Ch. 16 -- Innate Immunity: Nonspecific Defenses of the Host

1st Line of Defense: Skin + Mucous Membranes

*Physical factors* - barriers to entry + processes that remove microbes from the body's surface *Skin* - consists of the dermis + epidermis; dermis is the inner, thicker portion comprised of connective tissue & epidermis is the outer, thinner portion; keratin is a protective protein found in the top layer of dead epidermal cells; shedding & dry skin also help to prevent microbes *Mucous Membranes* - consist of an epithelial layer + a connective tissue layer; line the GI, respiratory, & genitourinary tracts; secrets mucus *Lacrimal apparatus* - manufactures + drains tears; protects the eye; washing actions prevents microbes from settling *Saliva* - washes microbes from surface of teeth & mucous membranes in the mouth *Mucus* - traps microbes in tracts & *hairs* filter inhaled air & trap microbes + dust + pollutants Mucous membranes of lower respiratory tract have cilia that propel inhaled dust + microbes towards the throat in a *ciliary escalator* *Epiglottis* - covers the larynx during swallowing & *earwax* helps prevent microbes from entering the ear *Urine* - cleanses the urethra & urogenital tract of microbes; *vaginal secretions* do as well *Peristalsis, defecation, vomiting, & diarrhea* also expel microbes -------- *Chemical factors* *Sebum* - forms a protective barrier over the skin; the unsaturated fatty acids prohibits growth of certain bacteria; skin's acidity also contributes to prohibit growth *Perspiration* - maintains body temp., eliminates certain wastes, & flushes microbes from the skin; also contains *lysozyme* which breaks down cell walls of gram (+); lysozyme also found in tears, saliva, nasal secretions, tissue fluids, & urine *Earwax* - a mix of secretions from glands producing earwax & sebaceous glands that produce sebum; fatty acid secretions keep ear pH low, which inhibits growth of microbes *Saliva* - has amylase, lysozyme, urea, & uric acid; slightly acidic & has IgA antibody *Gastric juice* - mix of hydrochloric acid, enzymes, & mucus; extremely acidic *Vaginal secretions* - glycogen produced by vaginal epithelial cells is broken down into lactic acid which created an acidic pH; cervical mucus also has antimicrobial activity *Urine* - lysozyme + acidic pH

Phases of Phagocytosis

1) Chemotaxis 2) Adherence 3) Ingestion 4) Digestion

Chemotaxis

The chemical attraction of phagocytes to microorganisms

Commensalism

1 organism uses the body of a larger organism as its physical environment & may make use of the body to obtain nutrients; 1 organism benefits while the other isn't affected Mostly found in the skin & GI tract; have highly specialized attachment mechanisms & precise environmental requirements for survival; harmless unless their environment changes

Inflammation

1) Activated C3 splits into C3a + C3b 2) C3a + C5a bind to mast cells & cause them to release histamine + other chemicals that increase blood vessel permeability during inflammation; C5a also functions as a very powerful chemotactic factor that attracts phagocytes to the site of an infection

Fixed Macrophages

AKA histiocytes; resident in certain tissues + organs of the body Found in: liver (Kupffer's cells), lungs (alveolar macrophages), nervous system (microglial cells), bronchial tubes, spleen (splenic macrophages), lymph nodes, red bone marrow, & the peritoneal cavity surrounding abdominal organs (peritoneal macrophages)

Interferons (IFNs)

A class of proteins produced by lymphocytes + macrophages that are active against viruses; play a major role in infections that are acute like colds + influenza; small proteins, stable at low pH, & fairly heat resistant; produced by fibroblasts in connective tissue, lymphocytes, & leukocytes 3 types: alpha, beta, & gamma a + b interfere with viral multiplication; produced by virus-infected host cells in very small quantities that diffuse to uninfected neighboring cells; both are host-cell-specific, not virus-specific; induce neighboring cells to make mRNA for synthesis of *antiviral proteins (AVPs)* which are enzymes that disrupt various stages of viral multiplication g is produced by lymphocytes & induces neutrophils + macrophages to kill bacteria; causes macrophages to produce nitric oxid that inhibits ATP production; increases expression of class I + class II molecles & increase antigen presentation

Inflammation

A local defensive response when there is damage to body tissues; 2nd line of defense Damage can be cause by microbial infection, physical agents (heat, radiant energy, electricity, sharp objects), or chemical agents (acids, bases, gases) 4 signs: redness, pain, heat, & swelling (5th is loss of function) Functions: 1) Destroy the injurious agent if possible & to remove it + its by products from the body 2) If destruction isn't possible, to limit the effects on the body by confining or walling off the injurious agent & its by-products 3) To repair/replace tissue damaged by the injurious agent & its by-products *Acute inflammation* - if the cause of inflammation if removed in a short period of time, the inflammatory response is intense *Chronic inflammation* - if the cause of inflammation is impossible or difficult to remove, the response is longer lasting but less intense *Acute-phase proteins* - induce both local + systemic responses & include proteins such as C-reactive protein, mannose-binding lectin, fibrinogen, & kinins for vasodilation; respond to tumor necrosis factor alpha (TNF-a) All cells involved in inflammation have receptors for TNF-a & are activated by it to produce more TNF-a to amplify the inflammatory response

