Functional Medicine Training Program Page1 of 23 Insider’s Guide – Physiology of Immune System Copyright © 2008 Sequoia Education Systems, Inc

Functional Medicine University’s Functional Diagnostic Medicine

Training Program

INSIDER’S GUIDE

PHysiOlogy of the Immune system:

Innate and acquired By Ron Grisanti, D.C. & Dicken Weatherby, N.D.

http://www.FunctionalMedicineUniversity.com

Limits of Liability & Disclaimer of Warranty We have designed this book to provide information in regard to the subject matter covered. It is made available with the understanding that the authors are not liable for the misconception or misuse of information provided. The purpose of this book is to educate. It is not meant to be a comprehensive source for the topic covered, and is not intended as a substitute for medical diagnosis or treatment, or intended as a substitute for medical counseling. Information contained in this book should not be construed as a claim or representation that any treatment, process or interpretation mentioned constitutes a cure, palliative, or ameliorative. The information covered is intended to supplement the practitioner’s knowledge of their patient. It should be considered as adjunctive support to other diagnostic medical procedures.

This material contains elements protected under International and Federal Copyright laws and treaties. Any unauthorized reprint or use of this material is prohibited

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THE IMMUNE SYSTEM -- AN OVERVIEW .............................................................................. 3 THE COMPOSITION OF THE IMMUNE SYSTEM.................................................................... 4

PHYSICAL AND CHEMICAL BARRIERS: THE BORDER PATROL OF THE IMMUNE SYSTEM.................... 4 THE ORGANS OF THE IMMUNE SYSTEM....................................................................................... 4

Bone Marrow ...................................................................................................................... 4 THYMUS .................................................................................................................................. 6 SPLEEN ................................................................................................................................... 6 LYMPH NODES ......................................................................................................................... 7 BLOOD .................................................................................................................................... 7 MUCOUS ASSOCIATED LYMPHOID TISSUES (MALT) .................................................................... 7

Gut associated lymphoid tissue (GALT) ............................................................................. 8 THE IMMUNE CELLS ............................................................................................................... 8

THE “SOLDIERS OF THE IMMUNE SYSTEM” ................................................................................... 8 Phagocytes......................................................................................................................... 8 Monocytes/Macrophages ................................................................................................... 9 Basophils and mast cells .................................................................................................... 9 Eosinophils ....................................................................................................................... 10

MORE SOLDIERS OF THE IMMUNE CELLS ........................................................................ 10 LYMPHOCYTES --- HEART OF THE IMMUNE SYSTEM ................................................................... 10

How lymphocytes recognize antigens .............................................................................. 11 LYMPHOCYTES - T CELLS AND B CELLS..................................................................................... 11 T CELLS (THYMUS-DERIVED CELLS).......................................................................................... 12

Helper T Cells................................................................................................................... 12 Killer T Cell ....................................................................................................................... 12 Plasma Cells .................................................................................................................... 13 Memory Cells ................................................................................................................... 13

WHAT HAPPENS WHEN AN ORGANISM ENTERS THE BODY.......................................... 13 General Defenses............................................................................................................. 13 Fever ................................................................................................................................ 14 Lysozyme, DNAse and RNAse......................................................................................... 14

INNATE IMMUNITY (OUR FIRST LINE OF DEFENSE) ................................................................ 14 Reticuloendothelial system............................................................................................... 15 Phagocytes....................................................................................................................... 15 Initiation of immune response: Phagocytosis ................................................................... 16 Other immune cells and chemical mediators.................................................................... 17

COMPLEMENT SYSTEM ........................................................................................................... 17 Complement Functions..................................................................................................... 17

TOXIC OXYGEN PRODUCTS ...................................................................................................... 18 ENZYMES............................................................................................................................... 18

Lysozymes ....................................................................................................................... 18 Nitric oxide........................................................................................................................ 18 Summary .......................................................................................................................... 18

ACQUIRED IMMUNITY– OUR 2ND LINE OF DEFENSE ............................................................... 19

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ANTIBODY-MEDIATED (HUMORAL IMMUNITY) .............................................................................. 19 CELL-MEDIATED IMMUNITY (T-CELL IMMUNITY) .......................................................................... 19 FOREIGN (PATHOGEN) ANTIGEN .............................................................................................. 20 IMMUNE RESPONSES TO EXTRACELLULAR BACTERIA................................................................. 20 IMMUNE RESPONSES TO INTRACELLULAR BACTERIA .................................................................. 21 IMMUNE RESPONSES TO VIRUSES............................................................................................ 21 IMMUNE RESPONSES TO FUNGAL INFECTIONS........................................................................... 22 IMMUNE RESPONSE TO PARASITES .......................................................................................... 22 TH1 CELLS ............................................................................................................................. 22 TH2 CELLS ............................................................................................................................. 22 SUMMARY.............................................................................................................................. 23

The Immune System -- An Overview The immune system is composed of organs, groups of cell types and molecules all working together to defend the body against foreign invaders that may cause disease, such as bacteria, viruses, and fungi. The health of the body is dependent on the immune system’s ability to recognize and then repel or destroy these invaders. Simply put, it’s all about defense i.e. defending the inner environment of the body from the external environment keeping foreign substances, usually called pathogens, from invading and infecting your body. One of the major challenges of the immune system is to be able to quickly and efficiently identify your own (“self”) cells so that only pathogens are targeted

A healthy immune system distinguishes organisms in the body as “self” or “non-self.” An intact immune response identifies pathogens as “non-self” and rapidly destroys them. A depressed immune system, by contrast, will allow invading organisms to flourish.

