Chapter 14: Innate Immunity

Sentinel cells

"lookouts" or "guards" that are positioned at strategic sites in the body to detect invading microbes in blood or tissues fluids. recognize microbes by detecting their unique components, using a special group of receptors called pattern recognition receptors (PRRs).

Effector actions

"security teams" that eliminate the invader.

PRRs that monitor material ingested by a cell

Toll-like receptors: in phagosomal and endosomal membranes; typically recognize characteristics of nucleic acids that indicate a microbial origin certain TLRs in endosomes or phagosomes are not fully functional until the vesicle fuses with lysosomes, exposing the contents of the vesicle to low pH and digestive enzymes.

mucous membrane

a first line defense against microbes, made up of columnar epithelial cells, found in the digestive respiratory and genitourinary tracts, constantly bathed in sectreations.

Fever

a higher temperature setting results when macrophages release pro-inflammatory cytokines in response to bacterial products; cytokines act as messages carried in the bloodstream to the brain, where the temperature-regulating center raises the body temperature in response. rise in temperature prevents microbes with lower optimum temperatures from growing, giving the immune system time to eliminate the bacteria before they cause too much harm. moderate fever has also been shown to enhance several protective processes, including the inflammatory response, phagocytic killing by leukocytes, multiplication of lymphocytes, release of substances that attract neutrophils, and production of interferons and antibodies.

dendritic cells

a leukocyte that acts as a sentinel cells that function as 'scouts' they engulf material and bring it to the cells of the adaptive immune system for inspection. usually develop from monocytes

Ligand

a molecule that can bind to a given receptor; when this binds to a surface receptor, the internal portion of the receptor is modified.

ligand

a molecule that can bind to a specific receptor

Regulation of the complement system

a number of different control mechanisms prevent host cells from activating the complement system and also protect them from the effector functions of the complement proteins.

salt

accumulates from perspiration

Adhesion molecules

allow cells to "grab" other cells; cells also use these to attach to other cells so that one cell can deliver cytokines or other molecules directly to another cell.

PRRs that monitor a cell's surroundings

allow cells to detect invaders in the surrounding environment. Toll-like receptors: the most well-characterized; some are on the cell surface, others are in endosomes and phagosomes; each one recognizes a distinct compound or group of compounds associated with microbes; those anchored in the cytoplasmic membrane generally detect components of the outermost layers of microbial cells, including LPS, lipoproteins, and flagellin. C-type lectin receptors: membrane-anchored; bind to certain carbohydrate molecules often found on the surface of microorganisms.

PRRs in cytoplasm

allow the cells to recognize when a microbe has invaded them.

red blood cells (erythrocytes)

blood cells that carry oxygen

white blood cells (leukocytes)

blood cells that defend against foreign invaders

Complement system activation

can be activated by 3 different pathways that converge when a complex called C3 convertase is formed; C3 convertase then splits C3, leading to additional steps of the activation cascade. Alternative pathway: quickly and easily triggered, providing vital early warning that an invader is present; triggered when C3b binds to foreign cell surfaces; the binding of C3b allows other complement proteins to then attach, eventually forming the C3 convertase. Lectin pathway: involves pattern recognition molecules called mannose-binding lectins; these bind to certain arrangements of multiple mannose molecules, a type of carbohydrate commonly found on the surface of some microbial cells, particularly bacteria and fungi. Classical pathway: activation requires antibodies; when antibodies bind to an antigen (forming an antigen-antibody complex, also called an immune complex), they interact with the same complement system component involved with the lectin pathway to form a C3 convertase.

phagocyte

cell type that specializes in engulfing and digesting microbes and cell debris

pyroptosis

cell undergoes death when PRRs are triggered with and inflammatory response

opsonization

coating of an object with molecules for which phagocytes have receptors, making it easier for phagocytosis to occur.

Protective effects of normal microbiota

competitive exclusion of pathogens. some produce compounds toxic to other bacteria. disruption of the normal microbiota, which occurs when antibiotics are used, can predispose a person to various infections. essential to the development of the immune system.

membrane attack complex (MAC)

complement system components that assemble to form pores in membranes of invading cells

Granulocytes

contain cytoplasmic granules filled with biologically active chemicals.

What is the purpose of inflammation?

contains the site of damage, localizes the response, eliminates the invader, and restores tissue function.

