Micro 14

The routine protection provided by skin, mucous membranes, and sensor systems in the tissues that detect invading microbes and direct/assist defenses to destroy the invaders

• a feature of innate immunity which detects molecules associated with invading microbes or tissues damage
• Molecules recognized include parts of bac cell walls & other compounds unique to microbes, as well as substances associated with damaged host cells

• More specialized defense system evolved by vertebrates
• develops throughout life and substantially increases host's ability to defend itself
• Each time body is exposed to microbe, it "learns" and then "remembers" most effective response to that specific material
• Then reacts accordingly if material is encountered again

substance that causes immune response

• Y-shaped proteins that are produced during adaptive immune response
• bind specifically to antigens, thereby targeting them for destruction or removal

the body's own cells that are destroyed by adaptive immune response if they harbor a virus or other invader

• First-line defenses - prevent microbial entry
• Sensory systems - detect microbial invasion
• Innate effector actions - destroy invader

• the barrier that separate and shield the interior of the body from the surrounding environment
• skin and mucous membranes

Pattern recognition receptors & complement system

• inflammatory response
• Interferon response
• Opsonization
• membrane attack complexes

• PRR's
• Proteins on or in cells that recognize specific compounds unique to microbes or tissue damage, allowing the cells to sense the presence of invading microbes or damage
• *cause inflammatory response and/or interferon response

• series of proteins always present in blood
• they can "complement" (act in combo with) the adaptive immune defenses
• activated in response to certain stimuli, setting off chain of events that results in removal/destruction of invading microbes
• *Cause inflammatory response, opsonization, membrane attack complexes

• occurs when invading microorganisms or tissue damage is detected
• cells that line local blood vessels undergo changes that allow complement system components and other proteins to leak into tissues

• cells that specialize in engulfing and digesting microbes and cell debris
• upon inflammation, leave bloodstream and accumulate in tissues
• some types play dual role, destroying invaders while communicating with cells of adaptive immune system

• the enzyme that degrades peptidoglycan
• is in tears, saliva, and mucus
• Also found within body, in phagocytic cells, blood, and fluid that bathes tissues

• break down hydrogen peroxide to produce reactive oxygen species
• in saliva and milk, body tissues and phagocytes

• Lactoferrin: iron-binding protein in saliva, mucus, and milk
• also found in some types of phagocytes

Transferrin: in blood and tissue fluids

Similar compounds. Iron is one of major elements. Withholding prevents microbe growth

• short antimicrobial peptides produced by neutrophils and epithelial cells
• insert into bac membranes, forming pores that damage cells

formation and development of blood cells

• the cell type which all blood cells, including those important to body's defenses, originate from 
• found in bone marrow
• capable of long-term self-renewal,

• WBC (duh)
• divided into four broad groups:
• granuloctytes
• mononuclear phagocytes
• dendritic cells
• lymphocytes

3 types: Neutrophils, Eosinophils, Basophils

• Also called PMN's, or polymorphonuclear neutrophilic leukocytes, or polys
• most common type of circulating leukocyte, accounting for over half of WBC in circulation (55-65%)
• Few in tissues except during inflammation
• They phagocytize and digest engulfed materials

• 2-4% of blood WBC
• Few in tissues except in certain types of inflammation and allergies
• Participate in inflammatory reaction and immunity to some parasites

• 0-1% of blood WBC
• involved in allergic reactions and inflammation
• Release histamine and other inflammatory-inducing chemicals from the granules

• Similar to basophils in appearance and function, but found in tissues rather than blood
• are important for inflammatory response and responsible for many allergic reactions

• make up MPS (mononuclear phagocyte system)
• includes monocytes and the cell types that develop from them as they leave the bloodstream and migrate into tissues
• Monocytes differenciate into macrophages and dendritic cells

• Make up 3-8% of blood WBC
• In circulation
• Differentiate into either macrophages or dendritic cells when the migrate into tissues
• Phagocytize and digest engulfed materials

• Present in virtually all tissues; known by various names based on tissue in which they are found
• particularly abundant in liver, spleen, lymph nodes, lungs and peritoneal cavity
• Phagocytize and digest engulfed materials

• Can be viewed as "scouts"
• engulf material in tissues and then bring to cells in adaptive immune system for "inspection"
• Initially in tissues, but migrate to secondary lymphoid organs (lymph nodes, spleen, appendix, tonsils)

• Make up 25-35% of blood WBCs
• responsible for adaptive immunity
• in lymphoid organs
• Involve B cells and T cells, remarkable specific in recognition of antigen
• generally reside in lymph nodes and other lymphatic tissue

• NK cells
• type of lymphocyte
• lack specificity in mechanisms of antigen recognition

• can be viewed as "eyes" and "ears" of a cell
• proteins that generally span plasma membrane, connecting outside with inside
• each receptor is specific with respect to compound it will bind

the molecule that can bind to a given receptor

movement of a motile cell or organism, or part of one, in a direction corresponding to a gradient of increasing or decreasing concentration of a particular substance.