Furthermore, when the immune system mistakenly recognizes a “self” cell as “non-self” and mounts an immune response, the result is an autoimmune disorder such as rheumatoid arthritis.

To summarize, the major functions of a healthy, balanced immune system are: 1: identify potential infectious or injurious substances 2: distinguish self antigen from non-self (threatening) 3: assess the potential level of threat posed by infectious, toxic or non-self antigens 4: mount a response that is appropriate to the level of threat 5: repair any damage that ensures from adversarial encounters

The Composition of the Immune System Physical and Chemical Barriers: The Border Patrol of the Immune System

The body's first lines of defense are the skin and mucous membranes, which prevent the entrance of many pathogens. Barriers are found at all surfaces exposed to the external environment including the gastrointestinal, respiratory, and the genito-urinary tracts. These areas are lined with mucous membranes that have the unique ability to prevent pathogens from breaking through into the internal environment. As long as it is intact, few organisms are able to penetrate to the interior of the body to establish an infection. The skin also secretes fatty acids preventing the growth of many types of bacteria There are also secondary barriers. For example, tears, sweat, and saliva combat some bacteria, and the hydrochloric acid and protein-digesting enzymes secreted by the stomach are lethal to many, but not all, pathogens.

The Organs of the Immune System Bone Marrow

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Bone marrow is a soft, pulpy tissue that fills the cavities of bones, occurring in two forms, red and yellow. Red marrow, present in all bones at birth, serves as the blood manufacturing center. Yellow marrow is composed primarily of specialized fat cells. All the cells of the immune system are derived from stem cells in the bone marrow. They form through a process called hematopoiesis.

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Hematopoiesis

Hematopoiesis is the term applied to a remarkable self-regulated system resulting in blood cell production.

Hematopoietic stem cells (HSCs) are stem cells that reside in the marrow give and rise to all the blood cell types. Because this cell can produce all blood cell types, it is called a pluripotential stem cell. These cells proliferate and form one cell lineage that will become lymphoid lineages: (lymphocytes: T-cells, B-cells, NK-cells) and another lineage that will form the myeloid lineages (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells),

When hematopoiesis is disturbed, the first cells to drop are usually the neutrophils (which have a life span in the blood of only 6 to 8 hours) followed by platelets (with a 10-day life span). Anemia develops more slowly, over a much longer span of time (since the red blood cells have a 120-day lifespan).

Thymus

The primary lymphatic organ in the body; it is located over the heart and/or in the neck area, anterior to the ascending aorta and posterior to the sternum. The thymus consists of two lobes enclosed in a capsule and is further divided internally by cross walls into many lobules, called thymic lobules. Immature lymphocytes leave the bone marrow and find their way to the thymus where they are educated to become mature T-lymphocytes. The principal function of the thymus is the processing and maturation of special lymphocytes (white blood cells) called T-lymphocytes or T-cells, which are associated with antibody production. T-lymphocytes migrate from the bone marrow to the thymus, where they mature and differentiate until activated. While in the thymus, the lymphocytes do not respond to pathogens and foreign agents. After the lymphocytes have matured, they enter the blood and go to other lymphatic organs where they help provide defense against disease. Loss of the thymus at an early age results in severe immunodeficiency and a high susceptibility to infection

Spleen This is one of the largest lymphoid organs in the body and can be thought of as an immunological conference center. There are two distinct components of the spleen, the red pulp and the white pulp. The red pulp consists of large numbers of sinuses and sinusoids filled with blood and is responsible for the filtration function of the spleen. The white pulp is responsible for the immunological function of the spleen.

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This immunologic filter of the blood is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. In addition to capturing foreign materials

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(antigens) from the blood that passes through the spleen, migratory macrophages and dendritic cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the macrophage or dendritic cells present the antigen to the appropriate B or T cells. In the spleen, B cells become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen.

Lymph Nodes Lymph nodes are found throughout the body particularly in areas draining the extremities (neck, axillae, groins and para-aortic region) and lungs, and act as an immunologic filter and/or trap destroying bacteria, viruses and foreign particles before they can gain access to blood circulation. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues. When the body is fighting an infection, lymphocytes multiply rapidly and produce a characteristic swelling of the lymph nodes.

Blood The circulatory system should be considered a transport system because few immunological reactions occur there.

