Nature of the Immune SystemI. Historical ConceptsII. Specific Immunity

Terry Kotrla, MS, MT(ASCP)BB

Age of Serology Time period from 1900 to 1950 called era of

international serology. Immunology is a relatively new science. Tests developed to detect presence of immune

substances in the blood.

Introduction Immunology defined as the study of the

reaction of a host when foreign substances are introduced into the body.

Immunity is the condition of being resistant to infection.

Serology is the study of the noncellular components in the blood.

Vaccination Purposeful exposure of individual to

infectious material. Early forms of vaccination were developed in

ancient China as early as 200 B.C. Used powdered scabs from people infected

with smallpox was used to protect against the disease.

Vaccination – Edward Jenner Smallpox affected all levels of society. Noticed that milkmaids did not generally get

smallpox. Jenner theorized that the pus in the blisters

which milkmaids received from cowpox (a disease similar to smallpox, but much less virulent) protected the milkmaids from smallpox.

Vaccination – Edward Jenner Inoculated 8 yr old with material from pus in

cowpox blisters. Exposed boy to infectious agents and no

disease followed. Jenner's unique contribution was not that he

inoculated a few persons with cowpox, but that he then proved they were immune to smallpox.

Cow Pox versus Small Pox

Vaccination A vaccine - biological preparation that improves

immunity to a particular disease. A vaccine typically contains a small amount of an

agent that resembles a microorganism. Stimulates the body's immune system to recognize

the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.

Vaccination - Types Killed microorganisms Attenuated – live organisms cultivated to disable

virulent properties Toxoid - inactivated toxic compounds in cases where

these (rather than the micro-organism itself) cause illness

Subunit -fragment create an immune response Conjugate-linking outer coats to proteins which can

the lead immune system to recognize

Rabies Louis Pasteur applied this principle of attenuation to

a rabies vaccine. Developed a rabies virus that was milder and had a

shorter incubation (development) period than the wild virus.

A person bitten by a rabid animal would be inoculated with the Pasteur virus and rapidly develop immunity to the wild strain.

Rabies He developed his rabies vaccine by growing the

virus in rabbits, then drying the affected nerve tissue to weaken the virus.

On July 6, 1885, the vaccine was administered to a 9-year-old boy who had been attacked by a rabid dog.

The boy survived and avoided contracting rabies, which would have almost certainly proved fatal.

Rabies

Cellular versus Humoral Immunity Cellular - Researchers observed that foreign

substances were removed by specialized cells in a process known as phagocytosis.

Humoral - Other researchers postulated that substances in the blood provided protection from microorganisms, humoral immunity.

Natural (Nonspecific , Innate) Immunity Non-specific immunity

First line of defense against infection Uses body functions

Coughing, sneezing, cilia HCl in stomach, wax in ears, enzymes in tears Circulating and tissue cells Circulating substances

Two mechanisms – external and internal

Physical barriers – Intact Skin

Physical Barrier - Cilia

Physiological factors Stomach acid kills pathogens and sterilizes food. Mucus lining of lungs traps pathogens and cilia move

particles out to throat and it is swallowed. Tears wash away pathogens and have bacteriocidal enzymes. Flushing action of urine Skin: Difficult for a pathogen to penetrate, sweat creates high

salt conditions, oil layer makes an inhospitable environment. Normal flora prevents growth of opportunistic pathogens in

mouth, large intestine and reproductive system

Factors Modify Defense Mechanisms Age Hormones Drugs and chemicals Malnutrition Fatigue and stress Genetic determinants

Nonspecific Immunity: Second line of defense Inflammatory response - four classic signs are

redness, swelling, heat and pain. Dilation of capillaries (hyperemia) to increase blood

flow to area Chemotaxis - chemicals released which cause phagocytic

white cells to migrate to the area. Increased capillary permeability allowing white cells to

go to injured area, a process known as “diapedesis” Formation of exudate - same composition as plasma and

it contains antibacterial substances, phagocytic cells, and drugs and antibiotics, if present.