Adaptive Immunity

A specific response to a specific microbe once it has breached the innate immunity defenses; slower to respond but has a memory component Involves: T cells + B cells Responses activated by protein receptors in the plasma membranes of defensive cells Activators: *toll-like receptors (TLRs)* which attach to *pathogen-associated molecular patterns (PAMPs)* on pathogens which can be LPS, flagellin in flagella, peptidoglycan, DNA of bacteria, & DNA + RNA in viruses; TLRs also attach to components of fungi + parasites

Fever

Abnormally high body temp; 2nd line of defense; caused by infection from bacteria or viruses Hypothalamus is the body's thermostat; set at 37 C (98.6 F) Constricts blood vessels, increases rate of metabolism, & *shivering* (all raise body temp); skin remains cold (called a chill, but disappears when it reaches the new thermostat setting); body will remain that temp until cytokines are eliminated; then it is reset at 37 C Heat losing mechanisms like vasodilation & sweating occur when infection subsides (this phase is called *crisis* & it indicates the body temp is falling) Interleukin 1 steps up the production of T cells High body temp intensifies the effect of antiviral interferons & increases production of transferrins that decrease the iron available to microbes; also helps body tissues repair themselves more quickly

Agranulocytes

Also have granules, but not visible after staining 3 types: *Monocytes* - not actively phagocytic until they leave blood, enter body tissues, & mature into *macrophages* (they dispose of worn out blood cells) *Dendritic cells* - have long extensions; abundant in the epidermis, mucous membranes, thymus, & lymph nodes; destroy microbes by phagocytosis & initiate adaptive immunity response *Lymphocytes* - includes NK cells, B + T cells NK cells found in blood, spleen, lymph nodes, & red bone marrow; attach any body cells that display abnormal plasma membrane proteins; release vesicles filled with toxic substances; have *perforin* which creates holes in the membrane (extracellular fluid flows into the cell causing it to burst *cytolysis*) or *granzymes* which are protein-digesting enzymes that induce the target cell to undergo apoptosis (this kills infected cells but not microbes inside the cells; released microbes can be destroyed by phagocytes) T + B cells play a role in adaptive immunity; occur in lymphoid tissues & circulate in blood Leukocytosis is when # of WBCs increase in response to bacterial infections Leukopenia is when the # of WBCs go down either due to infections, impaired WBC production, or effect of increased sensitivity of WBC membranes to damage by complement, antimicrobial serum proteins *Differential WBC count* - calculation of the % of each kind of white cell in a sample of 100 WBCs

Siderophores

Bacteria secrete these proteins that bind iron more tightly than iron-binding proteins; once iron-siderophore complex is formed, it is taken up b siderophore receptors on the bacterial surface & brought into the bacterium; then the iron is split from the siderophore & utilized Iron can also be taken by bacteria that have receptors that bind directly to iron-binding proteins & pathogens that release hemolysinn

Kinins

Cause vasodilation & increased permeability of blood vessels; present in blood plasma & attract chemotaxis by attracting phagocytic granulocytes, mainly neutrophils, to injured area

Formed Elements

Cells + cell fragments suspended in plasma Include: RBCs + WBCs + platelets Created in bone marrow by stem cells in a process called *hematopoiesis*; a pluripotent stem cell develops into 2 other types of cells called myeloid stem cells + lymphoid stem cells

Innate Immunity

Defenses that are present at birth; always available to provide rapid responses to protect us against disease; doesn't involve recognition of a specific microbe; no memory response; immunity's early warning system 1st line of defense: skin & mucous membranes 2nd line of defense: NK cells, phagocytes, inflammation, fever, & antimicrobial substances

Mononuclear Phagocytic (Reticuloendothelial) System

Comprised of the various macrophages of the body

Lymphatic System

Consists of lymph, lymphatic vessels, organs containing lymphoid tissue, & red bone marrow Lymph nodes are the sites of activation of T + B cells; they also have reticular fibers that trap microbes, macrophages, & dendritic cells, which destroy microbes by phagocytosis Lymphatic capillaries are located in spaces b/w cells; permit IF derived from blood plasma to flow in but not out; lymphatic vessels keep lymph flowing in 1 direction only; lymph flows into lymph nodes and eventually passes into the thoracic (left lymphatic) duct & right lymphatic duct before going into their respective subclavian veins where the fluid is now called blood plasma, which becomes IF b/w tissue cells & another cycle begins Multiple large aggregations of lymphoid tissue are the tonsils & Peyer's patches in the small intestine Spleen has lymphocytes + macrophages that monitor the blood for microbes + toxins Thymus is a site for T cell maturation; also contains dendritic cells + macrophages