Mucous Associated Lymphoid Tissues (MALT) The mucosa-associated lymphoid tissue (MALT) is the diffuse system of small concentrations of lymphoid tissue found in various sites of the body such as the gastrointestinal tract, thyroid, breast, lung, salivary glands, eye, and skin.

It’s primary function is to initiate immune responses to specific antigens encountered along all mucosal surfaces. MALT inductive sites are secondary immune tissues where antigen sampling occurs and immune responses are initiated.

Populated by T cells, which are well-situated to encounter antigens that enter through the intestinal mucous epithelium. They also include B cells, plasma cells, activated TH cells and macrophages in loose clusters.

The components of MALT are sometimes subdivided into the following:

• GALT (gut-associated lymphoid tissue. Peyer's patches are a component of GALT found in the lining of the small intestines.)

• BALT (bronchus-associated lymphoid tissue) • NALT (nose-associated lymphoid tissue) • LALT (larynx-associated lymphoid tissue) • SALT (skin-associated lymphoid tissue) • VALT (vascular-associated lymphoid tissue. A newly recognized entity that exists inside

arteries; its role in the immune response is unknown. ) • CALT (conjunctiva-associated lymphoid tissue in the human eye)

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Gut associated lymphoid tissue (GALT)

About 70% of the body's immune system is found in the digestive tract. The GALT is made up of several types of lymphoid tissue that produce and store immune cells, such as T and B lymphocytes, that carry out attacks and defend against pathogens.

This comprises:

• tonsils, adenoids (Waldeyer's ring) • Peyer's patches • lymphoid aggregates in the appendix and large intestine • lymphoid tissue accumulating with age in the stomach • small lymphoid aggregates in the esophagus • diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut

The Immune Cells The “soldiers of the immune system” Phagocytes

This is a group of immune cells specialized in finding and "eating" bacteria, viruses, and dead or injured body cells. There are three main types, the granulocyte, the macrophage, and the dendritic cell.

The granulocytes or polymorphonuclear leukocytes primarily neutrophils often take the first stand during an infection. They attack any invaders in large numbers, and "eat" until they die. The pus in an infected wound consists chiefly of dead granulocytes. A small part of the granulocyte community is specialized in attacking larger parasites such as worms.

The macrophages ("big eaters") are slower to respond to invaders than the granulocytes, but they are larger, live longer, and have far greater capacities. Macrophages also play a key part in alerting the rest of the immune system of invaders. Macrophages start out as white blood cells called monocytes. Monocytes that leave the blood stream turn into macrophages.

The dendritic cells are "eater" cells and devour intruders, like the granulocytes and the macrophages. And like the macrophages, the dendritic cells help with the activation of the rest of the immune system. They are also capable of filtering body fluids to clear them of foreign organisms and particles.

Macrophages and PMNs engulf and kill pathogens, especially bacteria. Macrophages and PMNs bind common surface molecules on pathogens or antibody-coated pathogens; phagocytes are not antigen-specific and are part of innate immunity. Macrophages also produce cytokines that attract other leukocytes and make blood vessels leaky, leading to inflammation.

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Monocytes/Macrophages Monocytes are phagocytic white blood cells released into the blood from the bone marrow. 1: replenish resident macrophages and dendritic cells under normal states. Monocytes leave the blood and become macrophages and dendritic cells. 2: Responds to inflammation signals When they get to a particular site in an organism they may change into macrophages that engulf and destroy invading pathogens.

Basophils and mast cells Basophils do not attack and “swallow” invading cells. Instead, they release chemicals that help the body’s allergic response to a pathogen.

When activated, basophils discharge the contents of their granules, releasing a variety of mediators such as:

• Histamine • Proteoglycans (e.g. heparin and chondroitin) • Proteolytic enzymes (e.g. elastase and lysophospholipase). They also secrete • Lipid mediators like leukotrienes • Serotonin • Several cytokines

These increase the blood flow to the area and add to the inflammatory process. The mediators released by basophils also play an important part in some allergic responses such as

• Hay fever and • An anaphylactic response to insect stings.

Clinical Pearls

The most important vasoactive mediators that are stored in mast cell and basophil granules are histamine in man, as well as serotonin. They both are also present in human platelets. Histamine is stored in mast cells and basophils largely complexed to mucopolysaccharide (glycosaminoglycans) such as heparin. Histamine has diverse functions including primary, local dilation of small vessels; widespread arteriolar dilatation; local increased vascular permeability by contracting endothelial cells; the contraction of nonvascular smooth muscle; chemotaxis for eosinophils; and blocking T lymphocyte function.

Serotonin is also capable of increasing vascular permeability, dilating capillaries and producing contraction of nonvascular smooth muscle. Most serotonin is stored in the gastrointestinal tract and central nervous system but a large amount is also stored in the dense granules of platelets.

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Recent evidence suggests that basophils are an important source of the cytokine, interleukin-4, perhaps more important than T cells. Interleukin-4 is considered one of the critical cytokines in the development of allergies and the production of IgE antibody by the immune system.

