Microbio Chapter 14: The Innate Immune Response

phagocytosis

a process where phagocytes engulf or digest microbes and cell debris.

complement system

a sensor that circulates in blood and tissue fluids. This sensor is a set of proteins collectively called the complement system. It acts in combination with the adaptive immune defenses. - the complement system 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.

pattern recognition receptors (PRRs)

a special group of receptors used to detect the unique components of microbes. - found on sentinel cells and other types of cells - many cell types have a different set of PRRs in their cytoplasm. These PRRs allow the cells to recognize when a microbe has invaded them.

interferon (IFN)

a type of protein that warns nearby cells about the virus.

phagocyte

cell type that specializes in engulfing and digesting microbes and cell debris (a process called phagocytosis).

opsonization

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

membrane attack complexes (MACs)

complement system components assembled to form pores in membranes of invading cells

inflammatory response

coordinated innate response with the purpose of containing a site of damage, localizing the response, eliminating the invader, and restoring tissue function

neutrophil

major type of phagocytic cell in blood; neutrophils quickly move to infected tissues, where they destroy invading microbes

Process of Phagocytosis: Step 2 - Recognition and Attachment

phagocytic cell 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. Opsonins are extracellular proteins that tag particles for phagocytosis and include the complement component C3b and certain classes of antibody molecules. - Phagocytes have specific receptors for opsonins, so opsonized material is easier for the phagocytes to attach to and engulf

pattern recognition receptors (PRRs)

proteins on or in cells that recognize specific compounds unique to microbes or tissue damage

antibodies

proteins produced by the adaptive immune response that bind specifically to antigens, thereby targeting them for destruction or removal by other host defenses.

Pattern Recognition Receptors (PRRs)

sensors that allow the body's cells to "see" signs of microbial invasion. - if a cell detects microbial invasion, it produces cytokines to alert other components of the defense system. - the PRRs of innate immunity help the body's cells to recognize the general category of an infectious agent, which plays an important role in shaping the immune response to that agent (e.g., if a macrophage's PRRs detect bacterial products, then that cell produces pro-inflammatory cytokines, leading to an inflammatory response., if a dendritic cell's PRRs detect bacterial products, then that cell relays that information to lymphocytes, allowing those cells to mount an appropriate response., if a virally infected cell's PRRs detect viral nucleic acid, then that cell produces an interferon. The interferon alerts immune cells to the presence of a virus, and also promotes an antiviral response in nearby tissue cells.) many PRRs detect components of certain groups of microbes - microbe-associated molecular patterns (MAMPS) include cell-wall associated compounds (i.e., peptidoglycan, teichoic acid, lipopolysaccharide, and lipo-proteins), flagellin subunits, and microbial nucleic acid - some PRRs recognize damage-associated molecular patterns (DAMPs), which are molecules that indicate host cell damage - Sentinel cells (i.e., phagocytes and cells that line blood vessels and other sterile body sites have pattern recognition receptors (PRRs)) on their cell surface - PRRs allow the cells to detect invaders in the surrounding environment - PRRs that monitor material ingested by the cell - PRRs that monitor a cell's surroundings: TLRs and CLRs - PRRs monitor a cell's cytoplasm

complement system

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

mast cells

similar in appearance and function to basophils but are found in tissues rather than blood. - do not come from the same precursor cells as basophils - important in the inflammatory response and are responsible for many allergic reactions

physical barriers

skin and mucous membranes

membrane anchored versions of a group called C-type lectin receptors (CLRs)

- PRR that monitors the cell's surroundings - type of PRR that binds to certain carbohydrate molecules often found on the surface of microorganisms. - dendritic cells have TLRs and CLRs, so they are able to gather a great deal of information about invaders they encounter. They then pass that information on to lymphocytes, thereby helping to shape that response

macrophages

- a differentiated form of monocytes meaning they have gained specialized properties - an important type of sentinel cell, present in nearly all tissues, and are particularly abundant in the liver, spleen, lymph nodes, lungs, and peritoneal (abdominal) cavity.

