chapter 16

Pain associated w/ tissue injury is thought to be due to

the release of *bradykinin*, a small peptide, at the injured site. - How bradykinin stimulates pain receptors in the skin is unknown, but cellular regulators called *PROSTAGLANDINS* seem to intensify bradykinin's effect.

the complement system works as a _________

*cascade* - a set of reactions that amplify some effect- that is, more product is formed in the second reaction than in the first, still more in the third, and so on. - of the 20 diff serum proteins so far identified, in the complement system, 13 participate in the cascade itself and 7 activate or inhibit reactions in the cascade

in an infection, cells also release

*leukocyte-endogenous mediator (LEM)*. - helps elevate body temp - decreases the amount of iron absorbed from the digestive tract and increases the rate at which it is moved to iron storage deposits. - lowers the plasma iron concentration. w/o adequate iron, growth of microorganisms is slowed

Most often, fever is caused by a substance called a

*pyrogen* - *Exogenous pyrogens*- include exotoxins and endotoxins from infectious agents. These toxins cause fever by stimulating the release of an *endogenous pyrogen* from macrophages. - The endogenous pyrogen is yet another cytokine, called INTERLEUKIN-1 (IL-1), that circulates via the blood to the hypothalamus, where it causes certain neurons to secrete prostaglandins. -The prostaglandins then reset the hypothalamus thermostat at a higher temp, which then causes the body temp to begin rising within 20 mins. in such situations, body temp is still regulated, but the body's "thermostat" is reset at a higher temp (sensation of chills that sometimes accompanies a fever)

innate defenses include the following

- *Physical barriers:* skin, mucous membranes and the chemicals they secrete - *Chemical barriers:* antimicrobial substances in body fluids such as saliva, mucus, gastric juices, and iron limitation mechanisms - *Cellular defenses:* certain cells that engulf (phagocytize) invading microorganisms - *Inflammation:* reddening, swelling and temperature increases in tissues at sites of infections - *Fever:* elevation of body temp. to kill invading agents and/or inactivate their toxic products - *Molecular defenses:* such as interferon and complement, that destroy or impede invading microbes

chemotaxis

- *Toll-like receptors (TLRs)-receptors on the phagocytic cells that recognize molecular patterns unique to the pathogen, such as peptidoglycan, lipopolysaccharide, flagellin, proteins, zymosan from yeast, and many other pathogen-specific molecules (how phagocytes recognize the invading microorganism) - - *macrophages and dendritic cells* can distinguish between gram-neg and gram-pos bacteria versus viral pathogens. they can tailor subsequent response to deal best w. that type of pathogen.

chemical barriers

- *sweat* glands produces watery-salty liquid. High salt content of sweat inhibits many bacteria from growing. - *acidic pH of stomach* major innate defense against intestinal pathogens - *lysozyme:* enzyme present in tears, saliva, and mucus, cleaves the covalent linkage between sugars in peptidoglycans; gram + bacteria susceptible to killing by this enzyme - *transferrin*: protein present in blood plasma, binds to any free iron present in blood. bacteria require iron as a cofactor for some enzymes. *The binding of iron by transferrin inhibits the growth of bacteria in bloodstream* - *lactoferrin*: present in saliva, mucus, and milk- also binds iron inhibiting bacterial growth - *defensins* - small peptides present in mucus and extracellular fluids- are a group of molecules that can kill pathogens by forming pores in their membranes, or inhibit growth by other mechanisms

basophils

- 0.1% of total leukocytes - release HISTAMINE, a chemical that helps initiate the inflammatory response. - responsible for allergic symptoms

Eosinophils

- 1-5% of total leukocytes - present in large numbers during allergic reactions and worm infections - detoxify foreign substances and help turn off inflammatory responses by releasing histamine-degrading enzymes from their granules

monocytes

- 2-8% of total leukocytes - derived from myeloid stem cells - in tissues, develop into macrophages, which are phagocytic

lymphocytes

- 20-50% of total leukocytes - derived from lymphoid stem cells (bone marrow) - contribute to adaptive host immunity - antibody production - circulate in blood, found in large numbers in lymph nodes, spleen, thymus and tonsils

Neutrophils

- 50-70% of total leukocytes - also called polymorphonuclear leukocytes (PMNLs) - guard blood, skin, and mucous membranes against infection - phagocytic and respond quickly wherever tissue injury has occured - granules contain myeloperoxidases, able to create cytotoxic substances killing bacteria and other engulfed pathogens

