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IMMUNE SYSTEM

LYMPHATIC SYSTEM
Much of the liquid which is brought to a tissue by arteries does not return through veins. The liquid is known as lymph (about 24 liters are made per day). Lymph returns to the cardiovascular system through lymphatic vessels and a break in a major lymphatic vessel is potentially fatal. The lymphatic system also performs immune reactions.

TYPES OF LYMPHATIC TISSUE

There are nodules of lymphatic tissue found in the tonsils, appendix, and lymphatic follicles of the small intestine (such as the Peyer's patches depiucted below)..

peyer's patches

1) Secondary lymphatic organs are where most immune responses occur. They include:
I) lymph nodes:
Lymph nodes are bean-shaped organs through which lymph must pass as it returns to the cardiovascular system. They are most concentrated in the armpit, groin, and neck. Leukocytes congregate here and many initial encounters between immune cells and microbes occur here. Lymph nodes filter lymph: foreign particles are caught in a web of reticular fibers where macrophages and lymphocytes can dispose of them.
II) spleen:
The spleen is a lymphoid organ that filters blood & fluid in a manner similar to lymph nodes. It phagocytizes bacteria and worn out blood cells. It is the largest mass of lymphatic tissue in the body, measuring about 5" in humans.
The spleen is pictured below in a human model.

spleen

2) primary lymphatic organs:
Primary lymphatic organs produce immunocompetent lymphocytes. Red bone marrow is the site where lymphocytes are made. Lymphocytes which that stay become B cells; pre-T cells travel to thymus where they mature into T cells.


IMMUNE SYSTEM
The world is full of organisms that would like to put the biomolecules of the human body to their own uses.Parasites obtain food (and sometimes shelter) from their hosts. Some are temporary (mosquitoes & fleas) while others are permanent (many microbes). Some are ectoparasites living on the outside of the host (mosquitoes & fleas) while others live inside the host as endoparasites (tapeworm, malaria, HIV). At least half of the people in the world have parasites.
1) VIRUSES
Viruses are not technically alive since they cannot perform metabolic reactions without utilizing the resources of a host cell. All viruses are intracellular parasites. Their structure varies: some have RNA, some DNA. Some are surrounded by protein coats; some have envelopes. In humans, viruses cause colds, flus, polio, smallpox, chickenpox, measles, hepatitis, rubella, herpes, genital warts, mumps, rabies, Ebola, Lassa, Hanta, and some cervical cancers (papillomaviruses). HIV evolved from a family of primate viruses (SIV) and within a 5 years of its discovery was known from every country on earth. HIV may remain dormant for a decade in cells with the appropriate cell membrane receptors (most are immune cells). As these immune cells die, the body is now vulnerable to many infections which never threaten healthy individuals.
2) BACTERIA
Bacteria are unicellular organisms that lack a nucleus and internal organelles; they are the smallest and simplest forms of life on earth. The vast majority of bacteria are free living and do not cause disease--they actually serve many positive roles in ecosystems from decomposing dead material to helping plants fix nitrogen from helping you absorb vitamins in your large intestine). Some bacteria are parasites that do cause disease in protists, fungi, plants, and animals. In humans they may be dangerous because they can destroy tissues, because their waste products are toxic to us, or because some have molecules in their cell walls that induce high fevers.
bacteriabacteria

bacteriabacteria
Bacteria are responsible for many human diseases including:


--respiratory infections (Streptococcus and Staphylococcus, pneumonia, Legionnaire's disease, tuberculosis, whooping cough, plague)
-- diarrheal diseases which kill 5 million annually (much more common in US before improved sanitation and water treatment; in 1900 killed more than 5% NYC infants
E.coli, typhoid fever, dysentery
toxins: diptheria, anthrax
--food poisoning: (Staphylococcus, botulism)
skin infections: leprosy, many rashes
urogenital infections: UTIs, vaginitis, gonorrhea
other: dental disease, ulcers, meningitis

3) PROTISTS
Protists, plants, animals, and fungi are all composed of cells that have nuclei and internal organelles.
Most protists are unicellular; many are free-living and do not cause disease (algae, Paramecia). Some diseases are caused by protists such as malaria, amoebic dysentery, African sleeping sickness, cholera, giardia, amoebic dysentery.