Eosinophils These white blood cells are responsible for combating infection and parasites. Once activated the eosinophil releases a number of mediators by a process called degranulation and are toxic to both parasite and host tissues.

For Your InformationDegranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes (neutrophils, basophils and eosinophils) and mast cells, and certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

These mediators include histamine and proteins such as eosinophil peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein.

Following activation via degranulation, eosinophils functions include production of:

• cationic granule proteins • reactive oxygen species such as superoxide. • lipid mediators like the eicosanoids from the leukotriene • enzymes, such as elastase • growth factors such as TGF beta, VEGF, and PDGF. • cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha

In addition, eosinophils play a role in fighting viral infections, which is evident from the abundance of RNAses they contain within their granules, and in fibrin removal during inflammation.

Eosinophils along with basophils and mast cells, are important mediators of allergic responses and asthma pathogenesis and are associated with disease severity.

They also fight helminth (worm) colonization and may be slightly elevated in the presence of certain parasites.

More Soldiers of the Immune Cells Lymphocytes --- Heart of the Immune System Lymphocytes are the principal active components of the adaptive immune system. The other components are antigen-presenting cells, which trap antigens and bring them to the attention of lymphocytes so that they can mount their attack.

Lymphocytes arise from stem cells in the bone marrow. Some lymphocytes travel to the thymus and become T cells that circulate in the blood and are associated with the lymph nodes and spleen. B cells remain in the bone marrow and develop before moving into the circulatory and lymph systems. B cells produce antibodies.

How lymphocytes recognize antigens A lymphocyte is different from all other cells in the body because on the surface of each lymphatic cell are about 100,000 identical receptors that enable it to recognize one specific antigen. These receptors are very specialized - each can match only one specific antigen.

Like a “key fitting into a lock” only those lymphocytes with receptors that fit the contours of that particular antigen take part in the immune response.

To understand the receptors, think of a hand that can only grab one specific item. Imagine that your hands could only pick up apples and nothing else. In your body, each single receptor equals a hand in search of its "apple." The lymphocyte cells travel through your body until they find an antigen of the right size and shape to match their specific receptors. It might seem limiting that the receptors of each lymphocyte cell can only match one specific type of antigen, but the body makes up for this by producing so many different lymphocyte cells that the immune system can recognize nearly all invaders.

Lymphocytes - T cells and B cells

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These two types of lymphocytes --- B cells and T cells --- play different roles in the immune response, though they may act together and influence one another's functions. The part of the immune response that involves B cells is often called humoral immunity because it takes place in the body fluids. The part involving T cells is called cellular immunity because it takes place directly between the T cells and the antigens. Although different in theory all adaptive immune responses are cellular --- that is, they are all initiated by cells (the lymphocytes) reacting to antigens.

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T Cells (thymus-derived cells) T cells which is named after the thymus are produced in the bone marrow and later move to the thymus where they mature. T cells come in two different types, helper cells and killer cells.

Helper T Cells Helper T cells and/or CD4+ T cell, are the major driving force and the main regulators of the immune defense. They secrete molecules called interleukins (abbreviated IL) that promote the growth of both B and T cells. Their primary task is to activate B cells and killer T cells. However, the helper T cells themselves must be activated. This happens when a macrophage or dendritic cell, which has eaten an invader, travels to the nearest lymph node to present information about the captured pathogen. The phagocyte displays an antigen fragment from the invader on its own surface, a process called antigen presentation. When the receptor of a helper T cell recognizes the antigen, the T cell is activated. Once activated, helper T cells start to divide and to produce proteins that activate B and T cells as well as other immune cells.

Killer T Cell The killer T cell and/or suppressor subset or CD8+ T cell is specialized in attacking certain tumor cells, viral-infected cells and sometimes parasites. It can also attack cancer cells. The killer T cell has receptors that are used to search each cell that it meets. If a cell is infected, it is swiftly killed. Infected cells are recognized because tiny traces of the intruder, antigen, can be found on their surface. The CD8+ T cells are also important in down-regulation of immune responses. Both types of T cells can be found throughout the body. They often depend on the secondary lymphoid organs (the lymph nodes and spleen) as sites where activation occurs, but they are also found in other tissues of the body, most conspicuously the liver, lung, blood, and intestinal and reproductive tracts. B Cells (bone-marrow-derived cells) The major function of B lymphocytes is the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibody production and binding to a foreign substance or antigen is critical as a means of signaling other cells to engulf, kill or remove that substance from the body.

Some antibodies attach themselves to invading microorganisms and render them immobile or prevent them from penetrating body cells. In other cases, the antibodies act together with a group of blood proteins, collectively called the complement system, that consists of at least 30 different components. In such cases, antibodies coat the antigen and make it subject to a chemical chain reaction with the complement proteins. The complement reaction either can cause the invader to burst or can attract scavenger cells that "eat" the invader.