Lymph Nodes

- @ intervals along the lymphatic vessels, lymph flows through the lymph nodes distributed throughout the body. They are most numerous in the thoracic (chest) region, neck, armpits, and groin. The lymph nodes filter out foreign material in the lymph. Most foreign agents passing through a node are trapped and destroyed by the defensive cells present. - lymph nodes occur in small groups, each group covered in a network of connective tissue fibers called a *capsule*. Lymph moves through a lymph node in one direction. Lymph first enters *SINUSES*, wide passageways lined w/ phagocytic cells, in the outer cortex of lymph node. The OUTER CORTEX houses large aggregations of B lymphocytes. The lymph then passes through the DEEP CORTEX, where T lymphocytes exist. The lymph moves through the inner region of a lymph node, the MEDULLA, which contain B lymphocytes, macrophages, and plasma cells. Finally, lymph moves through sinuses in the medulla and leave the lymph node. - This filtration of lymph is important when an infection has occurred. ex- if bacterial infection occurs, the bacteria that are not destroyed at site of infection may be carried to lymph nodes. as the lymph passes through the nodes, majority of bacteria removed. macrophages & other phagocytic cells, especially dendritic cells, in the nodes bind to and phagocytize the bacterial cells, thereby initiating an adaptive immune response

antiphagocytic capsule

- a fundamental requirement of many pathogenic bacteria is to escape phagocytosis - the most common means by which bacteria avoid this defense mechanism - the capsules present on bacteria responsible for pneumococcal pneumonia (streptococcus pneumonia) and childhood meningitis (Haemophilus influenzae) make adherence difficult for phagocytes - the cell walls of the bacterium responsible for rheumatic fever (Streptococcus pyogenes) contain molecules of M protein, which interferes w/ adherence

Thymus gland

- a multi-lobed lymphatic organ located beneath the sternum (breastbone) - present @ birth, grows until puberty, then atrophies (shrinks) and is mostly replaced by fat and connective tissue by adulthood - around time of birth, it begins to process lymphocytes and release them into the blood as T cells. - *T cells* play several rolls in immunity: they regulate the development of B cells into antibody producing cells, and subpopulations of T cells can kill virus-infected cells directly.

fever

- a rise in temp in infected or injured tissue is one sign of a local inflammatory reaction - *a systematic increase in body temp, often accompanies inflammation* - first studied in 1868 when Carl Wunderlich devised a method to measure body temp. He placed a foot-long thermometer in the armpit of his patients and left it in place for 30 mins. Using this technique, he could record human body temps during FEBRILE (feverish) illnesses.

vertebrates

- almost all invertebrates also can reject grafts of foreign tissue - VERTEBRATEs reject such grafts more vigourosly on a second encounter, but invertebrates do not; in fact, the second rejection may be slower thanfirst presence of such specific immune defenses in vertebrates is considered an advanced characteristic- B cells Tcells and antibodies - swiftest and most complex immune responses found in mammals and birds - birds have a saclike structure, the bursa of Fabricius, that is not present in mammals and probably represents a hgher state of evolution in immune system

invertebrates

- also have nonspecific defenses for fending off invaders - phagocytosis is important to invertebrates in obtaining food, but is also necessary for preventing sedentary organisms permanently fixed to a surface, and living where space is limited, from being overgrown by neighbors - phagocytosis is used to defend one's territory - animals lacking cardiovascular system, amoebocytes wander through the body, engulfing foreign material and damaged or aged cells - opsonization made possible by complement like components of body. ex= fluids in body of sea urchins

Membrane Attack Complexes

- another defense triggered by C3b is cell lysis. - by a process called *immune cytolysis*, complement proteins produce lesions in the cell membranes of microorganisms and other types of cells. These lesions cause cellular contents to leak out. - to cause immune cytolysis, C3b initiates the splitting of C5 into C5a and C5b. C5b then binds to C6 and C7, forming a *C5bC6C7 complex.* This protein complex is hydrophobic and inserts into the microbial cell membrane. C8 then binds to C5b in the membrane. Each V5bC6C7C8 complex causes the assembly in the cell membrane of up to 15 C9 molecules. - by extending all the way through the cell membrane, these proteins form a pore and constitute the *membrane attack complex (MAC)*.

tonsils

- another site for the aggregation of lymphocytes - although these tissues not essential for fighting infections, they do contribute to immune defenses as they contain B cells and T cells

Lymphoid nodules

- called Peyer's patches - lymphoid masses found in the ileum of small intestines - unencapsulated area filled w/ lymphocytes

Type II interferons (gamma)

- can also block virus replication by AVP synthesis - however, lymphocytes and NK cells do not have to be infected w/ a virus to synthesize gamma-interferon. rather, it is produced in uninfected lymphocytes and NK cells that are sensitive to specific foreign agents (viruses, bacteria, tumor cells) present in the body - the exact role of gamma-interferon is unclear, but it is known to enhance the activities of lymphocytes, NK cells, and macrophages- the cells needed to attack microbes and tumors. - it also enhances adaptive immunity by increasing antigen presentation - gamma-interferon (along w/ tumor necrosis factor alpha or TNF-ALPHA) also helps infected macrophages rid themselves of pathogens. (ex- when macrophages become infected w/ Mycobacterium bacilli, infected macrophages can be activated by gamma-interferon and TNF-Alpha, which bind to infected macrophages. New bactericidal activity is thereby triggered within the macrophage, usually leading to death of the bacteria and the restoration of normal macrophage function)

inflammatory process can be harmful

- can cause swelling (edema) of the membranes (meninges) surrounding the brain or spinal cord, leading to brain damage. - swelling, which delivers phagocytes to injured tissue, can also interfere w/ breathing if it constricts the airways in the lung. moreover, vasodilation delivers more oxygen and nutrients to injured tissues - even though rapid clotting and the walling off of an injured area prevents pathogens from spreading, it can also prevent natural defenses and antibiotics from reaching pathogens - boils must be lanced before therapeutic drugs can reach them - attempting to suppress the inflammatory response also can be harmful. such attempts allow boils to form when natural defenses might otherwise destroy the bacteria.