Peristalsis

contractions of intestinal tract; propels food and liquid and also helps remove microbes

inflammatory response

coordinated innate response with the purpose of containing a site of damage, localizing the response, eliminating the invader and restoring tissue function. the signs are; swelling, heat, redness, and pain in the infected area.

Chemokines

cytokines important in chemotaxis of immune cells. certain types of cells have receptors for chemokines, allowing the cells to sense the location where they are needed, such as an area of inflammation.

skin

difficult to penetrate, made of stratified epithelium, continually sloughs off with any attached microbes

vasodilation

dilation of small blood vessels, results in freater blood flow at slower rate

Tumor necrosis factor (TNF)

discovered because of its role in killing tumor cells, but it has multiple roles. it helps initiate the inflammatory response and triggers one process of "cell suicide", a programmed cell death called apoptosis.

Interferons (IFNs)

discovered because of their antiviral effects, but they have several roles in the host defenses. important in a number of regulatory mechanisms, stimulating the responses of some cells and inhibiting others.

peroxidase

enzyme that breaks down hydrogen peroxide to produce reactive oxygen species. Found in saliva and milk, also found in body tissues and in phagocytes

pyrogen

fever inducing substance that includes some cytokines released by macrophages.

hematopoiesis

formation and development of blood cells

hematopoietic stem cell

found in the bone marrow, induced to develop blood cells by colony-stimulating factors

Sensor systems

function as "security cameras" within the body, which allows the immune system to recognize when the first-line defenses have been breached.

Cell death and the inflammatory response

host cells can self-destruct: this capability allows the host to eliminate any cells no longer needed, and it also serves as a mechanism for sacrificing "self" cells that might otherwise spread an infection. Apoptosis: programmed cell death that does not trigger an inflammatory response; dying cells undergo certain changes; some changes appear to serve as a signal to macrophages that the remains of the cell are to be engulfed without the events associated with inflammation. Pyroptosis: programmed self-destruction triggers an inflammatory response; sacrifices infected macrophages so that they cannot play host to an invader, and it also recruits various components of the immune system to the region.

Colony-stimulating factors (CSFs)

important in multiplication and differentiation of leukocytes. when more leukocytes are needed during an immune response, a variety of different colony-stimulating factors direct immature cells into the appropriate maturation pathways.

What is the process of the interferon response?

interferon molecules attach to specific receptors on neighboring cells, causing the cells to express inactive antiviral proteins; these iAVPs can be activated by viral dsRNA; once activated, the antiviral proteins degrade mRNA and stop protein synthesis, leading to apoptosis of that cell. a key feature of this response is that the iAVPs are activated by long dsRNA, which should only be found in virally infected cells; thus, when cells bind interferon, only the infected ones are sacrificed; their uninfected counterparts remain functional but are prepared to undergo apoptosis should they become infected.

platelets (magakaryocytes)

involved in clotting

Inflammatory process

involves a sequence of events that result in dilation of small blood vessels, leakage of fluids from those vessels, and the migration of leukocytes out of the bloodstream and into the tissues. extent of inflammation varies depending on the nature of the injury, but the response is localized, begins immediately upon injury, and increases rapidly.

Phagocytosis

involves a series of steps. Chemotaxis: phagocytic cells are recruited to the site of infection or tissue damage by chemicals that act as chemoattractants. Recognition and attachment: phagocytic cells use various receptors to bind invading microbes either directly or indirectly; direct binding occurs when a phagocyte's receptors bind mannose; indirect binding happens when a particle has first been opsonized. Engulfment: once the phagocyte has attached to a particle, it sends out pseudopods that surround and engulf the material. Phagosome maturation and phagolysosome formation: initially, a phagosome has no antimicrobial capabilities, but it matures to develop these; maturation stages are highly regulated and depend on the type of material ingested; eventually, phagosome fuses with enzyme-filled lysosomes, forming a phagolysosome. Destruction and digestion: a number of factors within the phagolysosome work together to destroy an engulfed invader. Exocytosis: following digestion, the phagolysosome fuses with the phagocyte's cytoplasmic membrane, expelling the undigested debris.

macrophages

leukocyte that is part of the MPS, they are monocytes that have gained specialized properties, they are an important sentinel cell and are present in almost all tissue.

monocytes

leukocyte that is part of the MPS, they circulate in the blood

lymphocytes

leukocyte that is responsible for adaptive immunity, includes B cells, T cells and NK cells

Mononuclear phagocytes

leukocyte that makes up the mononuclear phagocyte system (MPS), includes monocytes and marophages

neutrophil

major type of phagocytic cell in blood, these move quickly to the site of infected tissues to destroy invading microbes

Mononuclear phagocytes

make up the mononuclear phagocyte system.