dendritic cells

- a type of mononuclear phagocyte - sentinel cells that function as "scouts" - engulf material in the tissues and then bring it to the cells of the adaptive immune system for "inspection" - develop from monocytes, but some develop from other cell types - scouts for the adaptive immune system

Immune cell communication: adhesion molecules

- adhesion molecules on the surface of cells allow those cells to "grab" other cells - ex. when phagocytic cells in the blood are needed in tissues, the endothelial cells that line the blood vessels synthesize adhesion molecules that bind to passing phagocytic cells. This slows the rapidly moving phagocytes, allowing them to then leave the bloodstream. - cells also use adhesion molecules to attach to other cells so that one cell can deliver cytokines or other molecules directly to another cell

antigen

substance that causes an immune response.

cells of the immune system

- can move from one part of the body to another, traveling through the body's circulatory system - always found in normal blood, but their numbers usually increase during infections, recruited from reserves of immature cells in bone marrow. - some of the cell types are found primarily in blood, but others leave the blood circulatory system ad take residence in various tissues - certain cell types play dual functions, having crucial roles in both innate and adaptive immunity

Cell death

- cells can die through necrosis - host cells can also self-destruct. This capability allows the host to eliminate any cells no longer needed, and also serves as a mechanisms for sacrificing "self" cells that might otherwise spread infection. - apoptosis - pyroprosis

Activation of the complement system eventually leads to 3 major protective outcomes: Lysis of foreign cells

- complexes of complement system proteins (C5b, C6, C7, C8, and multiple C9 molecules) spontaneously assembly in cell membranes, forming doughnut-shaped structures called membrane attack complexes (MACs). This creates pores in the membrane causing the cells to lose.

RIG-like receptors (RLRs)

- cytoplasmic proteins that detect viral RNA, - found in most cell types; widespread - they represent a very important early-warning system for viral infections - any virally infected cell can alert neighboring cells that a virus is present - RLRs can distinguish viral RNA from normal cellular RNA because at least 2 characteristics differ: 1) viral RNA is often double-stranded 2) viral RNA often lacks a cap

Characteristics of Macrophages

- everyday protectors of tissues - 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 - these phagocytic cells play an essential role in every major tissue in the body - live for weeks to months, or even longer - maintain their killing power by continually regenerating their lysosomes - as macrophages die, circulating monocytes - which can differentiate into macrophages - leave the blood and migrate increases in response to invasion and tissue damage

fever

- fever results when macrophages relapse pro-inflammatory cytokines. This occurs when macrophages detect microbial products - An important host defense mechanisms and a strong indication of infectious disease, particularly a bacterial one - during an infection, the temperature regulation center in the brain sets the body's thermostat higher than 37 degrees C. an oral temperature above 37.8 degrees C is regarded as a ever - a higher temperature setting results when macrophages release pro-inflammatory cytokines in response to microbial products. The cytokines act as messages carried in the blood stream to the brain, where the temperature regulating center raises the body temperature in response. - the rise in temperature prevents microbes with lower optimum temperatures from growing, giving the immune system time to eliminate the microbes before they cause too much harm

Membrane attack complexes (MACs) effect on gram negative and gram positive bacteria

- have little effect on Gram-positive bacteria because the thick peptidoglycan layer of these cells prevents the complement systems from reaching their cytoplasmic membranes. - MAC damages both the outer and the cytoplasmic membranes of Gram-negative bacteria

Pyroptosis

- if pattern recognition receptors in a macrophage's cytoplasm are triggered, that cell might initiate pyroptosis - this programmed self-destruction triggers an inflammatory response - pyroptosis sacrifices infected macrophages so that they cannot play host to an invader. - recruits various components of the immune system to the region

Process of Phagocytosis: Step 5 - Destruction and Digestion

- multiple factors within the phagolysosome work together to destroy an engulfed invader - O2 consumption increases dramatically = respiratory burst - respiratory burst allows an enzyme to produce reactive oxygen species (ROS), which are toxic - another enzyme makes nitric oxide, which reacts with ROS to produce additional toxic compounds - special pumps move protons into the phagolysosome, further lowering the pH - the various enzymes contributed by the lysosomes degrade peptidoglycan and other components. Antimicrobial peptides damage membranes of the invader, and lactoferrin binds iron