phagocytes

- cells that literally eat or engulf other materials - circulate through body destroying dead cells and cellular debris that must be removed constantly from body as cells die and are replaced - guard the skin and mucous membranes against invasion by microorganisms - first attack microbes and other foreign materials at portals of entry, such as wounds in skin or mucous membranes - if an infection occurs, *neutrophils* usually first on scene b.c they migrate quickly to site of infection. Being avid phagocytes, they are best at inactivating bacteria and other small particles. they are not capable of cell division and are "programmed" to die after only 1 or 2 days. they are killed in process of killing microbes and form PUS.

Dendritic cells

- cells w/ long membrane extensions that resemble the dendrites of nerve cells - phagocytic, involved in initiating the adaptive defense response - in the skin, known as Langerhans cells, produce immune tolerance to good bacteria, preventing overreaction of our immune system

defense cells

- cellular defense mechanisms use special-purpose cells found in blood and other tissues of body - blood consists of about 60% liquid called *plasma* and 40% *formed elements* (cells and cell fragments.) - formed elements include *erythrocytes* (RBCs), *platelets*, and *leukocytes* (WBCs) - all derived from PLURIPOTENT STEM CELLS, cells that form a continuous supply of blood cells, in the bone marrow - Platelets, which are short-lived fragments of large cells called megakaryocytes, are important components of the blood-clotting mechanism - *Leuokocytes* are defensive cells that are important to both adaptive and innate host defenses. these cells are divided into 2 groups: granuloyctes and agranulocytes.

lymphatic system

- closely associated w/ cardiovascular system, consists of a network of vessels, nodes and other lymphatic tissues, and the fluid LYMPH - has 3 major functions 1: collects excess fluid from the spaces between body cells 2: transports digested fats to cardiovascular system 3: provides many of the innate and adaptive defense mechanisms against infection and disease.

mucous membrane (mucosa)

- covers those tissues and organs of the body cavity that are exposed to the exterior - another physical barrier that makes it difficult for pathogens to invade internal body - mucus contains numerous bacteriophages - hair & mucus of nasal and respiratory system present mechanical barriers -physical reflex activities of coughing and sneezing - vomiting and diarrhea flush harmful microbes and their chemical products from digestive tract - tears and saliva also flush bacteria from eyes and mouth - urinary flow is important in removing microbes that enter urinary tract

adherence

- following chemotaxis & the arrival of phagocytes @ site of infection, the infectious agents become attached to the plasma membranes of phagocytic cells. - *the ability of the phagocyte cell membrane to bind to specific molecules on the surface of the microbe is called adherence*

granulocytes

- have granular cytoplasm and an irregular shape. - derived from MYELOID STEM CELLs in bone marrow - basophils, mast cells, eosinophils, and neutrophils - distinguished from one another by the shape of their cell nuclei and by their staining reactions w/ specific dyes

Interferon

- in 1957, a small, soluble protein was discovered that was responsible for viral interference - *"interfered" w/ virion replication in other cells"* - such a molecule suggested to virologists that they might have the "magic bullet" for viral infections, similar to the antibiotics used to treat bacterial infections - many different subtypes of interferons exist in diff animal species, and that those produced by one species may be ineffective in other species - diff interferons also exist in different tissues of same animal - in humans, there are 3 groups of interferons, called alpha, beta, and gamma. - analysis of the protein structure and function show alpha-interferon and beta-interferon to be so similar, they are placed together as *type I interferons.* - gamma-interferon is different structurally and functionally and represents the only known *type II interferon*

Agranulocytes

- lack granular cytoplasm an have round nuclei - monocytes and lymphocytes

Spleen

- located in upper left quadrant of abdominal cavity, is the largest of the lymphatic organs - anatomically similar to lymph nodes - it is encapsulated, and well supplied w/ blood and lymphatic vessels - it does not filter material, however its *sinusoids* contain many phagocytes that engulf and digest worn-out erythrocytes and microorganisms - also contains B cells and T cells

Lymphoid Organs

- lymph nods, thymus and spleen; essential in body's defense against infectious agents and cancers - all contain numerous lymphocytes, these cells originate in bone marrow and are released into the blood and lymph. Live from weeks to years, becoming dispersed to various lymphatic organs or remaining in blood and lymph - most lymphocytes are either B Lymphocytes (B cells) or T lymphocytes (T cells) - *B cells*- differentiate in the bone marrow itself and migrate to the lymph nodes and spleen - *Immature T cells* from the bone marrow migrate to the thymus, where they mature; they then migrate to the lymph nodes or spleen

skin

- not only exposed directly to microorganisms and toxic substances but also is subject to objects that touch, abrade, and tear it. - sunlight, heat, cold, and chemicals can damage skin - cuts, scratches, insect and animal bites, burns, and other wounds can disrupt the continuity of the skin and make it vulnerable to infections