Plasmodium in malaria:
plasmodia

African Sleeping Sickness
trypanosome


4) FUNGI
Fungi grow in filaments called hyphae (which are often multinucleate); masses of hyphae are called mycelia. Most fungi are decomposers, many of our antibiotics come from fungi. Although many fungi are plant parasites, very few affect human health (the most common fungal infections being athlete=s foot, jock itch, and barber=s itch; ergot can cause food poisoning leading to convulsions). Yeast are single celled fungi which can cause serious infections of the respiratory, digestive, and reproductive tracts if their reproduction is not controlled (e.g. in those that are taking antibiotics which kill the bacteria yeasts compete with, HIV patients).

5) PLANTS
Virtually all plants obtain their energy from photosynthesis and they do not cause disease in humans.

6) ANIMALS
--Fatworms (tapeworms):
Tapeworm larvae may be ingested (especially undercooked pork) or burrow through skin (especially after wading in water contaminated with fecal material where the intermediate snail host may occur). They travel through blood, mature in liver, and take up residence near intestines. Females may store over 100,000 eggs. Tapeworms can reach great lengths in a variety of animal hosts, 6-20 meters.
Roundworms (including hookworm & pinworm)
Some roundworms are ingested in fecally contaminated food or water (flies may transport eggs from latrines). They inhabit intestines and females may release 200,000 eggs/day. One class can be ingested in undercooked pork.

worm


Arthropods
Insects such as mosquitoes, flies, fleas, lice, bedbugs not are only ectoparasites, but many carry pathogenic microbes (mosquitoes carry malaria, Chagas disease, and yellow fever; fleas bubonic plague; lice carry typhus; flies African sleeping sickness).
Arachnids include ticks (ectoparasites and may carry diseases such as Rocky Mountain spotted fever and Lyme disease) and mites (common in oil glands near hair; barbers itch and chiggers)

tick

Mammals
Many mammals can be carriers of rabies; felines commonly transmit toxoplasmosis.

7) CANCER CELLS

Many cancer cells can be identified as foreign and destroyed by immune cells. Cells of breast and uterinc cancers are depicted below.

cancercancer

IMMUNE SYSTEM
A) INNATE IMMUNITY
1) anatomical barriers
Our outer skin is composed of dead epithelial cells cemented together and filled with keratin waterproofing. This results in a tough, impervious, waterproof covering of our bodies. The flaking away of cells from all epithelial surfaces removes microbes which have attached. Microbes can be flushed from body surfaces through sweat, urine, lacrimation (eye), saliva (brings them into harsh environment of stomach), vomiting, defecation, and sneezing. Nasal hair traps large particles, air turbulence causes smaller ones to stick to mucus that the ciliated cells of trachea escalate to be swallowed or removed.
2) antimicrobial chemicals
Our bodies produce a number of antimicrobial chemicals. Lysozyme kills bacteria and is present in tears, saliva, and nasal secretions. Our skin contains NaCl (from sweat), K ions, urea, and lactic acid inhibit microbial growth. The acidic environments of skin (from secreted fatty acids and lactic acid), stomach (pH 1.2-3.0), and vagina inhibit microbial growth. Interferon is secreted by cells infected with viruses secrete; this stimulates neighboring cells to make antiviral proteins (slow or inhibit viral replication).
3) white blood cells (leukocytes):
Leukocytes serve as the second line of defense for bacteria that have entered the body. Neutrophils, macrophages, and eosinophils undergo phagocytosis of microbes (eosinophils may spit their enzymes at multicellular parasites). Basophils induce inflammation.
Inflammation and fever are innate responses to infection.

The following images depict a neutrophil and a macrophage ingesting microbes.

neutrophilmacrophage

B) ACQUIRED IMMUNITY
Only vertebrates have acquired immunity; this is our 3rd line of defense for microbes that have penetrated the innate defenses. There are two primary types of lymphocytes which function in our acquired immunity:

lymphocytes
--B cells mature in the bone marrow and make antibodies. They primarily attack bacteria & dissolved antigens (toxins, allergins).
--T cells mature in the thymus and are responsible for cell-mediated immunity. They primarily attack intracellular pathogens such as viruses, some fungi and can defend against some cancer cells.