Chronic inflammation

- occurs if the body's defenses cannot limit the infection - long-term inflammatory process that can last for years - macrophages and giant cells accumulate, and granulomas form

Moderate fever

- shown to enable several protective processes, including inflammatory response, phagocytic activity, multiplication of lymphocytes, release of substances that attract neutrophils, and production of interferons and antibodies. - release of leukocytes into the blood from the bone marrow also increases. - these effects are likely due to creased rates of enzymatic reactions

Giant cells

- when macrophages fail to destroy microbes, phagocytes form together to form giant cells

The interferon response

- when the cell's cytoplasmic pattern recognition receptors (PRRs) detect viral RNA, the cell responds by synthesizing and secreting a type of interferon (IFN) that induces nearby cells to develop an antiviral state - INF molecules attach to specific receptors on neighboring cells, causing the cells to express what can be views as inactive "suicide enzymes"

3 general components of the innate immune system

1) first-line defenses (security walls surrounding the property) 2) sensor systems (security cameras scattered throughout the property monitoring the environment for signs of invasion) 3) innate effector actions (security teams sent to remove any invaders that have been detected, thereby eliminating the threat)

3 broad groups of Leukocytes (white blood cells)

1) granulocytes 2) mononuclear phagocytes 3) lymphocytes

the human body was several mechanisms of defense

1) innate immunity 2) adaptive immunity

Activation of the complement system eventually leads to 3 major protective outcomes

1) opsonization 2) inflammatory response 3) lysis of foreign cells

inflammatory mediators

A collective term for various pro-inflammatory cytokines and chemicals such as histamine

Abscess

A large amount of pus in a confined region

Mannose

A type of carbohydrate commonly found on the surface of some microbial cells, particularly bacteria and fungi

host cells/"self" cells

the body's own cells

innate immunity

the routine protection present at birth; it is germ-line encoded meaning that it is passed from one generation to the next, and includes anatomical barriers as well as certain cell types and chemicals. host defenses involving anatomical barriers, sensor systems that recognize patterns associated with microbes or tissue damage, phagocytic cells, the inflammatory response, and fever

Pyrogens

Fever-inducing cytokines and other substances - pyrogens cytokines and endogenous pyrogens = the body makes them - Lipopolysaccharides (microbial products) = exogenous pyrogens (introduced from an external source)

location of PRRs

PRRs are located in 3 distinct locations on or in cells: 1) on the cell surface 2) in endosomes and phagosomes 3) free in the cytoplasm - because of these locations, PRRs provide cells with information about not only which microbes are present, but also whether the microbes are inside or outside a host cell. - the signals of PRRs in different locations can complement each other, provoking a stronger response when an invader is detected

Necrosis

traumatic cell death that results from tissue damage

Process of Phagocytosis: Step 1- Chemotaxis

Phagocytic cells are recruited to the site of infection or tissue damage by chemicals that act as chemoattractants. - these chemicals include products of microorganisms, phospholipids released by injured host cells, chemokines, and the complement system component C5a

Acute inflammation

Short-term inflammatory response - characterized by an abundance of neutrophils - as the infection if brought under control, resolution of inflammation begins. - neutrophils stop entering the area, and macrophages clean up the damage by ingesting dead cells and debris - as the area heals, new capillaries grow, destroyed tissues are replaced, and scar tissue forms

Activation of the complement system eventually leads to 3 major protective outcomes: Opsonization

The C3b concentration increases substantially when the complement system is activated. These molecules bind to bacterial cells or other foreign particles. This produces 2 effects: 1) continued complement activation via the alternative pathway 2) opsonization - material that has been opsonized is easier for phagocytes to bind to and engulf because phagocytes have receptors that attach specifically to molecules referred to as opsonins.