Ingestion

- once captured, phagocytes rapidly ingest (engulf) the microbe - the cell membrane of the phagocyte forms fingerlike extensions called PSEUDOPODIA, that surround the microbe. - these pseudopodia then fuse, enclosing the microbe within a cytoplasmic vacuole called a *PHAGOSOME*

extracellular killing

- other microbes, such as viruses and parasitic worms, are destroyed w.o being ingested by a defensive cell; they are destroyed *extracellularly* by products secreted by defensin cells - neutrophils and macrophages are too small to engulf a large parasite such as a worm (helminth), therefore eosinophils take the leading role in defending the body - *EOSINOPHILS* can be phagocytic, however they are best suited for excreting toxic enzymes such as *MAJOR BASIC PROTEIN (MBP)* that can damage or perforate a worm's body. once such parasites are destroyed, macrophages can engulf the parasite fragments.

phagocytosis

- phagocyte digest and generally destroy invading microbes and foreign particles - 4 step process to destroy invading microorganisms 1- find 2- adhere to 3- ingest, and 4- digest the microorganism

Digestion

- phagocytic cells have several mechanisms for digesting and destroying ingested microbes - one mechanism uses the *lysosomes* found in the phagocytes cytoplasm. these organelles, which contain digestive enzymes and small proteins called DEFENSINS, fuse with the phagosome membrane, forming a *phagolysosome*. in this way the digestive enzymes and defensins are released into the phagolysosome. the *defensins* eat holes in the cell membranes of microbes, allowing lysosomal enzymes to digest almost any biological molecule they contact. Thus, lysosomal enzymes rapidly ( within 20 mins) destroy the microbes breaking them into smaller molecules (amino acids, sugars, fatty acids) that the phagocyte can use as building blocks for its own metabolic and energy needs. - Macrophages can also use other metabolic products to kill ingested microbes. These phagocytic cells use oxygen to form hydrogen peroxide, nitric oxide, superoxide ions and hypochlorite ions. all these are effective in damaging plasma membranes of the ingested pathogens. - once microbes have been destroyed, there may be some indigestible material left over. such material remains in the phagolysosome, which now is called a *RESIDUAL BODY*. the phagocyte transports the residual body to the plasma membrane, where the waste is excreted.

Lymphoid tissues contribute to innate defenses by

- phagocytizing microorganisms and other foreign material - they contribute to adaptive immunity through the activities of their B and T cells

lymphatic circulation

- process of draining excess fluid from the spaces between cells starts w/ the LYMPHATIC CAPILLARIES found throughout the body. These capillaries collect the excess fluid and plasma proteins that leak from the blood into the spaces between the cells. once in the lymphatic capillaries, this fluid is called *LYMPH*. - Lymphatic capillaries join to form larger *LYMPHATIC VESSELS*. - Finally, the lymph is returned to the venous blood via the RIGHT and LEFT LYMPHATIC DUCTS, which drain the fluids into the right and left subclavian veins. - there is no mechanism to move or pump lymphatic fluid. Hence, the flow of lymph depends on skeletal muscle contractions, which squeeze the vessel, forcing the lymph toward the lymphatic ducts. throughout the lymphatic system, there are one-way valves to prevent backflow of lymph.

plants

- produce chemical defenses that can wall off areas damaged or infected by bacteria or fungi - an important determinant of how well a given strain of plant can resist infection after pruning or damage is its chemical and defensive abilities - many fungi are plant pathogens, to infect a plant, the fungus must penetrate the plant cell. During infection, the plant cells produce enzymes that release carbohydrate molecules from fungal cell walls. these fragments of fungal wall, called ELICITORS, trigger an imunnological-like response by the plant. Elicitors cause the plant to produce lipidlike chemicals called PHYTOALEXINS. Phytoalexins inhibit fungal growth by restricting the infections to a small portion of the plant tissue.

Complement or complement system

- refers to a set of more than 20 large regulatory proteins that play a key role in host defense - produced by the liver and circulate in plasma in an inactive form - these proteins account for about 10% (by weight) of all plasma proteins -although can be activated by immune reactions, its effects are non-specific- it exerts the same defensive effects regardless of which microorganisms has invaded the body

Opsonization

- some bacteria w/ capsules or surface proteins (M proteins) can prevent phagocytes from adhering to them. The complement system can counteract these defenses, making possible a more efficient elimination of such bacteria. - First, special antibodies called *opsonins* bind to and coat the surface of the infectious agent. C1 binds to these antibodies, initiating the cascade. C1 causes the cleavage of C4 into C4a and C4B and C1 then cause C2 to split into C2a and C2b. - The C4bC2a complex in turn leads to the splitting of C3 into C3a and C3b. - C3b then binds to surface of the microbe. - complement receptors on plasma membrane of phagocytes recognize C3b molecules; this recognition stimulates phagocytosis. This process, initiated by opsonins, is called *opsonization* or IMMUNE ADHERENCE