The B lymphocyte cell searches for antigen matching its receptors. If it finds such antigen it connects to it, and inside the B cell a triggering signal is set off. The B cell now needs proteins produced by helper T cells to become fully activated. When this happens, the B cell starts to

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divide to produce clones of itself. During this process, two new cell types are created, plasma cells and B memory cells.

Plasma Cells The plasma cell specializes in producing antibodies that will respond to the same antigen that matched the B cell receptor. Antibodies main mission are to seek out intruders and help destroy them. Plasma cells have the unique ability to release tens of thousands of antibodies per second.

When the Y-shaped antibody finds a matching antigen, it attaches to it. The attached antibodies serve as an appetizing coating for eater cells such as the macrophage. Antibodies also neutralize toxins and incapacitate viruses, preventing them from infecting new cells. Each branch of the Y-shaped antibody can bind to a different antigen, so while one branch binds to an antigen on one cell, the other branch could bind to another cell - in this way pathogens are gathered into larger groups that are easier for phagocyte cells to devour. Bacteria and other pathogens covered with antibodies are also more likely to be attacked by the proteins from the complement system.

Memory Cells The Memory Cells are the second cell type produced by the division of B cells. These cells have a prolonged life span and can thereby "remember" specific intruders. The second time an intruder tries to invade the body, B and T memory cells help the immune system to activate much faster. The invaders are wiped out before the infected human feels any symptoms. The body has achieved immunity against the invader.

What happens when an organism enters the body General Defenses

Barriers to entry are the skin and mucous membranes. The skin is a passive barrier to infectious agents such as bacteria and viruses. The organisms living on the skin surface are unable to penetrate the layers of dead skin at the surface. Tears and saliva secrete enzymes that breakdown bacterial cell walls. Skin glands secrete chemicals that retard the growth of bacteria. Mucus membranes lining the respiratory, digestive, urinary, and reproductive tracts secrete mucus that forms another barrier. Physical barriers are the first line of defense.

When microorganisms penetrate skin or epithelium lining respiratory, digestive, or urinary tracts, inflammation results. Damaged cells release chemical signals such as histamine that increase capillary blood flow into the affected area (causing the areas to become heated and reddened). The heat makes the environment unfavorable for microbes, promotes healing, raises mobility of white blood cells, and increases the metabolic rate of nearby cells. Capillaries pass fluid into interstitial areas, causing the infected/injured area to swell. Clotting

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factors trigger formation of many small blood clots. Finally, monocytes (a type of white blood cell) clean up dead microbes, cells, and debris.

The inflammatory response is often strong enough to stop the spread of disease-causing agents such as viruses, bacteria, and fungi. The response begins with the release of chemical signals and ends with cleanup by monocytes. If this is not enough to stop the invaders, the complement system and immune response act.

Protective proteins that are produced in the liver include the complement system of proteins. The complement system proteins bind to a bacterium and open pores in its membrane through which fluids and salt move, swelling and bursting the cell.

The complement system directly kills microbes, supplements inflammatory response, and works with the immune response. It complements the actions of the immune system.

Fever Pathogens, like all other living organisms have an optimum temperature range for growth. Fever may raise the temperature above that optimum for a given organism thereby slowing its growth. The reduced growth rate may allow the body's defenses to more easily eradicate the pathogen. The elevated temperature may also speed up some of the body's defense mechanisms.

Lysozyme, DNAse and RNAse Blood, hemolymph, and secretions contain various factors which inactivate or kill many pathogens before they can establish a clinically apparent infection. These include the acid environment of the stomach and (to a lesser extent) skin, enzymes such as lysozyme which attacks the cell walls of some types of bacteria, and DNAse and RNAse that destroy any unprotected RNA or DNA they encounter.

INNATE IMMUNITY (Our First line of defense) Innate immunity refers to antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to an antigen. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.

The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. This means that the cells of the innate system recognize, and respond to, pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection.

The major functions of the innate immune system include:

• Recruiting immune cells to sites of infection and inflammation, through the production of chemical factors, including specialized chemical mediators, called cytokines.

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• Activation of the complement cascade to identify bacteria, activate cells and to promote clearance of dead cells or antibody complexes.

• The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells.

• Activation of the adaptive immune system through a process known as antigen presentation.

Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes also prostaglandilins) sensitize pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagocytes, especially neutrophils. Neutrophils then trigger other parts of the immune system by releasing factors that summon other leukocytes and lymphocytes.

Reticuloendothelial system The reticuloendothelial system (RES), part of the immune system, consists of the phagocytic cells located in reticular connective tissue, primarily monocytes and macrophages. These cells accumulate in lymph nodes and the spleen. The Kupffer cells of the liver and tissue histiocytes are also part of the RES.

Phagocytes

This is a group of immune cells specialized in finding and "eating" bacteria, viruses, and dead or injured body cells. There are three main types, the granulocyte, the macrophage, and the dendritic cell.