Damaging effects of inflammation

- the process usually limits damage and restores function, but the response itself can cause significant harm undesirable consequences: 1) some enzymes and toxic products contained with phagocytic cells are inevitably released, damaging tissues 2) if the process occurs in a delicate system such as the membranes that surround the brain and spinal cord, the consequences can be severe.

Process of Phagocytosis: Step 3 - Engulfment

One the phagocyte has attached to a particle, it sends out pseudopods that surround and engulf the material - this action brings the material into the cell, enclosed in a phagosome. - If a phagocyte encounters something to large to engulf, it releases its toxic contents as a means of destroying it

Complement system activation

The complement system can be activated by 3 different pathways that converge when a complex called C3 convertase is formed. - C3 convertase splits C3 leading to additional steps of the activateion cascade 3 pathways: 1) alternative pathway 2) lectin pathway 3) classical pathway

Immune cell communication: surface receptors

- "eyes:" and "ears" of a cell. - 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 - each receptor is specific with respect to the compound or compounds it will bind; a molecule that can bind to a given receptor is called a ligand for that receptor - Cells can alter the types and numbers of surface molecules they make, allowing them to respond to signal relevant to their immediate situation

phagocytes

- In response to sensor signals that indicate a bacterial infection or tissue damage, a group of cells called phagocytes are recruited to the site of invasion. - phagocytes specialize in engulfing and digesting microbes and cell debris in a process called phagocytosis - some types of phagocytes play multiple roles including destroying invaders, but also serving as sentinel cells. Certain activated complement system proteins recruit phagocytic cells; others bind to foreign material - this makes it easier for phagocytes to engulf the material

Granulomas

- Macrophages, giant cells, and T cells for concentrated groups called granulomas that wall off and retain organisms or other material that cannot be destroyed - this is an example of the cooperation between defense systems - granulomas are part of the disease process in tuberculosis and several other illnesses, prevent the microbes from escaping to infect other cells. But they also harm the host because they interfere with normal tissue function

toll-like receptors (TLRs)

- PRR that monitors a Cell's surrounding - most well characterize of the PRRs. - some are on the cell surface, and others are in endosomes and phagosomes. - each TLR recognizes a distinct compound or group of compounds associated with microbes - TLRs anchored in the cytoplasmic membrane generally detect components of the outermost layers of microbial cells, including polysaccharide (LPS), lipoproteins, and flagellin.

defensins

- a group of AMPs are known to be very important in protecting epithelial borders. - directly kill invading microorganisms - they are positively charged AMPs that insert into microbial membranes, forming pores that damage cells. - Certain epithelial cells produce and release defensins, preventing invasion of those body surfaces. - Expression of defensins increases when microbial invasion is detected, helping the body to eliminate the infection. - They are also produced by phagocytes, which use to destroy the microorganisms they have ingested. - defensins and other AMPs also promote and direct various immune responses.

inflammasome

- a structure that triggers inflammation by activating a potent pro-inflammatory cytokine - formed by the combination of macrophages, dendritic cells, and other proteins when NLRs in macrophages and dendritic cells detect invasion.

antimicrobial substances: lysozyme

- an enzyme that degrades peptidoglycan - in tears, saliva, and mucus - also found within the body in phagocytic cells, blood, and the fluid that bathes tissues

antimicrobial substances: lactoferrin

- an iron building protein in saliva, mucus, milk, and sometimes phagocytes - a similar compound, transferrin, is found in blood and tissue fluids. - by binding to iron, these proteins make it unavailable to microorganisms. (iron is one of the major elements required by organisms) - however, some microorganisms can capture iron from the host thus counteracting this defense