Chronic Inflammation

- sometimes an acute inflammation becomes a chronic inflammation, in which neither the agent of inflammation nor the host is a decisive winner of the battle. - rather, the agent causing the inflammation continues to produce tissue damage as the phagocytic cells and other host defenses attempt to destroy or at least confine the region of inflammation. - in the process, pus may be formed continuously. such chronic inflammation can persist for years. -b/c cause of inflammation is not destroyed, host defenses attempt to limit or confine the agent so that it cannot spread to surrounding tissue. - for example, *granulomatous inflammation* results in granulomas. - a *granuloma* is a pocket of tissue that surrounds the walls off the inflammatory agent. The central region of a granuloma may fuse to form giant, multinucleate cells. Collagen fibers, which help wall off the inflammatory agent, and lymphocytes surround the core. Granulomas associated w/ a specific diseases are sometimes given special names- for example, GUMMAS (syphilis), LEPROMAS (Hansen's disease), and TUBERCLES (TB). -Tubercles usually contain necrotic (dead) tissue in the central region of the granuloma. As long as necrotic tissue is present, the inflammatory response will persist. If only a small quantity of necrotic tissue is present, the lesions sometimes become hardened as calcium is deposited in them. Calcified regions are common in tuberculosis patients. When an anti-inflammatory drug such as cortisone is given, the organism isolated in tubercles may be liberated and signs and symptoms of tuberculosis reappear (Secondary tuberculosis)

Therapeutic Uses of Interferon

- stimulate adaptive immune defenses, therefore interferons provide a potential therapy for viral infections and tumors - RECOMBINANT INTERFERON (rINF) can be produced more cheaply and abundantly by using recombinant DNA techniques. - manufacture of rINF starts w. the isolation and copying of the interferon gene and its insertion into plasmids. When recombinant plasmids are mixed w/ appropriate bacterial or yeast cells, some cells will take up the gene-containing plasmid and thereby acquire the human interferon gene. by growing these bacterial or yeast cells in very large vats and extracting the interferon that they produce, pharmaceutical companies can produce relatively significant quantities of recombinant interferon - in 1986, alpha-interferon was approved by the FDA for treating hairy cell leukemia, a very rare blood cancer. since then, interferons have been approved for treatment of several other viral diseases, including genital warts and cancer. However, in most cases, INTERFERON IS A TREATMENT, NOT A CURE. patients must remain on the drug throughout their lives. W/ hairy cell leukemia, for example, removal of the drug results in a recurrence of the disease in 90% of the patients. For hepatitis C virus infection, treatment must be given 3x a week for 6 mos. even so, if the patient is taken off treatment, disease will reappear after 6 mos in 70% of cases. - tests on one form of bone cancer show that after most of the cancerous tissue is removed by surgery or destroyed by radiation, interferon therapy will reduce the incidence of metastasis (spread). how interferon stops metastasis is unknown. some cancers are the result of viral infections. Perhaps interferon interferes with viral replication. - in addition to bone cancer, interferon is now used to treat renal cell carcinoma, carcinoid tumors, and some lymphomas. -Interferon therapy could also prevent growth of the cancer cells through their destruction by macrophages and NK cells

acute inflammation

- the battle between microbes (or other agents of inflammation) and host defenses usually is won by the host. - in an infection, acute inflammation functions to 1- kill invading microbes 2- clear away tissue debris 3- repair injured tissue

Inflammation

- the body's defensive response to tissue damage from microbial infection - also a response to mechanical injury (cuts and abrasions), heat and electricity (burns), ultraviolet light (sunburn), chemicals (phenols, acids, and alkalis), and allergies. - whatever the cause is, it is characterized by CARDINAL SIGNS or symptoms: 1- calor- increase in temperature 2- rubor- redness 3- tumor- swelling 4- dolor- pain at the infected or injured sight - duration of inflammation can be either acute (short-term) or chronic (long term)

Inflammation (complement system)

- the complement system is also potent in initiating and enhancing inflammation. -C3a, C4a, and C5a enhance the acute inflammatory reaction by stimulating chemotaxis and thus phagocytosis. -These 3 complement proteins also adhere to the membranes of basophils and mast cells, causing them to release histamine and other substances that increase the permeability of blood vessels

to overcome such resistance to adherence,

- the host's nonspecific defenses can make microbes more susceptible to phagocytosis - if microbes are first coated w/ antibodies, or with proteins of the COMPLEMENT SYSTEM, phagocytes have a much easier time binding to them

natural killer cells (NK cells)

- the leukocytes responsible for killing intracellular viruses - a type of lymphocyte whose activity is greatly increased by exposure to interferons and cytokines - probably recognize specific glyco-proteins on the cell surface of virus infected cells. such recognition does not lead to phagocytosis; rather, the *NK cells secrete cytotoxic proteins that trigger the death of the infected cell* - *they are the first line of defense against viruses, until the adaptive immune system can become effective days later*