The granulocytes or polymorphonuclear leukocytes primarily neutrophils often take the first stand during an infection. They attack any invaders in large numbers, and "eat" until they die. The pus in an infected wound consists chiefly of dead granulocytes. A small part of the granulocyte community is specialized in attacking larger parasites such as worms.

The macrophages ("big eaters") are slower to respond to invaders than the granulocytes, but they are larger, live longer, and have far greater capacities. Macrophages also play a key part in alerting the rest of the immune system of invaders. Macrophages start out as white blood cells called monocytes. Monocytes that leave the blood stream turn into macrophages.

The dendritic cells are "eater" cells and devour intruders, like the granulocytes and the macrophages. And like the macrophages, the dendritic cells help with the activation of the rest of the immune system. They are also capable of filtering body fluids to clear them of foreign organisms and particles.

Macrophages and PMNs engulf and kill pathogens, especially bacteria. Macrophages and PMNs bind common surface molecules on pathogens or antibody-coated pathogens; phagocytes are not antigen-specific and are part of innate immunity. Macrophages also

produce cytokines that attract other leukocytes and make blood vessels leaky, leading to inflammation.

Initiation of immune response: Phagocytosis Phagocytosis (literally, cell-eating) is the process by which cells ingest large objects, such as cells which have undergone apoptosis, bacteria, or viruses. The membrane folds around the object, and the object is sealed off into a large vacuole known as a phagosome.

For Your Information Phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested. Phagosomes fuse with lysosomes in their maturation process, forming phagolysosomes. Some bacterial pathogens which enter cells inside phagosomes, actually reproduce either inside of the formed phagolysosome (Coxiella ), or escape into the cytoplasm before the phagosome fuses with the lysosome (Rickettsia). http://academic.brooklyn.cuny.edu/biology/bio4fv/page/phago.htm

In the process of phagocytosis the cell changes shape by sending out projections which are called pseudpodia (false feet).

The phagocytic cell such as a macrophage may be attracted to a particle like a bacteria or virus by chemical attractant.

This process is called chemotaxis (movement toward a source of chemical attractant).

The phagocytic cell sends out membrane projections that make contact with some particle.

Some sort of receptor ligand interaction occurs between the phagocytic cell surface and the particle that will be ingested.

The pseudopodia then surround the particle and when the plasma membrane of the projection meet membrane fusion occurs.

This results in the formation of an intracellular vesicle.

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Other immune cells and chemical mediators • Basophils/mast cells • Eosinophils

Complement System The complement system is one of the most important humoral (ie circulating) defense systems, responsible for:

• opsonization • lysis • a variety of other reactions including chemotaxis

For Your Information

Opsonisation is the process of coating micro-organisms with plasma proteins to increase their adherence to phagocytic cells in preparation for phagocytosis. The two main opsonins are IgG antibody and the third component of complement (C3) which bind to the surfaces of micro-organisms.

Complement Functions

Complement is a group of serum proteins which work with (complement) antibody activity to eliminate pathogens. Complement is NOT antigen-specific and it is activated immediately in the presence of pathogen, so it is considered part of innate immunity. However, antibody activates some complement proteins, so complement activation is also part of humoral immunity. Complement stimulates inflammation, facilitates antigen phagocytosis, and lyses some cells directly. Because it is such a powerful inflammatory agent, its activity is tightly regulated.

The main function of complement proteins is to aid in the destruction of pathogens by piercing their outer membranes (cell lysis) or by making them more attractive to phagocytic cells such as macrophages (a process known as opsonization). Some complement components also promote inflammation by stimulating cells to release histamine and by attracting phagocytic cells to the site of infection.

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The action of complement is nonspecific—i.e., complement proteins are not recognized by and do not interact with antigen-binding sites.

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Toxic oxygen products Probably the most important killing mechanism is the generation of toxic oxygen products. H2O2 is generated by the pentose phosphate pathway. H2O2 itself kills many bacteria. It is also converted to the much more toxic halide compounds. In addition, the hydroxyl radical (OH., a very potent oxidizer) can be generated from H2O2 and O2

-. These reactants disrupt membrane integrity by oxidizing various membrane lipids and proteins.

Enzymes Lysozymes Lysozyme is present in body secretions and in serum due to secretion by macrophages. Lysosomes contain 40-50 hydrolytic enzymes, including nucleases, proteinases, lipases, phosphatases, phospholipases, glycosidases, and sulfatases. Together, they can degrade all major classes of biological macromolecules to small molecules that can be transported across biological membranes. Most of them are acid hydrolases with an optimum pH between 4.5 and 5.

Nitric oxide NO is an Fe scavenger. When released by activated macrophages into the area of a parasite, it binds all the available Fe, thereby shutting down cytochrome activity and oxidative metabolism.