Immune cell communication: cytokines

- can be viewed as the "voices" of a cell - produced by one cell 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 (e.g., growth, differentiation, movement, cell death) - act at extremely low concentrations, having local, regional, or systemic effects - groups of cytokines often act together or in sequence to generate a response (e.g., pro-inflammatory cytokines - TNF< Il-q, IL-6, etc. - contribute to inflammation) Types of Cytokines: A) Chemokines - 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 inflammation B) Colony-stimulating factors (CSFs) - important in the 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 C) Interferons (IFNs) - plays several roles in the host defenses. important in a number of regulatory mechanisms, stimulating the responses of some cells and inhibiting others. D) Interleukins (ILs) - produced by leukocytes and have diverse, often overlapping functions. as a group they are important in both innate and adaptive immunity. E) Tumor necrosis factor (TNF) - role in killing tumor cells, but has multiple roles. helps initiate the inflammatory response and triggers one process of "cell suicide," apoptosis

features that distinguish microbial nucleic acid from normal host nucleic acid

- certain nucleotide sequences are much more common in bacterial DNA that in normal host cell DNA, which can be recognized by a TLR - the genome of RNA viruses is often double-stranded during the viral replication cycle - DNA viruses may generate long dsRNA because both strands of NFA are sometimes used as templates for transcription, leading to production of complementary RNA molecules - long pieces of cellular RNA are typically not double-stranded because only one DNA strand in a gene is used in a template for RNA synthesis - certain TLRs in endosomes or phagosomes re not fully functional until the vesicle fuses with lysosomes, exposing the contents of the vesicle to low pH and digestive enzymes. Because of this requirement, the LTRs are less likely to contact host cell nucleic acid, thereby avoiding an inappropriate response

3 broad groups of Leukocytes (white blood cells): granulocytes

- contain cytoplasmic granules filled with various compounds important for the cells' protective functions 3 types of granulocytes: a) 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. The most numerous and important granulocytes of the innate responses. They are called polymorphonuclear neutrophilic leukocytes, polys, or PMSs. They normally account for over half of the circulating white blood cells, and their numbers increase during most bacterial infections. few neutrophils are generally found in tissues, except during inflammation. b) basophils - involved in allergic reactions and inflammation. their granules, which stain dark purplish-blue with the basic dye methylene blue, contain histamine and other chemicals that increase capillary permeability during inflammation c) eosinophils - important in ridding the body of parasitic worms. They are also involved in allergic reactions, causing some of the symptoms associated with allergies, but reducing others. The granules of eosinophils, stain red with the acidic dye eosin, and contains antimicrobial substances and histamines (an enzyme that breaks down histamine).

NOD-like receptors (NLRs)

- 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 - the microbial products detected by the most well-characterized NLRs include peptidoglycan, flagellin, and components of a secretion system that some pathogenic bacteria use to inject various molecules into host cells. - when certain NLRs in macrophages and dendritic cells detect invasion, they combine with other proteins in the cytoplasm to form a inflammasome

Immune cell communication

- immune cells must communicate to mount a coordinated response to microbial invasion - communication is done though surface receptors, cytokines, and adhesion molecules

the outcome of certain disease is influenced by PRR generated signals from sentinel cells and infected cells

- in some cases the signals induce a protective response, but in other cases the response can be excessive and therefore damaging - people who have mutations in the genes encoding some PRRs are more likely to develop certain inflammatory diseases or autoimmune diseases.

inactive antiviral proteins (iAVPs)

- inactive "suicide enzymes" are referred to as inactive antiviral proteins (iAVPs) - iAVPs can be activated by viral dsRNA - once iAVPs is activated, the antiviral proteins (AVPs) degrade mRNA and stop protein synthesis, leading to apoptosis of that cell - a key feature of the activation response is that the iAVPs are activated by long dsRNA, which is typically found only in virally infected cells. Therefore, when cells bind interferon, only the infected cells will be sacrificed. Their uninflected counterparts remain functional but are prepared to undergo apoptosis if they become infected

Process of Phagocytosis: Step 4 - Phagosome Maturation Phagolysosome Formation

- initially the phagosome has no antimicrobial capabilities, but it matures to develop them (ex of antimicrobial capability: the pH becomes progressively more acidic) - The maturation state is highly regulated and depends on the type of material ingested (ex. If a phagocyte's toll-like receptors (TLRs) indicate that a phagosome contains microbial components then that phagosome will have a different fate than if the contents were only host cell material) - Eventually, the phagosome fuses with enzyme-filled lysosomes, forming a phagolysosome