MHC


How do our immune cells know which cells belong to our bodies and which must be destroyed? One set of human genes (called the Major Histocompatibility Complex (MHC) codes for our "cellular fingerprint". This consists of the glycoproteins found on the surfaces of all cells (except rbcs) which is the code for "self"; cells that lack this code are "nonself". Each human cells has several thousand of these glycoproteins.
In addition to lacking the proteins for self, microbial molecules can be recognized as antigens--foreign molecules that trigger the immune response. Antigens are molecules, molecular complexes, or parts of a microbe that lymphocytes can recognize as foreign--microbial fingerprints. Small molecules typically aren't antigenic although some may bind to human proteins and cause allergies. Such molecules are called haptens.

1) Humoral Immunity--refers to "humor" or liquid; immunity can be transferred between individuals through blood serum which is cell-free; the serum contains antibodies (such as that depicted below).


As your body attempts to produce antibodies against every possible kind of microbe, many antibodies develop that would cause a reaction against "self". These are usually suppressed in the thymus and bone marrow. Unfortunately, this suppression is not always complete and there are a number of autoimmune diseases in which immune cells attack the host cells (psoriasis, rheumatoid arthritis, multiple sclerosis, narcolepsy, type I diabetes, Grave's disease, Addison's disease, chronic hepatitis, and systemic lupus)

There are various classes of antibodies. IgG composes 80% of the antibodies in blood plasma. IgM antibodies are the largest class and are located on B cells; they are the first produced in response to antigen. IgA antibodies are located in body's secretions such as milk, saliva, nasal & intestinal mucus; protects mucus membranes. IgE antibodies are involved in allergic reactions and responses to parasites.

B cells may have 100,000 antibodies of a single class on cell membrane serving as receptors. When an antigen binds to an antibody, the B cell rapidly divides to produce 2 types of cells:
a) memory cell
Memory cells contain the same antibody and may live over lifetime; thousands may be created during an infection. If microbes with the same antigen ever invade the body again, the immune response will occur more quickly.

b) plasma cell:
Plasma cells make antibodies and release them into the blood. Antibodies bind to antigens. The antibody/antigen interaction activates a set of complement proteins which circulate in the blood; these complement proteins form a complex that generates a permanent hole in the microbial membrane. These complement proteins also stimulate the histamine release of basophils, attract neutrophils and macrophages, and cover the microbial membrane to make it easier to phagocytize (opsonization)and limits its movement.

 


2) Cell-Mediated Immunity
T cells recognize subtle changes in infected cells & cancerous cells; have receptors that must detect both the normal cell fingerprint and altered or foreign proteins. There are various kinds:
--Killer T cells kill specific foreign or infected cells by putting holes in the membrane with proteins called perforins. They attack fungi, protozoa, virally infected cells, abnormal cancerous cells, and may attack cells from other cells or humans (graft rejection). If they are not controlled properly, they can cause autoimmune diseases.
--T-helper cells are needed for killer T cell & B cell function. They are the primary target of HIV. Without T helper cells, other immune cells can do very little on their own.


--T-suppressor cells limit antibody production to only that which is needed by secreting suppressor factors that control T and B cell replication after the response is over. They can prevent autoimmune diseases.


Immunization is similar to boot camp: immune defenses practice on a dummy army. As a result of this practice memory T & B cells produced that will improve the response if a real army is ever encountered. Before a specific antigen is introduced to the body, there may only be a few T or B cells that could identify it; after memory cells are created, there are thousands.
Vaccines may be produced from killed micro-organisms, strains which are cultured to lose virulence, inactivated toxins, and pathogen parts that serve as antigens. Many vaccines are being produced through genetic engineering to limit the risk of accidental infection.

Allergies:


The most common type of allergy occurs when IgE is (mistakenly) produced as the major antibody in response to a specific antigen (thought to be genetic). IgE has a receptor that attaches to basophils and mast cells that contain granules of molecules that can trigger the inflammatory response (histamine, serotonin, leukotrienes). When the antigen is present (after a sensitizing dose that causes no effect), the reaction with the IgE receptors causes these cells to release their granules causing a general inflammatory response, decreased blood pressure, strained breathing, and perhaps even anaphylactic shock.