Inflammatory Response

Inflammatory Response

Inflammatory Response

Second Line of Defense If bacteria are not successfully killed locally, may further

invade the host by way of the lymphatics to the regional lymph nodes. within lymph nodes the bacteria meet other phagocytic cells bacteria may overcome these and gain access to the

bloodstream where they meet circulating phagocytes (neutrophils and monocytes).

may pass through the bloodstream and reach organs such as the liver and spleen where they come into contact with tissue macrophages.

although a powerful defense system, this final phagocytic barrier may be overcome, with seeding of the microorganism to organs such as bone, brain, and kidney, terminating in fatal septicemia.

Phagocytosis1. Initiation is caused by damage to the tissues, either by trauma or as a

result of microbial multiplication.2. Chemotaxis, attraction of leukocytes or other cells by chemicals.3. Opsonization - Opsonization coating a pathogen by substances so as to

enhance phagocytosis.4. Adherence, firm contact between phagocyte and microorganism.5. Engulfment into cytoplasm and enclosed in a vacuole.6. Digestion enzymatic contents in vacuole destroy the microorganism.

Number of killing mechanisms operating in the vacuoles of phagocytic cells. One of the major mechanisms involves hydrogen peroxide which, acting

along with an intracellular enzyme, is rapidly lethal to many bacteria.

Phagocytosis

Phagocytosis http://www.cellsalive.com/ouch.htm http://health.howstuffworks.com/adam-200096.htm

http://tinyurl.com/6oa779

Cells of the Non-Specific Immune System Cells involved in non specific immunity.

Phagocytic cells Mononuclear phagocytes Polymorphonuclear phagocytes Eosinophils

Mediator cells Basophils and mast cells Platelets

Cells involved in specific immunity

Lymphocytes Plasma cells

Origin of immune cells Origin of all these cell types are stem cells found in the bone

marrow. These self replicating cells differentiate into two types of

"committed" stem cells. One group differentiates further and matures to become platelets,

erythrocytes (red blood cells), monocytes or granulocytes. Second group produces cells of the lymphoid line only.

The lymphoid line will develop into 2 different types, T and B cells, depending upon where they complete their maturation, thymus or bone marrow.

Phagocytic Cells Mononuclear phagocytes - include both circulating blood

monocytes and tissue macrophages found in various tissues of the body. Arise from bone marrow stem cells Not end cells, they may divide. Ingest and destroy material such as bacteria, damaged host cells or

tumor cells (non-specific immunity). Stay in peripheral blood 70 hours - migrate to tissues, double in size,

then called tissue macrophages. Tissue macrophages named according to tissue location-

liver=Kupffer cells, brain-microglial cells, etc. Phagocytosis takes place to a greater degree in tissues.

Monocyte and Tissue Macrophage

Polymorphonuclear phagocytes AKA Neutrophils

Characterized by a large nucleus, usually with 3 - 5 lobes, and the presence of numerous, specific granules in the cytoplasm.

Arise from bone marrow stem cells. They are end cells. Primary function is ingestion (phagocytosis). Clear body of debris such as dead cells and thrombi. Able to move into tissues by diapedesis -wander

randomly

Neutrophil Involved in Phagocytosis

Eosinophils Easily distinguished by the presence of large granules in their

cytoplasm which appear red when stained by routine hematology stains.

Much less phagocytic than macrophages or neutrophils Function is far from clear, however the numbers increase

greatly in certain parasitic diseases and allergic diseases. Both neutrophils and eosinophils contain specific granules,

the granules contain various enzymes which are released under certain circumstances.

Eosinophil

Mediator Cells Influence the immune response by releasing various

chemical substances into the circulation. Have a variety of biological functions

Increase vascular permeability Contract smooth muscle Enhance the inflammatory response

Two types basophils/mast cells Platelets

Basophils and Mast cells

Basophils easily identified due to large numbers of bluish-black granules in the cytoplasm.

The granules are a source of mediators such as histamine (vasoactive amine that contracts smooth muscle) and heparin.