Macrophages are important sentinel cells

- macrophages are well-equipped with pattern recognition receptors (PRRs), allowing them to "see" microbes in the surrounding environment, in material they have ingested, and in their cytoplasm - if a macrophage detects a microbe that has invaded the body, it produces cytokines that alert and stimulate various other cells of the immune system. - if a macrophage's cytoplasmic PRRs detect microbial components, indicating that the phagocytic cell itself is infected, an inflammatory forms, an even that triggers a strong inflammatory response

3 broad groups of Leukocytes (white blood cells): mononuclear phagocytes

- make up the mononuclear phagocyte system (MPS) - this grouping includes monocytes and the cell types that develop from them as they leave the blood stream and migrate into tissues Types of Mononuclear Phagocytes: - monocytes 2) macropahges

Factors that trigger an inflammatory response

- many things can trigger an inflammatory response, but they all often involve the pattern recognition receptors (PRRs) - the triggers of inflammation cause host cells to release inflammatory mediators

adaptive immunity

- more specialized defense system compared to innate immunity. - develops through life as a result of exposure to microbes or certain other types of foreign material, and substantially increases the host's ability to defend itself. The substance that causes an immune response is called an antigen. - each time the body is exposed to an antigen, the adaptive defense system first "learns: and then "remembers" the most effective response to that specific antigen; it then reacts accordingly if the antigen is encountered again. - an important action of the adaptive immune response if the production of proteins called antibodies. - The adaptive immune response can also destroy the body's own cells - referred to as host cells or "self" cells that are infected with a virus or other invader.

PRRs that monitor a cell's cytoplasm

- most host cells have at least one category of pattern recognition in their cytoplasm - PRRs that monitor a cell's cytoplasm are not as well characterized as the membrane-associated PRRs, but they allow cells to monitor their own cytoplasmic contents for signs of invasion - ex. RIG-like receptors (RLRs) and NOD-like receptors (NLRs)

physical barriers: mucous membranes

- mucous membranes line the digestive tract, respiratory tract, and genitourinary tract. They are constantly bathed with mucus or other secretions that help wash microbes from the surface - most mucous membranes have mechanisms that move microbes toward areas where they can be eliminated (e.g., peristalsis - the contractions of the intestinal tract - propels food and liquid toward the anus and also helps removes microbes)

Characteristics of neutrophils

- neutrophils are quick to move into an area of trouble and readily eliminate the invaders - these phagocytic cells play a crucial role during the early stages of inflammation, being the first cell type recruited to the site of damage from the bloodstream - more killing power than macrophages - relatively short life span of only a few days in the tissues; once they have used their granules, they die. - there are many neutrophils in the body's reserve - kill microbes through phagocytosis and also release contents of their granules to kill microbes. - also release their DNA to form neutrophil extracellular traps (NETs). The DNA strands in the NET ensnare microbes, allowing the granule contents that accumulate with the NET to destroy them

Inflammation

- occurs when microbes are introduced into normally sterile body sites or when tissues are damaged - the purpose of inflammation is to contain a site of damage, localize the response, eliminate the invader, and restore tissue function 4 cardinal signs of inflammation: 1) swelling 2) redness 3) heat 4) pain 5) sometimes loss of function

Phagocytosis

- phagocytes routinely engulf and digest material, including invading microbes - in routine situations (i.e., when microbes enter through a minor skin wound), resident macrophages in the tissue destroy the relatively few invaders that enter. - if microbes are not rapidly cleared, macrophages produce cytokines to recruit additional phagocytes - particularly neutrophils - for extra help

PRRs that monitor material ingested by a cell

- phagocytic cells have pattern recognition receptors that allow them to inspect material ingested by the cell - specific toll-like receptors (TLRs) are in phagosomal and endosomal membranes, facing the lumen of the organelle (the inside of the organelle, which is exposed to the organelle's contents). These TLRs typically recognize characteristics of nucleic acids that indicate a microbial origin.