Summary There are several host defenses that act immediately and nonspecifically to limit the access and/or growth of potential pathogens. They interact with each other through soluble factors to keep potential pathogens in check until the immune response can be activated to eliminate the last of the pathogens. The defenses include barriers such as skin and mucous membranes that are not often thought of in this context. The barriers are enhanced by the presence of an acid environment (skin and stomach) and by mucous. Comensal bacteria limit the growth of potential pathogenic organisms by competing for oxygen and by secreting antibiological factors. Physiological responses (e.g., fever and inflammation) to pathogens also tend to limit the spread of the pathogen and facilitates the accumulation of protective factors and cells in the area. Ultimately, most pathogens are killed by phagocytic cells, particularly macrophage-lineage cells and PMNs. They use a variety of lytic enzymes and toxic oxygen products to effect killing of potential pathogens. Much of the activity of the immune response is to enhance the activity of the evolutionarily older non-specific defenses.

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ACQUIRED IMMUNITY– our 2nd line of defense Long ago, physicians realized that people who had recovered from the plague would never get it again—they had acquired immunity. This is because some of the activated T and B cells had become memory cells. Memory cells ensure that the next time a person meets up with the same antigen, the immune system is already set to demolish it.

Immunity can be strong or weak, short-lived or long-lasting, depending on the type of antigen it encounters, the amount of antigen, and the route by which the antigen enters the body. Immunity can also be influenced by inherited genes. When faced with the same antigen, some individuals will respond forcefully, others feebly, and some not at all.

Acquired immunity is immunity that develops with exposure to various antigens. Your immune system builds a defense that is specific to that antigen. Acquired immunity is made up of:

• Antibody-mediated (humoral immunity) • Cell-mediated immunity (T-cell immunity)

Antibody-mediated (humoral immunity) The Humoral Immune Response (HIR) is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.

Antibody-mediated (humoral) immunity is regulated by B cells and the antibodies they produce. Antibody-mediated reactions defend against invading viruses and bacteria.

Cell-mediated immunity (T-cell immunity) Cell-mediated immunity is an immune response that does not involve antibodies or complement but rather involves the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Cellular immunity protects the body by:

1. activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;

2. activating macrophages and natural killer cells, enabling them to destroy intracellular pathogens; and

3. stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.

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Cell-mediated immunity is directed primarily at microbes that survive in phagocytes and microbes that infect non-phagocytic cells. It is most effective in removing virus-infected cells, but also participates in defending against fungi, protozoans, cancers, and intracellular bacteria.

Foreign (Pathogen) Antigen Antigens were originally defined as non-self molecules which bound specifically to antibodies. In practice, the term antigen is used to mean any molecule recognized by the immune system.

Antigens which induce adaptive immunity are called immunogens. All immunogens are antigens, and are usually called antigens unless their ability to induce an immune response is being discussed. Some antigens, called haptens, are not immunogenic unless they are covalently linked to immunogenic carriers (usually proteins). Haptens can bind antibodies once the antibodies are produced, but haptens will not induce antibody synthesis on their own. Small non-protein organic molecules, for example the antibiotic penicillin, are haptens.

Immunogenicity is influenced by

• the chemical nature of the antigen. • the antigen's size. • the antigen's usual presence in the body. • antigen dose and route and timing of administration. • whether the antigen is easily phagocytosed. • whether antigen is efficiently presented to T cells on MHC. • the maturity of the immune system and specific lymphocytes.

Immune Responses to Extracellular Bacteria Effective resistance to bacterial infections requires synergistic activity between immune and non-specific defenses. All the protective mechanisms described previously for antibodies (opsonization, neutralization, aggregation, lysis, and inflammation) are involved in protecting against bacteria and/or their products. In addition, complement can act directly, via the alternative pathway, to lyse gram negative bacteria. Even for gram positive bacteria, complement activation via the classical pathway can contribute C3b to further opsonize the bacteria. Ultimately, most bacteria are killed by phagocytes. Before they can engulf and kill the pathogen, phagocytes must come into direct contact with the pathogen. Once phagocytes come into contact with the targets, they must distinguish the foreign invaders from normal self tissue. They have some ability to do this on the basis of ionic charge since bacteria (and damaged tissue) has a higher negative charge than normal tissue. However, they are greatly aided in the identification problem by binding to opsonin coated targets via specific receptors for the opsonins. IgG and C3b are the most important opsonins. IgG is not normally made to self tissue, so the phagocytes are using the specificity of the immune system to identify the pathogens. Similarly complement is activated by immunoglobulins or by endotoxin and zymosan that are not found on human tissues.

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Phagocytes then engulf the organisms and kill them via mechanisms primarily toxic oxygen products. T cell responses are often required for full expression of immunity against these pathogens.

Immune Responses to Intracellular Bacteria A few types of bacteria; e.g., mycobacteria, live most of their life cycle inside of host cells and cannot be attacked by soluble antibacterial factors nor by phagocytes. Host defenses deal with this by destroying the infected cell thereby releasing them into the intercellular spaces where they can be attacked by the phagocytes similar to the way other bacteria in the extracellular spaces are handled.