37 degrees C

normal body temp

PRRs that monitor cell's cytoplasm

not nearly as well-characterized as the membrane-associated PRRs, but it is clear that they allow cells to monitor their own cytoplasmic contents for signs of invasion. RIG-like receptors: cytoplasmic proteins that detect viral RNA, and are found in most cell types; so widespread, so they represent a very important early-warning system for viral infections - any virally infected cell can alert neighboring cells that a virus is present; can distinguish viral RNA from normal cellular RNA. NOD-like receptors: cytoplasmic proteins that detect either microbial components or signs of cell damage; found in a variety of cell types, but are particularly important in macrophages and dendritic cells; microbial products detected by these receptors include peptidoglycan, flagellin, and components of a secretion system that some pathogenic bacteria used to inject various molecules into host cells.

Interferon response

occurs when a cell's cytoplasmic pattern recognition receptors detect viral RNA; this response induces nearby cells to develop an antiviral state.

Characteristics of neutrophils

play a critical role during the early stages of inflammation, being the first cell type recruited to the site of damage from the bloodstream; have more killing power than macrophages; can also release the contents of their granules; also release their DNA to form neutrophil extracellualr traps (NETs): the DNA strands in the NET ensnare microbes, allowing the granule contents that accumulate within the NET to destroy them.

marginiation

process that allows the neutrophils line up along the wall of the dilated blood vessel and squeeze between the endothelial cells and into the tissue.

Interleukins (ILs)

produced by leukocytes and have diverse, often overlapping, functions; as a group, they are important in both innate and adaptive immunity.

apoptosis

programmed cell death

lactoferrin

protein that binds iron, found in saliva, mucus, and milk. it is also found in some phagocytes

pattern recognition receptors (PRRs)

proteins on or in cells that recognize specific compounds unique to microbes or tissue damage, allowing cells to sense the presence of invading microbes or damage.

cytokines

proteins that function as chemical messengers, the voice of the cell, allows cells to communicate, they can diffuse to other cells and bind to cytokine receptors. It can effect growth, differentiation, movement, and cell death.

Surface receptors

proteins that generally span the cytoplasmic membrane, connecting the outside of the cell with the inside, allowing the cell to sense and respond to external signals.

Lymphocytes

responsible for adaptive immunity. B and T cells: participate in the adaptive responses; found in lymphoid organs (e.g., lymph nodes, spleen, appendix, tonsils, thymus, bone marrow); also in blood. Innate lymphoid cells: various subsets have different roles and different locations

Characteristics of macrophages

routinely phagocytize dead cells and debris, but are ready to destroy invaders and call in reinforcements when needed; always present in tissues, where they either slowly wander or remain stationary; can develop into activated macrophages if surrounding cells produce certain cytokines or other chemicals. if activated macrophages fail to destroy microbes, the phagocytes can fuse together to form giant cells.

Complement system

sensor that circulates in blood and tissue fluids; named because it can "complement" (act in combination with) the adaptive immune defenses. the proteins circulate in an inactive form, but they become activated in response to certain stimuli, setting off a chain of events that results in removal and destruction of invading microbes.

complement system

series of proteins in blood and tissue fluids that can be activated to help destroy and remove invading microbes

defensins

short antimicrobial peptides produced by neutrophils and epithelial cells. they form pores in microbial membranes.

Acute inflammation

short-term inflammatory response; marked by prevalence of neutrophils. as the infection is brought under control, resolution of inflammation begins; neutrophils stop entering the area and macrophages clean up the damage by ingesting dead cells and debris.

first line defense

skin and mucous membranes are the bodys ___ ___ ___ against microbial entry

Pattern recognition receptors (PRRs)

some are located on the surface of sentinel cells, allowing the cells to detect surrounding invaders; others are within the sentinel cells' endosomes or phagosomes, allowing the cells to determine what they have engulfed.

