hair loss
17%               Raynaud's phenomenon (fingers
                  turning white and/or blue in the
                  cold)
15%               Seizures
12%               Mouth or nose ulcers
SLE type can present itself in very different ways regarding of the person’s body. About 80%

of people develop joint and muscle pain, skin

 rashes, fatigue and a general feeling of being unwell. Often symptoms are worse before a

menstrual period and they are often thought to be just pre-menstrual tension. The most common

signs and symptoms are arthritis, fatigue, skin rashes, sun sensitivity, hair loss, kidneys,
depression, and some other symptoms.       During a lupus flare-up the most common complaints

are of flu-like symptoms (with or without fever), fatigue, muscle and joint pains. Often

symptoms are reported to be worse before a menstrual period and they are often thought to be

just pre-menstrual tension. People with lupus can also have a variety of other symptoms

including high temperature, blood disorders, miscarriage, headaches, weight loss, chest pain and

abdominal pain. However, it is important to remember that the symptoms can vary greatly from

person to person. People with DLE tend to be quite sensitive to the sun. They are more likely to

get sunburn and the sun is likely to worsen their discoid lesions (Lahita, 2001).

         Neonatal Lupus has few symptoms like skin rash, liver abnormalities, low blood

counts, and heart defects. Since it happens in babies given by the mom who is pregnant with the

baby the symptoms could be seen in the mom. Flares most often occur during the first or

second trimester, or during the two months immediately after delivery. Most of the flares tend

to be mild. Approximately 33 percent of lupus patients will have a decrease in platelet count

during pregnancy, and about 20 percent will have an increase in or new occurrence of protein in

the urine. It is important to distinguish the symptoms of a lupus flare from the normal body

changes that occur during pregnancy (Lockshin, 1994).

Treatments:

         Treatments for lupus are not easy to find. There is no known cure for lupus so the

only option is to use home care. Home care for lupus generally involves taking prescribed

medications and using sunscreen whenever patients go outside because lupus patients are known

to be sensitive to the sun. For most of the symptoms, they can take medications because the

symptoms are from swelling or inflammation and there are medications for it. Some

medications are non-steroidal anti-inflammatory drugs (NSAIDS), which are often used to
moderate joint/muscle pain and inflammation in people who have minor SLE. This medication

comes in many different forms. Another kind of medicine is anti-malarial drugs, which are

medicines that are used to prevent or treat malaria, joint pain, skin rashes, and ulcers. Two

types of anti-malarials are hydroxychloroquine (Plaquenil) and chloroquine (Aralen). In

addition, there are corticosteroid hormones that are powerful drugs, which reduce inflammation

in various tissues of the body. This medication can be taken by mouth, by cream applied to the

skin, or by injection.

          When a patient has a severe case of lupus and their major organs don’t function

properly, there is a treatment that is used known as Immunosuppressive agents/chemotherapy.

All of these drugs suppress the immune system to limit damage to the organs. Some examples

are azathioprine (Imuran) and cyclophosphamide (Cytoxan). For a patient without a known

diagnosis of lupus, the doctor will assess, but never likely provide a major diagnosis of lupus

unless there are clear and unmistakable features. Evaluation of chronic (not acute) diseases is

done in a medical office setting. However, certain tests to assess the possibility of organ

damage including some blood and urine tests, imaging studies, and heart tracings will allow the

doctors to assess an acute disease if someone with lupus seeks treatment in an emergency

department (Lahita, 2001).
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