Disease and History
Humanity has long suffered from devastating diseases. In many instances, epidemics have been so significant that they have impacted history. In 430-429 B.C., Athens (along with Egypt and Persia) suffered a disease which killed 1/4 of its army; this was a factor in its losing the war against Sparta. In 161-2 A.D. a plague in China that kills 30-40% of the population; the Han dynasty fell soon afterwards. In 165 A.D. Roman troops brought back a disease from Mesopotamia (smallpox or its ancestor?) that decreased the population around the Mediterranean for 500 years. A great outbreak occurred in Rome from 251-266 at the height of which 5,000 people a day were dying in Rome. The Roman Empire declined after 180 A.D. and was sacked in 410 A.D.
Charlemagne's conquest of Europe was slowed by an 8th century flu. A 310-12 A.D. a plague in China only leaves 2-3% of the population alive in the northwest; the government breaks down in 317. In 542-3 A.D. the bubonic plague arrives in Europe; up to 10,000 a day died in Constantinople at its height; Justinian's efforts to reunite the Roman Empire fail; Rome and Persia offer little resistance to the Moslem Invasion in 634. Between 526-1027 A.D., 49 epidemics hit Britian; the last few were minor; only in the year 950 could they repel a Viking raid. In 742 8.9 million Chinese die in a plague; there is a military revolt in 755. In 1346, the bubonic plague returns to Europe; between 20-45% of the population dies. Typhus contributed to the French halting their invasion of Italy (before conquering Naples) in the wars of 1494-1559. From 1200 to 1400, China's population halves due to plague.
In 1580 a flu hits Spain, some cities are virtually depopulated; during the 1600s, 1 million Spaniards die of the plague, Spain afterwards decreases in economic and political power. Many in Europe felt that the plague was a sign of God's wrath and Jews were often blamed (tens of thousands of Jews were killed as a result; Strasburg alone slew 16,000); Jews migrated to Eastern Europe where the plague was less severe. The Catholic Church could not justify the plague; anti Church sentiment grew, contributing to Martin Luther's later success.
American Indians were decimated by European diseases; overall, 95% of the populations died. Smallpox reached Mexico before Cortez weakening the Aztecs. In the 100 years after Cortez, Mexican tribes lost 4.6 million individuals (90%). Plagues hit Peru and kill the Inca and his heir; civil war broke out; Pizarro arrived in the aftermath. Plague in New England 3 years before pilgrims arrive; in later plagues the pilgrims think that God is on their side as only the Indians were affected.
In 1802 yellow fever kills 33,000 of Napolean's troops in the New World, he enters into the Louisiana Purchase in 1803. More die from disease in Napoleanic Wars and the U.S. Civil War than by gunfire; Napolean had hemorroids at Waterloo and could not mount his horse until 10 AM; he would have most likely won the battle if he had attacked at dawn (as was his habit); in the Crimean War (1854-6) 10 times the number of British died from dysentery as from gunfire; in the Boer War, the British lost 5 times those shot due to dysentery. In 1845 potato blight leads to famine that affects Irish, Belgians, and Germans; typhus spread more easily; millions die, many migrate to U.S. During the Franco-Prussian War, 20,000 French troops died of smallpox; the Prussian losses were minimal since the soldiers were vaccinated.
Between 2-3 million die in WWI from typhus. In 1793 a yellow fever outbreak in Philadelphia killed 15% of the city's population. In 1918, the Spanish flu kills 21 million people worldwide; 500,000 in U.S. (10% U.S. population was bedridden; 20,000 died in NYC); Ghana and W. Somoa lost 20% their populations.
As the use and availability of antibiotics increased in the early 20th century, there was a great feeling of optimism concerning humanity's eventual defeat of communicable diseases (in 1967 the U.S. Surgeon General stated it was time to close the book on these diseases); many diseases were eradicated from the U.S., smallpox was eradicated from the world. This triumph was premature and at the close of the 20th century, microbes were staging a frightening comeback:
--new, deadly diseases appeared: Marburg virus (1967), Lassa (1969), Ebola (1976), Legionaire's disease (1976), HTLV I & II (early 1980s), HIV-1 (1981), HIV-2 (1984), a variety of hanta viruses (first seen in Korea in the 1950s, outbreaks in U.S. in late 1980s), TSS-1 Staph (1982), Lyme's disease, E. coli 0157:147 (1982), hybrid HIV-herpes viruses, and a number of lesser microbes
--antibiotic resistant strains of most microbes were becoming difficult (if not impossible to treat) especially malaria, gonorrhea, syphillis, Strep, Staph, pneumococcus, leprosy, Shigella, Enterococcus, HIV, and tuberculosis
--chlorine resistant strains of E. coli, Legionnaire's disease, and Cryptosporidium were spread by water systems
These diseases were affecting Third World Countries most: each year 3 million children (mostly infants) died of respiratory diseases, 2 million from diarrheal diseases, and 2 million from malaria; some previously expanding countries actually have negative growth rates due to HIV .