• can be viewed as "voices" of cell
• a cytokine produced by one cell diffuses to another and binds to the appropriate cytokine receptor of that cell
• Binding to it's receptor induces change in cells such as growth, differentiation, movement, or cell death

• type of cytokine important in chemotaxis of immune cells
• allows cells to sense the location where they are needed, such as inflammation

• CSF
• important in multiplication and differentiation of different kinds of leukocytes
• direct immature cells into appropriate maturation pathways

• IFN
• important in control of viral infections
• Also, IFN-gamma helps regulate function of cells involved in inflammatory response and adjusts certain actions of adaptive immunity

• Interferon alpha - Leukocytes - antiviral
• Interferon beta - fibroblasts - antiviral
• Interferon gamma - T cells, NK cells - Macrophage activation; promotes certain adaptive immune responses

• IL's
• produced by leukocytes and have diverse, often overlapping, functions
• important in both innate and adaptive immunity
• Types include: IL-1, IL-2, IL-4, IL-6

• Source: macrophages & epithelial cells
• Effect: T-cell activation; macrophage activation; induces fever

• Source: T cells
• Effect: T-cell proliferation

• Source: T cells, mast cells
• Effect: Promotes antibody responses

• Source: T lymphocytes, macrophages
• Effect: T and B cell growth; inflammatory response; fever

• TNF
• Source: Macrophages, T cells, NK cells
• helps initiate the inflammatory response and triggers the process of "cell suicide", a programmed cell death called apoptosis
• Also regulates certain immune functions

• groups of cytokines which contribute to inflammation
• TNF, IL-1, IL-6, and others

on the surface of cells, allows cells to "grab" other cells

• Pathogen-associated molecular pattern
• patterns detected by PRR's (pattern recognition receptors)

• Danger-associated molecular patterns
• molecules that indicate host cell damage

• anchored in membranes of sentinel cells such as macrophages, dendritic cells, and cells that line sterile body sites
• Number of different TLR's, each recognize a distinct compound or group of compounds associated with microbes
• allow the detection of extracellular molecules that signify the presence of microbes
• When it detects compound, signal is transmitted to nucleus, causing certain genes to be expressed. 
• Can be tailored to situation and category of pathogen

• crtoplasmic proteins that detect bacterial components, allowing cell to recognize when it's own borders have been breached
• Some also detect signs of cell damage
• When they detect PAMP's or DAMP's, they unlease a series of events that lead to outcomes that protect hose, sometimes at expense of cell itself

• In macrophages, a form of NRL (NOD-like receptor) the has joined with other protein in cytoplasm
• This complex activates a potent pro-inflammatory cytokine, initiating inflammatory response

Crohn's disease

• cytoplasmic proteins that detect viral RNA
• provides mechanism for infected cell to detect invader
• Can distinguish viral RNA from normal cellular RNA 
• Virally infected cells respond by making interferons

• When cell's RLR detect viral RNA, cell responds by synthesizing & secreting interferons
• These proteins attach to specific receptors on both infected and neighboring cells
• However, only infected ones are sacrificed
• The nearby cells remain functional but prepare to undergo apoptosis if they become infected with virus

• series of proteins that circulate in blood and fluid that bathes tissues
• complement function of antibodies
• Each major complement system protein has a number along with the letter C
• 9 major proteins, C1 through C9
• When protein is split into 2 fragments, each is distinguished by adding lowercase letter to each name Ex: C3a and C3b

• Can be activated by 3 different pathways that converge when the complex C3 convertase is formed
• C3 convertase then splits C3, leading to additional steps of the activation cascade

• Alternative pathway
• Lectin pathway
• Classical pathway

Triggered when C3b binds to foreign cell surfaces, which allows other complement proteins to then attach, eventually forming C3 convertase

• is somewhat unstable, and spontaneously splits into C3a and C3b at a low rate even when complement system has not been activated
• The C3a and C3b formed this way are rapidly inactivated by regulatory proteins, but some C3b is always present to trigger alternative pathway when needed

• activation of complement system via lectin pathway involves pattern recognition molecules called mannose-binding lectins (MBL's)
• These bind to certain arrangements of multiple monnonse molecules that characterize microbe cells
• Once MBL attaches to surface, can interact with complement system to form C3 convertase

• requires antibodies, a component of adaptive immunity
• when antibodies bind to antigen (forming antigen-antibody complex) interact with same complement system involved with lectin & form C3 convertase

• opsonization
• inflammatory response
• lysis of foreign cells

material that has been opsonized (meaning "prepared for eating") is easier for phagocytes to bind to and engulf because phagocytes have receptors that attach specifically to the opsonins (in this case, C3b)

*can be thought of as coating microbe with layer of velcro, and phagocytes have opposing layer on their surface