Complement system activation: Classical Pathway

- requires antibodies - when antibodies bind to an antigen (forming an antigen-antibody complex/immune complex) they interact with the same complement system component involved with the lectin pathway to form a C3 convertase

Complement system

- series of proteins that circulate in the blood and the fluid that bathes the tissues - the proteins routinely circulate in an inactive form, but certain signals that indicate the presence of microbial invaders start a reaction cascade that rapidly activates the system - the activated complement proteins have specialized functions that help remove and destroy the invader - each of the major complement system proteins has been given a number along with the letter C. - when a complement protein is split into 2 fragments, this fragments are distinguished by adding a lowercase letter to each name (e.g., C3 is split into C3a and C3b)

antimicrobial substances: antimicrobial peptides (AMPs)

- short chains of amino acids (usually 15-20 amino acids long) that have antimicrobial activity and are produced by a wide range of organisms - defensins, a group of AMPs are known to be very important in protecting epithelial borders. - vitamin D plays a role in the regulation of expression of some AMPs

3 broad groups of Leukocytes (white blood cells): lymphocytes

- specific groups of lymphocytes are responsible for adaptive immunity 2 major groups of lymphocytes: - remarkably specific in their recognition of antigen 1) B cells 2) T cells - another group of lymphocytes called innate lymphoid cells (ILCs) differ from B and T cells in that they lack specificity in their mechanism of antigen recognition. ILCs are common near mucous membranes, and appear to have multiple roles that can promote a balanced inflammatory response. - one type of ILC, called a natural killer (NK) cell, kills certain types of cells

ligand

- surface each receptor is specific with respect to the compound or compounds it will bind; a molecule that can bind to a given receptor is called a ligand for that receptor - when a ligand binds to its surface receptor, the internal part of the receptor is modified. This change triggers some type of response by the cell (e.g., chemotaxis).

Process of Phagocytosis: Step 6 - Exocytosis

- the phagolysosome releases undigested debris to the outside of the cell by fusing with the phagocyte's cytoplasmic membrane - a special process in macrophages puts some of the ingested material on the cell's surface as a way of displaying bits of invaders to certain cells of the adaptive immune system

Normal Microbiota (flora)

- the population of microorganisms that routinely grow on the body surfaces of healthy humans - not technically part of the immune system but still provide considerable protection Protective effects of the flora: - competitive exclusion of pathogens. prevents pathogens from adhering to host cells by covering binding sites that might otherwise be used for attachment. - consumes available nutrients that could otherwise support the growth of less desirable organisms - some members of the flora produce compounds toxic to other bacteria (e.g., in the hair follicles of the skin, Cutibacterium species degrade lipids, releasing fatty acids that inhibit the growth of many pathogens) - essential to the development of the immune system. As certain microbes are encountered, the system learns to distinguish harmless ones from pathogens. An inability to tolerate harmless microbes can result in chronic inflammatory conditions such as Crohn's disease - disruption of the flora, which occurs when antibiotics are used, can predispose a person to various infections (e.g., antibiotic-associated diarrhea and pseudomembranous colitis, caused by growth of toxin-producing strains of Clostridium difficile in the intestine, and vulvovaginitis, caused by excessive growth of Candida albicans in the vagina)

antimicrobial substances

- the skin and mucous membranes are protected by a variety of substances that inhibit or kill microorganisms (e.g., the salty residue that accumulates on the skin as perspiration evaporates inhibits all but salt-tolerant microbes) - antimicrobial substances: lysozyme, peroxidases, lactoferrin, antimicrobial peptides (AMPs)

physical barriers: skin

- the skin is the most difficult for microbes to penetrate. - composed of two main layers: 1) dermis - contains tightly woven fibrous connective tissue, making it extremely tough and durable 2) epidermis - composed of many layers of epithelial cells that become progressively flattened toward the surface. The outermost sheets are made up of dead cells filled with a water-repelling protein called keratin; the result is that the skin is a dry environment. The cells continually flake off, taking with them any microbes that might be adhering.