AIDS
--there are a number of simian viruses that are relatives of HIV viruses including SIVmac (macaques), SIVagm (African green monkeys), SIVsb (sooty mangabey), and SIVcpz (chimpanzee)
--HIV-2 and SIVmac are now considered to be the same disease; SIVcpz is as similar to HIV-1 as the various strains of HIV-1 are to eachother; two lab workers in U.S. obtained HIV-2 directly from monkey bites
--there are a number of patients who are thought to have died from HIV before the 1970s; some positive blood tests were erroneous, others may be true but cannot be repeated
--although HIV may have caused deaths in various continents prior to the 1970s, it did not enter large populations of people until the 1970s
--all the data collected suggests that in the early 1970s "something" happened
--a new strain of HIV-1 appeared at a time when there were very favorable conditions for its spread: large scale instability in large areas of sub-Saharan Africa (war, large migrations), reuse of needles due to scarcity in African clinics, sexual promiscuity in the U.S. and Europe (especially among homosexual men) which caused the NIH to change its definition of multiple sex partners in surveys from 10-20 per year (1975) to 100 (1978) to 500 or more (1980), heroin epidemics throughout the world in which needles were shared, a significant rise (in U.S. and throughout the world) of all classes of STDs, and untested global blood supplies (where drug addicts would often donate for extra money) coupled with new technology for obtaining clotting factors for hemophiliacs
--in the U.S., another factor which retarded prevention efforts (compared, for example, to the TSS outbreaks that occurred at the same time and cost fewer lives) was the philosophy that communicable diseases no longer posed serious threats and an Administration that did not receive its support from the groups that were first hit with the disease
--frozen blood samples from late 1970s contained HIV; in San Francisco and New York blood samples frozen from hepatitis B study involving 7000 homosexual men show that in 1978 3% samples HIV +, by 1979 12% were positive, and by 1981 45% were positive
6/5/81: federal Centers for Disease Control (CDC) published in weekly bulletin Morbidity and Mortality report
--5 young men at 3 L.A. hospitals suffered form protozoan Pneumocytosis carinii pneumonia (lungs progressively fill with liquid); by the time the article was published, 2 had died
--"three patients had profoundly depressed numbers of thymus-dependent lymphocyte cells and profoundly depressed ... responses to mitogens and antigens"
7/3/81: CDC published in MMWR
--described Kaposi's sarcoma as well as Pneumocytosis carinii pneumonia in 26 young homosexual men, 20 patients from NYC and 6 from California
--Kaposi's sarcoma is a mild skin cancer of older men of Mediterranean descent but in these patients it was aggressive and deadly, with blue-violet lesions on the skin and mucous membranes
--in some publications, termed gay-related immune deficiency, GRID
--late in 1981, CDC received reports of IV drug users who suffered from Pneumocytosis pneumonia and immune deficiency
--early 1982, seemed that heterosexual couples could transmit the disease to each other; later found from blood transfusions to hemophiliacs
--in the first year of the disease's discovery, heterosexual victims were diagnosed; nevertheless, the White House would not formally accept that HIV could be transmitted heterosexually until 1990 and one 1988 candidate for presidential nomination, Pat Robertson, stated that all scientists who made such a claim were "frankly lying"
--by 6/11/82, 355 cases from 5 states
--9/3/82 named AIDS
--early 1983, 16 countries reporting AIDS, more than 1,000 Americans from 34 states diagnosed (of which more than 1/2 had died); later first cases of mother-child transmission
--concern increased when a California man who was a hemophiliac gave AIDS to his wife who then gave it to her newborn; no longer considered a disease of homosexuals and drug-users
--for the first 3 years, the number of diagnosed cases doubled every 6 months
--1985 Gallo's group developed a blood test for AIDS; over the next 4 years only 4 cases of AIDS were linked to transfused blood
--1985 health officers in Africa report that AIDS epidemic was widespread
--seemed to spread in a way similar to other sexually transmitted diseases