• Complement component C5a is a potent chemoattractant, drawing phagocytes to the area where complement system has been activated
• In addition, C3a and C5a induce changes in endothelial cells that line blood vessels, contributing to vascular permeability associated with inflammation
• Also cause mast cells to release various pro-inflammatory cytokines

• Complexes of complement system proteins (C5b, C6, C7, C8, & multiple C9) spontaneously assemble in cell membranes, forming doughnut-shaped structures called MAC's
• creates pores in membrane, disrupting integrity of cell

• C5b combines with C6, C7, C8, and C9 to form membrane attack complexes that insert into cell membrane
• creates pores in membrane
• Have little effect of Gram +, as peptidoglycan layer prevents complement system components from reaching cytoplasmic membranes
• Outer membranes of gram-neg make them susceptible

complement regulatory proteins prevent host cell surfaces from activating the complement system via the alternative pathway

• Chemotaxis
• Recognition and attachment
• Engulfment
• Phagosome Maturation and Phagolysosome Formation
• Destruction and Digestion
• Exocytosis

• Phagocytic cells are recruited to site of infection or tissue damage by chemicals that act as chemoattractants
• Includes products of microorganisms, phospholipids released by injured host cells, chemokines, and complements system component C5a

• Phagocytic cells use various receptors to bind invading microbes either directly or indirectly
• Direct binding occurs when receptors bind mannose (a sugar)
• Indirect binding happens when a particle has first been opsonized

• secreted proteins that tag particles for phagocytosis and include the complement component C3b and certain classes of antibody molectules
• Phagocytes have specific receptors for opsonins, making it easier to attach and engulg

• Once phagocyte has attached, sends out pseudopods to surround and engulf material
• Encloses into a phagosome

• in engulfment, when pseudopods surround and engulf the material, and material is brought into the cell
• refers to the enclosed structure the material is in

• *Phagosome has no antimicrobial capabilities, but matures to develop them
• As part of process, fuses with various endosomes, allowing it to gain properties that characterize those endosomes
• Finally forms phagolysosome
• Maturation stages are highly regulated and depend on material ingested

what the phagosome becomes after it fuses with enzymes-filled lysosome

• # of factors within phagolysosome work together to destroy invader:
• O2 consumption increases - phenomenon called respiratory burst - produces reactive o2 species (ROS) which is toxic
• Another enzyme makes nitric oxide, reacts with ROS to produce additional toxic compounds
• Special pumps move protons in, lowering pH

Following digestion, vesicle fuses with plasma membrane, expelling remains

• macrophages stimulated by cytokines to enlarge and become metabolically active, with greatly increased capability to kill and degrade intracellular organisms and materials
• Compounds the produce, however, also damage tissue, so it would be potentially harmful for macrophages to routiney be in activated state

• Very large cell with many nuclei, formed by fusion of many macrophages during a chronic inflammatory response
• found in granulomas

• concentrated groups of macrophages, giant cells, and T cells
• wall off and retain organisms or other material that cannot be destroyed
• Prevent microbes from escaping to infect other cells

• Can be viewed as rapid response team
• Critical role during first stages of inflammation
• first cell type recruited to site of damage from bloodstream
• Have more killing power than macrophage
• Live span is short, 1-2 days

Set of S/S (swelling, heat, redness, and pain) that characterizes an innate immune response to infection or injury

• Contain a site of damage
• Localize the response
• Eliminate the invader
• Restore tissue function

• released from host cells in response to triggers of inflammation
• a collective term for various pro-inflammatory cytokines and chemicals such as histamine and bradykinin

• Initiated when microbes are detected by TLR's, NLR's or the complement system
• Or when tissue damage occurs

• cause small blood vessels to dilate
• Results in greater blood flow to area, causing heat and redness associated with inflammation
• Also slows blood flow in capillaries
• Because of dilation, normally tight junctions btwn endothelial cells are disrupted, allowing fluid to leak from vessels to tissue
• Fluid contains substances such as transferrin, complement system proteins, and antibodies

• short term inflammation
• marked by prevalence of neutrophils

• occurs if acute inflammation can't limit infection
• can last for years
• Macrophages and giant cells accumulate and gronulomas form

• Although process usually limits damage and restores function, can cause significant damage
• One undesirable consequence is that some enzymes and toxic product contained within phagocytic cells are inevitably released, damaging tissue
• If process occurs in delicate system, such as brain or spinal cord, can be sever & even more life threatening

• programmed cell death that does not trigger an inflammatory response
• dying cells undergo certain changes
• Ex: the shape of cell changes, enzymes cut the DNA, portions of cell bud off, effectively shrinking cell

• Programmed self-destruction which triggers an inflammatory response, recruiting various components of immune system to region
• initiated if pattern recognition receptors in macrophage's cytoplasm are triggered

37.8 or higher

• cytokines and other fever-inducing substances
• Fever inducing cytokines are endogenous, indicating body makes them
• Microbial products are called exogenous pyrogens

inhibits growth of many pathogens and increases rate of various body defenses