Complement System

Consists of over 30 proteins produced by the liver that circulate in blood serum & within tissues throughout the body; assists cells of the immune system in destroying microbes Not adaptable (never changes); can be recruited into action by the adaptive immune system Proteins of this system destroy microbes by cytolysis, opsonization, & inflammation; also prevent excess damage to host tissues Inactive until split into fragments (products); active fragments carry out destructive actions; numbered C1-C9; inactive complement protein C3 is split into C3a & C3b Complement proteins act in a cascade; more product is formed with each succeeding reaction, amplifying the effects; during an infection, this is called *complement activation* which occurs in 3 pathways that end in the activation of C3

Vasodilation

Dilation of blood vessels; responsible for the redness (erythema) & heat associated with inflammation Help deliver clotting elements of blood into injured area Blood clots that form around activity site prevents microbes/toxins from spreading; a collection of pus (mix of dead cells + body fluids) results; focus of infection is an *abscess* (pustules + boils)

Alternative Pathway

Doesn't involve antibodies; activated by contact b/w certain complement proteins & a pathogen 1) C3, constantly present in the blood, combines with complement proteins factor B, factor D, & factor P (properdin) on the microbe's surface; the complement proteins are attracted to microbial cell surface material (most lipid-carb complexes of certain bacteria + fungi) 2) Once complement proteins combine + interact, C3 splits into fragments C3a + C3b; C3a participates in inflammation & C3b functions in cytolysis + opsonization

Plasma

Fluid in blood

Normal Microbiota

Help prevent the overgrowth of pathogens; in microbial antagonism, the normal microbiota prevent pathogens from colonizing by competing for nutrients (competitive exclusion), by producing substances harmful to pathogens, & by altering conditions that affect the survival of the pathogen like pH + O2 availability

Opsonization

Immune adherence; promotes attachment of a phagocyte to a microbe; enhances phagocytosis 1) Activated C3 splits into activated C3a + C3b 2) C3b binds to microbe surface, & receptors on phagocytes attach to C3b

Classical Pathway

Initiated when antibodies bind to antigens 1) Antibodies attach to antigens, forming antigen-antibody complexes; the antigen-antibody complexes bind to activate C1 2) Activated C1 activates C2 + C4 by splitting them; C2 splits into C2a + C2b; C4 is split into C4a + C4b 3) C2a + C4b combine & together activate C3 by splitting it into C3a + C3b fragments; C3a participates in inflammation & C3b functions in cytolysis + opsonization

Cytolysis

Involves membrane attack complex (MAC); C5b-C8 & multiple C9 fragments; creates a hole in pathogen's cell membrane & makes transmembrane channels, allowing for flow of extracellular fluid into the pathogen, causing the cell to burst 1) Activated C3 splits into C3a + C3b 2) C3b splits C5 into C5a + C5b 3) Fragments C5b, C6, C7 + C8 bind together sequentially & insert into the plasma membrane of the invading cell; C5b-C8 act as a receptor that attracts a C9 fragment; additional C9 fragments are added to form a transmembrane channel Gram (-) more susceptible to cytolysis b/c they have few layers of peptidoglycan to protect their plasma membrane

Susceptibility

Lack of immunity

Probiotics

Live microbial cultures applied to or ingested that intended to exert a beneficial effect May be administered with prebiotics, which are chemicals that selectively promote the growth of beneficial bacteria

Iron-binding Proteins

Molecules like transferrin, lactoferrin, ferritin, & hemoglobin whose function is to transport + store iron *Transferrin* - found in blood + tissue fluids *Lactoferrin* - found in milk, saliva, & mucus *Ferritin* - found in liver, spleen, & red bone marrow *Hemoglobin* - located in RBCs They deprive most pathogens of the available iron

Free (Wandering) Macrophages

Motile; roam the tissues & gather at sites of infection/inflammation

Increased Permeability

Permits defensive substances normally retained in the blood to pass through the walls of blood vessels & enter the injured area; this is responsible for the *edema* (accumulation of fluid) of inflammation Vasodilation & increased permeability in response to *histamine* being released (from mast cells, basophils, & blood platelets) in response to injury or by stimulation of components in the complement system; phagocytic granulocytes can also produce chemicals that cause the release of histamine

Cytokines

Proteins that regulate the intensity & duration of immune responses They recruit other macrophages + dendritic cells + other defensive cells to isolate & destroy the microbes as part of the inflammatory response; they can also activate T + B cells involved in adaptive immunity

Antimicrobial Peptides (AMPs)