--although some African countries did have the highest known infection rates (under 10%), the original estimates were much higher (50-70% because malaria caused false positives); many African authorities were reluctant to cooperate with international efforts afterwards
--1986 international commission of biologists named the virus that causes AIDS HIV (ending the use of both the American and French names together, HTLV-III/LAV)
--8/ 1989, 100,000 diagnosed cases of AIDS in U.S.
--1/25/91, more than 100,000 had died of AIDS in U.S.; for men aged 25-44, AIDS was second only to unintentional injuries as causes of mortality; in women of the same age it was in the top 5
--1993, more than 275,000 AIDS cases diagnosed in U.S., estimated that more than 1 million in total
--AIDS has been reported form every country
--1995: Asian epidemic great enough that a dispute over which continent is now the AIDS epicenter, Africa or Asia (Asia will almost certainly be the epicenter by the year 2000)
--some countries such as Bangladesh are addressing this issue while others, such as India, are denying it
--in 1996, India is approaching the 5 million infection mark; China is very vulnerable but as yet may have under 100,000 infections
--Bangladesh still has a problem: it is estimated that there are 100,000 sex acts with HIV+ prostitutes
--Thailand will soon have a negative growth rate
--80% those who die in Zimbabwe die of AIDS related illnesses; in major hospitals, over 300 die/week
--in 1995, U.S. infection rate dropped with only 40,000 new cases
--in 1995 worldwide, 1 million people died of AIDS (bringing the total to 4.5 million); U.N. predicts that 11-14 million will be infected by the year 2000
--in 1996 drug treatments became available that made HIV treatable
--90% cases are in developing nations; new drug treatments cost $15,000/year and will be unaccessible to most infected
--HIV-1 viruses have already become resistant to individual drugs, this rapidly mutating virus (mutations change 1% genome/year), some strains resistant to the multi-drug cocktail; resistant strains have already been spread
Number of HIV cases at the end of 1999:
North America 920,000, Caribbean 360,000, South America 1,300,000, North Africa 220,000 , Sub-Saharan Africa 23,300,000, Europe 520,000, Russia 360,000, East Asia 530,000, South-east Asia 6,000,000, Australia 12,000
Number of HIV deaths by the end of 1999:
North America 450,000, Caribbean 160,000, South America 520,000, North Africa 70,000, Sub-Saharan Africa 13,700,000, Europe 210,000, Russia 17,000, East Asia 40,000, South-east Asia 1,100,000, Australia 8,000
New Infections in 1999:
North America 44,000, Caribbean 57,000, South America 150,000, North Africa 19,000, Sub-Saharan Africa 3,800,000, Europe 30,000, Russia 95,000, East Asia 120,000, South-east Asia 1,300,000, Australia 500
2000B18.8 million have died from world wide; it is the 4th largest killer; 34.3 are currently infected; 2.8 million died in 1999
BRussia is still at an early stage but is one of the fastest growing regions for infections

HOST EFFECTS
--HIV can incorporate itself in human chromosomes and remain relatively dormant for years, sometimes a decade; during this time the infected individual does not display symptoms but can transmit the disease
--levels of T cells drop from the normal 600-700 cells/ml blood to 200 as full-blown AIDS begins (less than 200 CD4 T cells/ ml in an HIV positive individual is the classification of AIDS) to near zero
--since T Helper cells are required for both killer T cell and B cell function, their death cripples the immune system
--the loss of these cells, which defend against fungi and protozoa in addition to bacteria and viruses, explains the prevalence of protozoal (Pneumocytosis carinii and Toxoplasma gondii) and fungal (Candida albicans and Cryptococcus neoformans) diseases
--macrophages have CD4 receptors and are not killed by the virus; macrophages are among the few cells that cross the blood-brain barrier;
--brain cells also have CD4 receptors; gp120 in brain tissue may interfere to the degree that it causes the AIDS-dementia complex