What are the damaging effects of inflammation?

some enzymes and toxic products contained within phagocytic cells are inevitably released, damaging tissues. if inflammation is limited, the damage caused by the process is normally minimal. if the process occurs ina delicate system, the consequences can be severe, even life-threatening.

adaptive immunity

specific immunity for certain pathogens, develops over your lifetime. includes- humoral response and the cell mediated response

pathogen-associated molecular patterns (PAMPs)

substances that are found on all microbes that trigger PRRs to a microbial invasion, may also be called MAMPs (microbial associated molecular patterns)

Antimicrobial substances

substances that inhibit or kill microorganisms. Lysozyme: an enzyme that degrades peptidoglycan, is in tears, saliva, and mucus; also found within the body, in phagocytic cells, blood, and the fluid that bathes tissues. Peroxidases: part of systems that form antimicrobial compounds, using hydrogen peroxide in the process. Lactoferrin: iron-binding protein in saliva, mucus, milk, and some types of phagocytes; by binding to iron, these proteins make it unavailable to microorganisms. Antimicrobial peptides (AMPs): short chains of amino acids that have antimicrobial activity and are produced by a wide range of organisms. Defensins: positively charged AMPs that insert into microbial membranes, forming pores that damage cells; also produced by phagocytes, which use them to destroy the microorganisms they have ingested.

What are the 4 cardinal signs of inflammation?

swelling, redness, heat, and pain; sometimes loss of function is present.

First-line defenses

the "walls" that prevent microbes and other foreign material from entering the body's tissues. include the skin and mucous membranes.

process of phagocytosis

1. chemotaxis- phagocytes recruited by chemoattractants 2. recognition and attachment- 3. engulfment- psedopods surround and form phagosome 4. phagosome maturation and phagolysosome formation: endosomes fuse, pH lowers, lysosomes bring enzymes 5. Destruction and digestion: toxic ROS and nitric oxide produced, pH decreases, enzymes degrade, definsins damage membrane of invader; lactoferrin ties up iron 6. Excytosis- vesicle fuses with membrane, expels the remains.

the inflammatory response

1. vasodilation/marginiation/diapedesis- neutrophils are the first phagocytes that arrive at the site of inflammation they begin to engulf and destroy invaders. 2. clotting factors wall off the site of infection 3. dead neutrophils, tissue, and debris accumulates as pus. 4. increased blood flow increases the temperature of the tissue, this can help fight the infection. 5. pain can result due to irritation of the nerves in the tissue

1. Granulocytes 2. Mononuclear Phagocytes 3. Dendritic Cells 4. Lymphocytes

4 types of Leukocytes

peristalsis

the contraction of the intestinal tract that propels food and liquid, it also helps remove microbes.

lysozyme

the enzyme that degrades peptidoglycan. found in tears, saliva, and mucus. it can also be found in some phagocytic cells, blood, and tissue fluid

normal microbiota (flora)

the population of micro-organisms that routinely grow on the body of healthy humans.

phagocytosis

the process by which a phagocyte engulfs and invader

Granulocytes

the type of leukocyte that contains cytoplasmic granules

adhesion molecules

these allow cells to adhere to other cells

chemokines

these are cytokines that are important in chemotaxis of immune cells. they will act as an attractant and result in the accumulation of white blood cells at the site.

interferons (INFs)

these are cytokines that are important in the control of viral infections. they also help to regulate the inflammatory response. they limit viral infection

colony simulating factors (CSFs)

these are cytokines that are important in the multiplication and differentiation of leukocytes. they direct immature cells to the appropriate maturation pathways

Interleukins(ILs)

these are cytokines that are produced by leukocytes and have diverse functions, important in innate and adaptive immunity

Tumor necrosis factors (TNF)

these are cytokines that help initiate the inflammatory response and trigger apoptosis.

RIG-like receptors

these are cytoplasmic proteins that detect viral RNA and produce interferon.

surface receptors

these are proteins that serve as the eyes and ears of cell, they bind to a specific ligand which induces a response. they generally span the plasma membrane allowing the inner workings of the cell to react to the external signals.

danger associated molecular patterns (DAMPs)

these are substances that indicate host cell damage to the PRRs

What are the factors that trigger an inflammatory response?

Microbes: when PRRs of sentinel cells such as macrophages detect microbe-associated molecular patterns, the cells produce inflammatory mediators; one of these, tumor necrosis factor, induces the liver to synthesize acute-phase proteins, a group of proteins that facilitate phagocytosis and complement activation; meanwhile, microbial surfaces trigger complement activation, also leading to an inflammatory response. Tissue damage: the sensors of damage-associated molecular patterns are not well understood, but seem to involve NLRs; as with detection of MAMPs, these cause cells to release inflammatory mediators; if blood vessels are injured, 2 enzymatic cascades are activated: 1 is the coagulation cascade, which results in blood clotting, and the other produces several molecules that increase blood vessel permeability.