Short peptides that consist of a chain of 12-50 a.a synthesized on ribosomes; have broad spectrum of antimicrobial activities; synthesis of AMPs is triggered by protein + sugar molecules on the surface of microbes; cells produce AMPs when chemicals in microbes attach to Toll-like receptors They inhibit cell wall synthesis; forming pores in the plasma membrane, resulting in lysis; destroying DNA + RNA Dermcidin (produced by sweat glands), Defensins + Cathelicidins (by neutrophils, macrophages, & epithelium), Thrombocidin (by platelets) AMPs have shown synergy in working with other antimicrobial agents; very stable over a wide range of pH; microbes don't develop resistance even after long periods of exposure; can sequester the LPS shed from gram (-); attract dendritic cells; recruit mast cells

Margination

Sticking response of phagocytes (neutrophils + monocytes) to the inner surface of the endothelium (lining) of blood vessels in response to local cytokines Then they perform *diapedesis* when they squeeze b/w the endothelial cells of the blood vessels to reach the damaged area Phagocytes then begin to destroy invading microbes by phagocytosis

Leukotrienes

Substances produced by mast cells + basophils; cause increased permeability of blood vessels & help attach phagocytes to pathogens

Prostaglandins

Substances released by damaged cells; intensify effects of histamine + kinins; help phagocytes move through capillary walls Also associated with the pain related to inflammation

Digestion

The phagosome pinches off from the plasma membrane & enters the cytoplasm, where it comes into contact with digestive enzymes + bactericidal substances On contact, the phagosome + lysosome membranes fuse to form a *phagolysosome*; the contents of the phagolysosome brought in by ingestion are digested in the phagolysosome After enzymes have digested the contents of the phagolysosome, the phagolysosome contains indigestible material called the residual body; the residual body moves toward the cell boundary & discharges its wastes outside the cell

Immunity/Resistance

The ability to ward off disease caused by microbes or their products & to protect against environmental agents such as pollen, chemicals, & animal dander

Adherence

The attachment of the phagocyte's plasma membrane to the surface of the microorganism or other foreign material; facilitated by the attachment of pathogen-associated molecular patterns (PAMPs) of microbes to receptors, such as Toll-like receptors (TLRs) on the surface of phagocytes (binding initiates phagocytosis); phagocyte releases specific cytokines to recruit more phagocytes Coating of serum proteins = microbes more readily phagocytized; coating process is called *opsonization*; proteins that act as opsonins include some components of the complement system & antibody molecules

Phagocytosis

The ingestion of a microorganism or other substance by a cell; *phagocytes* are capable of performing phagocytosis & are types of WBCs or WBC derivatives; monocytes develop into phagocytic macrophages

Ingestion

The plasma membrane of the phagocyte extends projections called *pseudopods* that engulf the microorganism Once the microorganism is surrounded, the pseudopods meet + fuse, surrounding the microorganism with a sac called a *phagosome* (phagocytic vesicle); the membrane of a phagosome has enzymes that pump protons (H+) into the phagosome, reducing the pH to 4; at this pH, hydrolytic enzymes activate

Tissue Repair

Tissues replace dead/damaged cells; begins during active phase of inflammation, but can't be completed until all harmful substances have been removed/neutralized at injury site Tissue repaired when its stroma (supporting connective tissue) or parenchyma (functioning part of the tissue) produces new cells If parenchymal cells more active in repair, a perfect reconstruction of tissue occurs; if repair cells of stroma are more active, scar tissue is formed

Process of Inflammation

Vasodilation & increased permeability of blood vessels, phagocyte migration + phagocytosis, & tissue repair

Granulocytes

WBCs that have large granules in their cytoplasm 3 types: *Neutrophils* - stain pale lilac with a mix of acidic + basic dyes; aka polymorphonuclear leukocytes (PMNs) or polymorphs; highly phagocytic + notile; active in initial stages of infection; have the ability to leave the blood, enter an infected tissue, & destroy microbes + foreign particles *Basophils* - stain blue-purple with basic dye methylene blue; release histamine *Eosinophils* - stain red or orange with acidic dye eosin; somewhat phagocytic & can leave blood; produce toxic proteins against certain parasites like helminths; discharge peroxide ions that destroy helminths; #s increase during parasitic worm infections & allergy reactions

Lectin Pathway

When macrophages ingest bacteria by phagocytosis, they release cytokines that stimulate the liver to produce *lectins* (proteins that bind to carbs) 1) *Mannose-binding lectin (MBL)* binds to the carb mannose; MBL binds to many pathogens bc MBL molecules recognize a distinctive pattern of carbs that includes mannose, which is found in bacterial cell walls & on some viruses 2) As a result of binding, MBL functions as an opsonin to enhance phagocytosis & activates C2 + C4 3) C2a + C4b activate C3; C3 splits into C3a + C3b; C3a participates in inflammation & C3b functions in cytolysis + opsonization