Type I interferons (alpha and beta)

- the synthesis of these interferons occurs after a virus infects a cell - they do not interfere directly w/ viral replication - after viral infection, the cell synthesizes and secretes minute amounts of interferon - interferon then fuses to adjacent, uninfected cells and binds to their surfaces. - binding stimulates those cells to transcribe specific genes into mRNA molecules, which are then translated to produce many new proteins, most of them enzymes. - together theses enzymes are called *antiviral proteins (AVPs)*. Although those viruses still infect cells possessing the AVPs, many of the proteins interfere w/ the virus replication - the AVPs are specifically effective against RNA viruses. Two of the AVPs digest mRNA and limit translation of viral mRNA. The result is that the AVPs prevent the formation of new viral nucleic acid and capsid proteins. the infected cell that initially produced the interferon is thus surrounded by cells that can resist the replication of viruses, limiting viral spread

innate defenses

- those that act against any type of invading agent - perform their function before adaptive body defense mechanisms are activated

several factors that affect healing process

- tissues of young people heal more rapidly than those of older people. the reason is that the cells of the young divide more quickly, their bodies are generally in a better nutritional state, and their blood circulation is more efficient. - certain vitamins are also important in healing process. Vitamin A- essential for the division of epithelial cells Vitamin C- essential for production of collagen and other components of connective tissue Vitamin K- required for blood clotting Vitamin E- may promote healing and reduce amount of scar tissue formed

macrophages

- when monocytes move from blood into tissues they go through series of cellular changes, maturing into macrophages - "big eaters" that destroy not only microorganisms but also larger particles, such as debris let from neutrophils that have died after eating bacteria. - take longer than neutrophils to reach infection sit but arrive in larger numbers - can be fixed or wandering

Drawback of therapeutic use of interefons

- when rINF is injected, it does not remain stable for very long in the body, making delivery of the interferons to site of infections difficult. - injection of interferon (especially alpha-interferon) also has side effects, including fatigue, nausea, headache, vomiting, weight loss,, and nervous system disorders. - whereas fevers normally increase interferon production, which helps body fight viral infections, the injection of interferon PRODUCES fever as a side effect. - high doses can cause toxicity to liver, kidneys, heart, and bone marrow. - some microbes have developed resistance to interferons. although some DNA viruses, such as the poxviruses, stimulate interferon synthesis, the human adenoviruses have resistance mechanisms to combat antiviral protein activity. in addition, the hepatitis B virus often fails to stimulate adequate interferon production in infected cells - the therapeutic usefulness of interferon is clearly not the viral magic bullet that was originally envisioned. Nevertheless, interferons are being used to treat life-threatening viral infections and cancers

repair and regeneration

-during entire inflammatory reaction, the healing process is also underway. Once the inflammatory reaction has subsided and most of the debris is cleared away, healing accelerates. - Capillaries grow into the blood clot, and *fibroblasts*, connective tissue cells, replace the destroyed tissue as the clot dissolves. These fragile, reddish, grainy tissue seen at the cut site consists of capillaries and fibroblasts called "GRANULATION TISSUE*. - As granulation tissue accumulates fibroblasts and fibers, it replaces nerve and muscle tissues that cannot regenerate. - new epidermis replaces the part destroyed. - in digestive tract & other organs lined w/ epithelium, an injured lining can similarly be replaced. - although scar tissue is not as elastic as original tissue, it does provide a strong durable "patch" that allows the remaining normal tissue to function.

3 pathways identified in the sequence of reactions carried out by complement system

1- classical pathway 2- lectin pathway 3-alternative pathway or PROPERDIN PATHWAY - The classical pathway begins when antibodies bind to antigens, such as microbes, and involves compliment proteins C1, C4, AND C2. - The lectin pathway begins when macrophages complete phagocytosis, releasing cytokines that cause the liver to produce lectin proteins. the lectins bind to carbohydrates such as mannose, which are part of a characteristic pattern of carbohydrates found on bacteria, and some viruses. This then activates C4 and C2. - The alternative pathway is activated by contact between complement proteins and polysaccharides at the pathogen surface. Complement proteins called factor B, factor D, and factor P (properdin) replace C1, C4, and C2 in the initial steps. However, the components of both pathways activate reactions involving C3 through C9. Consequently, the effects of the complement systems are the same regardless of the pathways by which C3 are produced. However, the alternative pathway is activated even earlier in an infection than is the classical pathway. - *The contributions of the complement system to innate defenses depend on C3, a key protein in the system.* Once C3 is formed, it immediately splits into C3a and C3b, which then participates in 3 kinds of molecular defenses: opsonization, inflammation, and membrane attack complexes.