Basophils and platelets are found in the circulation, mast cells are situated in the tissues of skin, lung and GI tract.

Circulating basophils greatly resemble tissue mast cells and it is likely that they are closely related in function.

Both of these cells play a role in hypersensitivity (allergic) reactions.

Basophil

Platelets Small non-nucleated cells derived from

megakaryocytes of the bone marrow. Important in blood clotting. Contribute to the immunological tissue injury

occurring in certain types of hypersensitivity reactions by releasing histamine and related substances which are contained within specialized granules in their cytoplasm.

Megakaryocyte & Platelets

Soluble Factors Many soluble tissue and serum substances help to suppress

the grow of or kill microorganisms. Interferons - family of proteins which are important non-

specific defense mechanisms against viral infections. Transferrin - Bacteria do not thrive well in serum that

contains low levels of iron but high levels of transferrin. Complement - a group of proteins that are essential for

bacterial destruction and plays an important role in both non-specific and specific immune mechanisms.

Acute Phase Proteins Defined-normal serum constituents that increase rapidly

because of infection, injury, or trauma to tissues. Acute-phase proteins are a class of proteins whose plasma

concentrations increase or decrease in response to inflammation.

This response is called the acute-phase reaction . In response to injury local inflammatory cells (neutrophils,

granulocytes and macrophages) secrete a number of cytokines into the bloodstream, most notable of which are the interleukins.

The liver responds by producing a large number of acute-phase reactants.

C-Reactive Protein Increases rapidly within 4-6 hours of infection

or injury. Returns to normal rapidly once condition

subsides. Used to monitor healing and has also

increased in usefulness in diagnosing Myocardial Infarction.

Complement A series of serum proteins involved in

mediation of inflammation but also involved in opsonization, chemotaxis, and cell lysis.

Alpha-1 Antitrypsin Plays important role preventing breakdown of

enzymes in various organs of the body and protects the lungs so they can work normally.

When the lungs do not have enough alpha-1 antitrypsin, neutrophil elastase is free to destroy lung tissue.

As a result, the lungs lose some of their ability to expand and contract (elasticity). This leads to emphysema and sometimes makes breathing difficult.

Haptoglobin Binds irreversibly to free hemoglobin to

protect kidneys from damage and prevent loss of iron by urinary excretion.

Haptoglobin - hemoglobin complex removed by RES, mainly spleen.

Used to monitor hemolysis

Fibrinogen A coagulation factor integral to clot formation

which serves as a barrier to prevent spread of microorganisms further in the body.

Levels increase with tissue inflammation or tissue destruction.

Thought to play a key role in the inflammatory response and development of rheumatoid arthritis.

Ceruloplasmin The major copper containing protein in plasma, plays a role in

iron metabolism and histamine regulation. Stimulates the immune system to fight infections, repair

injured tissues and promote healing. Depletion found in Wilson’s disease, causes the body to

absorb and retain excessive amounts of copper. Copper deposits in the liver, brain, kidneys, and the eyes. The deposits of copper cause tissue damage, necrosis (death of the

tissues), and scarring, which causes decreased functioning of the organs affected.

Liver failure and damage to the central nervous system (brain, spinal cord) are the most predominant, and the most dangerous, effects of the disorder.

Alpha-1 Acid Glycoprotein(AGP) An acute phase protein manufactured in the liver and found

in the blood of humans and animals. In simplest form, detection of elevated levels of AGP has

been shown to indicate background illness or other stressors when animals appear clinically normal.

Acute phase proteins such as AGP are elevated during acute or chronic periods of inflammation or infectious diseases, following surgery, with malignant tumors, in autoimmune diseases, liver cirrhoses and with all types of stress in general.

Other effects related to elevated levels of AGP are immunosuppression, poor response to vaccines, etc.

Immunity – Very Complex System

References http://www.horton.ednet.ns.ca/staff/Selig/isu/Immunity/Innate.htm http://www.metacafe.com/tags/neutrophil/most_popular/