Immune Responses to Viruses The immune response to viruses varies with the phase of the infection. Viruses that infect via the respiratory or GI tracts are exposed to IgA, IgG and probably complement in the secretions. The virus must either infect or penetrate the epithelial layer of the skin, respiratory or GI tracts to establish an infection. It is then transported to its target tissue via the blood or lymph during which time the virus is exposed to both the humoral and cellular arms of the immune system. Antigen presenting cells can take up the virus, process it, and present viral antigens to B cells thereby inducing antibody synthesis. Presence of these antibodies in the blood and tissue fluids will allow them to bind to the viruses during subsequent infections during transit to their target. Binding may neutralize them by interfering with the virus's ability to bind to the target cell. Antibody bound to the virus may also opsonize it for removal and destruction by phagocytic cells. Once the virus has infected its target cell, it is hidden from antigen presenting cells and antibodies. At this point, Tc cells take over. They recognize and lyse infected cells, often before the virus is able to complete its coat proteins. The unprotected nucleic acid is then destroyed by nucleases in tissue fluids.

For Your Information Cytotoxic T cells (Tc cells) are responsible for destroying virally infected cells and cells that have been transformed into cancer cells. Since these cells are part of ourselves, Tc cells must recognize subtle alterations in the cell surface that arise from within the cells rather than blatantly foreign invaders. Some viruses do not immediately take over the infected cell's machinery to reproduce themselves. They may integrate themselves into the cell's DNA and remain latent for a variable amount of time. Subsequently, it may be triggered to enter the replicative cycle with the consequent tissue damage. A few viruses; e.g., herpes, do not always have a viremic phase, but rather they are transmitted directly from cell to cell. In these cases, it becomes difficult to completely eradicate the virus.

Immune Responses to Fungal Infections It appears that it is at least partly T cell mediated in that people with deficiencies in cellular immunity often have repeated and severe fungal infections. The best evidence indicates that Helper T Cells (Th1 cells) are most important.

It appears that the Th1 cells secrete various macrophage activating factors to help limit the infection. Macrophages and neutrophils activated by Th1 cells products appear to be the major cell involved in clearing up these infections.

Immune Response to Parasites Parasites present particular problems to the immune system due to their complex life cycle in which the different stages often have completely different antigens and are found in different places in the body. The multicellular forms often have surface layers (their form of skin) that is quite resistant to attack.

The range of parasites is so large that one would expect that host defenses will also be diverse. The parasites are even more resistant to killing by macrophages than intracellular bacteria, so activation by Interferon alpha - and TNF- (from Th1 cells) is critical to eliminating the parasites. IgG antibodies opsonize the parasites and may cause some direct membrane damage and activate complement, but these humoral mechanisms are generally ineffective. Moreover, Th2 cells needed to initiate antibody synthesis also produce IL-10 which inhibits development of the effective Th1 cells. In fact, for many diseases in which the pathogen/parasite lives inside of the cells, resistance is directly proportional to the cell mediated (Th1) response and inversely proportional to the antibody mediated (Th2) response.

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For Your Information

Th1 cells Type 1 helper T cells are characterized by the production of pro-inflammatory cytokines like IFN-γ, IL-2, and TNF-β. Th1 cells are involved in cell-mediated immunity. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens. Several chronic inflammatory diseases have been described as Th1 dominant diseases i.e. multiple sclerosis, diabetes, and rheumatoid arthritis.

Th2 cells Type 2 helper T cells are characterized by the production of IL-4, IL-5, IL-9, and IL-13. Th2 cells are thought to play a role in allergy responses. Cytokines like IL-4 generally stimulate the production of antibodies directed toward large extracellular parasites. IL-5 stimulates eosinophil response toward large extra cellular parasites. Atrophy and allergy are thought to be Th2 dominant conditions.

Improved understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune system, its response to infection and aberrant responses that lead to disease.

When Th1 cells produce IFN-γ, this prompts the macrophages to produce TNF and toxic forms of

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oxygen which destroy the microorganisms within the phagosomes and lysosomes. On the other hand, when Th2 cells produce IL-4 and IL-10, these cytokines block the microbe killing that is activated by IFN-γ. The larger forms require different mechanisms since they are bigger than the macrophages. Macrophages produce two potent inflammatory agents, interleukin -1 and tumor necrosis factor. Among other results of inflammation is attraction of more effector cells to the area (production of chemokines and expression of ligands on endothelial cells). They also surround the helminth and secrete various cytotoxic factors that may be able to kill the parasite. The most potent of these is NO (nitric oxide). This molecule is a very powerful iron (Fe) scavenger. By binding all the Fe, it inhibits oxidative respiration of the parasite which then dies.

Summary The objective of this lesson was to re-acquaint you with the physiology of the immune system. As you continue on your journey studying functional diagnostic medicine you will gain an appreciation of the enormous impact FDM can make on restoring optimal immune function.