General functions of the complement system

1- enhance phagocytosis by phagocytes 2- lyse microorganisms, bacteria, and enveloped viruses directly 3- generate peptide fragments that regulate inflammation and immune responses -Furthermore, complement goes to work as soon as an invading microbe is detected; the system makes up an effective innate host defense long before adaptive host immune defenses are mobilized

fever has several beneficial roles

1- raises the body temp above the optimum temperature for growth of many pathogens. This slows their rate of growth, reducing the number of microorganisms to be combated 2- @ the higher temps of fever, some microbial enzymes or toxins may be inactivated 3- fever can heighten the level of immune responses by increasing the rate of chemical reactions in the body. This results in faster rate at which the body's defense mechanisms attach pathogens, shortening the course of infection. 4- Phagocytosis is enhanced 5- production of antiviral interferon is increased 6- breakdown of lysosomes is heightened, causing death of infected cells and the microbes inside of them 7- fever makes a patient feel ill. in this condition, the patient is more likely to rest, preventing further damage to the body and allowing energy to be used to fight the infection

Some microbes resist digestion by phagocytes in 1 of 3 ways:

1- some bacteria, such as those that cause the plague (Yersinia pestis), produce capsules that are not vulnerable to destruction by macrophages. If these bacteria are engulfed my macrophages, their capsule protects them from lysosomal digestion, allowing the bacteria to multiply, even within a macrophage. Other bacteria- such as those that cause Hansen's disease, or leprosy (Mycobacterium leprae), and TB (M. tuberculosis)- and the protozoan that causes leishmaniasis (Leishmania species) can resist digestion by phagocytes. in the case of Mycobacterium, each engulf bacillus resides in a membrane-enclosed, fluid-filled compartment called a *PARASITOPHORUS VACUOLE (PV)*. No lysosomal enzyme activity is associated w/ the PVs as they do not fuse w/ lysosomes. *these organisms resistance to lysosomal activity is due to the complexity of their acid-fast cell walls, which consist of wax D and mycolic acids. lysosomal enzymes are unable to react w/ and digest these components.* For Leishmania infections, each PV contains several protozoan cells. although the lysosomal enzymes are active in these PVs, microbiologists do not understand how the pathogens resist digestion 2- Still other microbes produce toxins that kill phagocytes by causing the release of the phagocyte's own lysosomal enzyme into its cytoplasm. Examples of such toxins are *LEUKOCIDIN*, released by bacteria such as staphylococci, and *STREPTOLYSIN*, released by streptococci. - Some pathogens survive phagocytosis and can even be spread throughout the body in the phagocytes that attempt to destroy them. B/c macrophages can live for months, they can provide pathogens w/ a long-term stable environment in which they can multiply out of the reach of other host defense mechhanisms

Nonspecific defenses such as phagocytosis and opsonization are often called

a primitive characteristic b/c most animals have these ancient mechanisms

Acute phase Response

a response to acute illness that involves increased production of specific blood proteins called *acute phase proteins* - in an acute phase response, pathogen ingestion by macrophages stimulate the synthesis and secretion of several cytokines. - one called interleukin-6 (IL-6) travels through the blood and causes the liver to synthesize and secrete the acute phase proteins into the blood. thus, acute phase proteins form a nonspecific host defense mechanism distinct from both the inflammatory response and host-specific immune defenses. This mechanism appears to recognize foreign substances before the immune system defenses do and acts early in the inflammatory process, before antibodies are produced. - best understood acute phase proteins are C-REACTIVE PROTEIN (CRP) and MANNOSE-BINDING PROTEIN (MBP). all humans have capacity to produce both. - CRP recognizes and binds to phospholipids, and MBP to mannose sugars, in cell membranes of many bacteria and plasma membranes of fungi. - once bound, these acute phase proteins act like an opsonin: they activate the complement systems and immune cytolysis and stimulate phagocyte chemotaxis

normal body temperature

about 37°C (98.6°F), although individual variations in normal temp within the range 36.1‡C-37.5°C (97.0°-99.5°F) are not uncommon. - Fever is defined clinically as an oral temperature above 37.8°C (100.5°F) or rectal temp of 38.4°C (101.5°F) - fever accompanying infectious diseases rarely exceeds 40°C (104.5°F); if it reaches 43°C (109.4°F), death usually results

act as second line of defense against pathogens

adaptive defenses

abscess

an accumulation of pus in a cavity hollowed out by tissue damage - boils and pimples are common kinds of abscesses

Inflamed tissues also stimulate *LEUKOCYTOSIS*

an increase in the number of leukocytes in the blood. - to do this, the damaged cells release cytokines that trigger the production and infiltration of more leukocytes - within an hour after the inflammatory process begins, phagocytes start to arrive at the injured or infected site. for ex- neutrophils pass out of the blood by squeezing between endothelial cells lining the vessel walls. This process, called *DIAPEDESIS* allows neutrophils to congregate in tissue fluids @ injured region

chemokines

are a class of cytokines that attract additional phagocytes to the site of infection

wandering macrophages

circulate in the blood moving into tissues when microbes and other foreign material are present