Types of mononuclear phagocytes

Monocytes: circulate in the blood; phagocytosis; they differentiate into either macrophages or dendritic cells when they migrate into tissues. Macrophages: phagocytosis; an important type of sentinel cell; found in tissues; sometimes known by different names based on the tissue in which they are found. Dendritic cells: collect antigens from the tissues and then bring them to lymphocytes that gather in the secondary lymphoid organs (e.g., lymph nodes, spleen, appendix, tonsils); an important type of sentinel cell.

importance of flora in the immune response

they out-compete more harmful bacteria for nutrients, they produce toxins compounds that damage other bacteria, and they cover most of the body's binding sites

chronic inflammation

this is a long term inflammatory process that can last for years. Macrophages accumulate and granulomas form.

fever

this is a strong indicator of infections, especially bacterial

innate immunity

this is routine protection, it involves the recognition of microbial patterns, it can tell the difference between 'self' cell and invaders. includes- defenses such as anatomical barriers, sensor systems, phagocytic cells, and the inflammatory response

acute inflammation

this is short term inflammation, as the infection is brought under control nuetrophils stop entering the areas and macrophages clean up the damage by ingesting cells and debris

diapedesis

this is the process that allows the neutrophils to leave the bloodstream due to the increased permeability.

neutrophils

this type of granulocyte engulfs and destroys bacteria and other materials. most common type of circulating leukocyte.

Types of granulocytes

Neutrophils: efficiently engulf and destroy bacteria and other material; their granules, which stain poorly, contain many enzymes and antimicrobial substances that help destroy the engulfed materials; most numerous and important granulocyte of the innate responses. Eosinophils: important in ridding the body of parasitic worms; also involved in allergic reactions, causing some of the symptoms associated with allergies, but reducing others; their granules, which stain red with the acidic dye eosin, contain antimicrobial substances and also histaminase, an enzyme that breaks down histamine; found mainly in tissues below the mucous membranes. Basophils: involved in allergic reactions and inflammation; their granules, which stain dark purplish-blue with basic dye methylene blue, contain histamine and other chemicals that increase capillary permeability during inflammation; found in blood, whereas mast cells are present in most tissues.

1. induces the inflammatory response 2. induces opsonization 3. forms pores in the cell membrane that lead to cell lysis

three things the compliment system does...

Effector functions of the complement system

Opsonization: "preparation for eating"; makes it easier for phagocytes to bind to and engulf material; this is because phagocytes have receptors that attach specifically to molecules referred to as opsonins. Inflammatory response: the complement component C5a is a potent chemoattractant, drawing phagocytes to the area where the complement system has been activated; in addition, C3a and C5a induce changes in the endothelial cells that line the blood vessels, contributing to the vascular permeability associated with inflammation; also cause mast cells to release various pro-inflammatory cytokines. Lysis of foreign cells: complexes of complement system proteins spontaneously assemble in cell membranes, forming doughnut-shaped structures called membrane attack complexes; this creates pores in the membrane, causing the cells to lyse; these have little effect on gram-positive bacteria because the thick peptidoglycan layer of these cells prevents the complement system components from reaching their cytoplasmic membranes; in contrast, they damage both the outer and cytoplasmic membranes of gram-negative bacteria.

eosinophils

type of granulocyte that fights parasitic worms, also involved in allergic reactions

basophils

type of granulocyte whose main function is in allergic reactions and the production of histamine

macrophage

type of phagocytic cell that resides in tissues and has multiple roles, including scavenging debris and producing pro-inflammatory cytokines

Physical barriers

Skin: most difficult for microbes to penetrate; composed of 2 main layers - the dermis and the epidermis; the dermis contains tightly woven fibrous connective tissue, making it extremely tough and durable; the epidermis is composed of many layers of epithelial cells that become progressively flattened toward the exterior. Mucous membranes: line the digestive, respiratory, and genitourinary tract; constantly bathed with mucus or other secretions that help wash microbes from the surface; most have mechanisms that move microbes toward areas where they can be eliminated.

Chronic inflammation

when the body's defenses cannot limit the infection; long-term inflammatory response that can last for years; macrophages and giant cells accumulate, and granulomas form.

Cytokines

when this is produced by one cell, it diffuses to another and binds to the appropriate cytokine receptor of that cell. binding of a cytokine to its receptor induces a change in the cell such as growth, differentiation, movement, or cell death. act at extremely low concentrations, having local, regional, or systemic effects.