Gut-associated lymphoid tissue (GALT)

collectively, the tissues of the lymphoid nodules are referred to as GALT- which are major sites of antibody production against mucosal pathogens. - similar nodules are found in the respiratory system, urinary tract, and appendix

in the past, ANTIPYRETICS

fever-reducing drugs such as aspirin- were given almost routinely to reduce fever caused by infections. - *for the beneficial reason stated before, many physicians now recommend to allow fevers to run their course* - however, if a fever goes above 40°C or if the patient has a disorder that might be worsened by a fever, antipyretics are still used. -in fact, untreated extreme fever increases the metabolic rate by 20%, makes the heart work harder, increases water loss, alters electrolyte concentrations, and can cause convulsions, especially in children. - thus, patients w. severe heart diseases or fluid and electrolyte imbalances, as well as children subject to convulsions, usually receive antipyretics

act as first line of defense agains pathogens

innate defenses

the most significant effect of complement deficiencies is the

lack of resistance to infection - deficiencies in several complement components have been observed. -the greatest degree of impaired complement function occurs w/ a deficiency of C3- bc C3 is key component. chemotaxis, opsonization and cell lysis are impaired. Such individuals are especially subject to infection by pyogenic bacteria. - deficiency in MAC components (C5-C9) associated w/ recurrent infections, especially by Neisseria species.

Mast cells

prevalent in connective tissue and alongside blood vessels, also release histamine and are associated w/ allergies

fixed macrophages

remain stationary in tissues and are given diff names depending on the tissue in which they reside

molecular defenses

represent another formidable innate defense barrier - involve the actions of interferon and complemets

adaptive defenses

respond to particular agents called antigens by producing antibodies - also involve activation of lymphocytes

congenital complement deficiencies are due to

specific genetic defects that prevent the synthesis of one or more complement proteins

acquired diseases result from

temporary depletion of a complement protein; they subside when cells again synthesize the protein

a great advantage of the complement system to host defenses is

that once it is activated, the reaction cascade occurs rapidly.

complement activity can be impaired by

the absence of one or more of its protein compartments. -impaired complement activity makes the host more vulnerable to various diseases, most of which are acquired or congenital.

Pus

the accumulation of dead phagocytes, injured or damaged cells, the remains of ingested organisms, and other tissue debris form this white or yellow fluid. - many bacteria, such as Streptococcus pyogenes, cause pus formation b/c of their ability to produce leukocidins that destroy phagocytes. Viruses lack this activity and do not cause pus formation. - *pus continues to form until the infection or tissue damage has been brought under control.*

the fluid that enters the injured tissue carries

the chemical components of the blood-clotting mechanism. - if the injury has caused bleeding, platelets and clotting factors, such as FIBRIN, stop the bleeding by forming a blood clot near the vessel. - b/c clotting takes place near the injury, it greatly reduces fluid movement around damaged cells and walls off the injured area around the rest of the body.

when cells are damaged:

the chemical substance histamine is released from basophils and mast cells. - *Histamine* diffuses into nearby capillaries and venules, causing the walls of these vessels to dilate (*vasodilation*) and become more permeable. - Dilation increases the amount of blood flowing to the damaged area, and it causes the skin around wounds to become red and warm to the touch. - b/c the vessel walls are more permeable, fluids leave the blood and accumulate around injured cells, causing *edema* (swelling). - the blood delivers clotting factors, nutrients, and other substances to injured area and removes wastes and some excess fluids. It also brings macrophages, which release cytokines. Some cytokines are chemokines and attract other phagocytes, and another cytokine, called TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA), additionally causes vasodilation and edema. - all kinds of tissue injury- burns, cuts, infections, insect bites, allergies- cause histamine release. in conjunction w/ its effects on blood vessels, *histamine* also causes the red, watery eyes and runny nose of hay fever and the breathing difficulties in certain allergies. - the drugs called *antihistamines* alleviate such symptoms by blocking the released histamine from reaching its receptors on target organs

The MAC is responsible for

the direct lysis of invading microorganisms. - importantly, host plasma membranes contain proteins that protect against MAC lysis. These proteins prevent damage by preventing the binding of activated complement proteins to host cells. - the MAC forms the basis of COMPLEMENT FIXATION, a laboratory test used to detect antibodies agains any one of many microbial antigens

chemotaxis (definiton)

the movement of cells toward a chemical stimulus - how phagocytes make their way to site of infection

cytokines

these chemicals are a diverse group of small soluble proteins that have specific roles in host defenses, including the activation of cells involved in the inflammatory response - released by phagocytes that are already at the site of infections

Lymphatic tissues can becomes sites of infections when

they encounter more pathogens than their cells that phagocytize microorganism can destroy, - Swollen lymph nodes and tonsillitis are common signs of many infectious diseases

body temperature is maintained

within a narrow range by a temperature-regulating center in the HYPOTHALAMUS, a part of the brain. - Fever occurs when the temp established for this mechanism is reset and raised to a higher temp. - Fever can be caused by many pathogens, by certain immunological processes (such as reactions to vaccines), and by nearly any kind of tissue injury, even heart attacks