Regulation of the Complement System

- there are a number of different control mechanisms that prevent host cells from activating the complement system and protect them from the effector functions of the complement proteins. Examples of control mechanisms: 1) molecules in host cell membranes bind regulatory proteins that quickly inactivate C3b. This prevents host cell surfaces from triggering the alternative pathway of complement regulation. It also prevents host cells from being opsonized. 2) most microbial cell surfaces do not bind the regulatory proteins but some pathogens have mechanisms to hack the host's protective mechanisms

Complement system activation: alternative pathway

- this pathway is quickly and easily triggered, providing early warning that an invader is present - the pathway is triggered when C3b binds to foreign cell surface - the binding of C3b allows other complement proteins to attach, eventually forming C3 convertase. - C3b is both a product of complement activation and triggers the alternative pathway. This occurs because C3 is somewhat unstable, and spontaneously splits to C3a and C3b at a low rate even when the 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 the alternative pathway when needed.

Process of Phagocytosis

1) Chemotaxis 2) Recognition and Attachment 3) Engulfment 4) Phagosomes Maturation and Phagolysosome 5) Destruction and Digestion 6) Exocytosis

Inducers of the inflammatory proces

A) microbes - when PRRs of sentinel cells such as macrophages detect MAMPs, the cells produce inflammatory medications. - ex. tumor necrosis factor (TNF), induces to synthesize a tube-phase proteins, a group of proteins that facilitate phagocytosis and complement activation. Meanwhile, microbial surfaces trigger complement activation, also leading to an inflammatory response B) tissue damage - the sensors of DAMPs involve NOD-like receptors (NLRs). When cells detect DAMPs, they respond by releasing inflammatory mediators. If blood vessels are injured, 2 enzymatic cascades are activated. One is the coagulation cascade, which results in blood clotting, and the other produces several molecules that increases blood vessel permeability

Complement system activation: lectin pathway

Activation of the complement system via the lectin pathway involves pattern recognition molecules called mannose-binding lectins (MBLs) - MBLs bind to certain arrangements of multiple mannose molecules. - Once an MBL attaches to a surface it can interact with other complement system components to form a C3 convertase

The inflammatory process

Events: 1) dilation of small blood vessels - the diameter of local blood vessels increases due to the action of inflammatory mediators. This results in greater blood flow to the area, causing heat and redness. It also slows the blood flow in the capillaries 2) leakage of fluids from small blood vessels - because of the dilation, normally tight junctions between endothelial cells are disrupted, allowing more fluid to leak from the vessels and into the tissue. This fluid contains various substances, such as transferrin, complement system proteins, and antibodies, that help out react invading microbes. - The increase in fluids in the tissues causes the swelling and pain associated with inflammation. pain also results from the direct effect of certain chemicals on sensory nerve endings - some of the pro-inflammatory cytokines cause endothelial cells of the local blood vessels to produce adhesion molecules that loosely "grab" phagocytes. The phagocytes normally flow rapidly through the vessels but slowly tumble to a halt as the adhesion molecules attach to them. The phagocytic cells themselves begin producing a different type of adhesion molecule that strengthens the attachment 3) migration of leukocytes out of the bloodstream and into the tissues - in response to various chemoattractants, the phagocytes leave the blood vessels and move into the surrounding tissues. They do this by squeezing between the cells of the dilated vessel. This is called diabetes is. - neutrophils are the first to arrive at the site of infection and they actively phagocytize foreign material - monocytes and lymphocytes arrive later. - clotting factors in the fluid that leaks into the tissues intimate clotting reactions in the surrounding area, walling off the site of infection. This helps stop the spread of invading microbes. - as the inflammatory process continues, large quantities of dead neutrophils accumulate. These dead cells, and tissue debris make up pus.

activated macrophages

Macrophages can develop into activated macrophages if surrounding cells produce certain cytokines or other chemicals. Ex. Certain pro-inflammatory cytokines activate macrophages, giving them greater killing power and encouraging a continued inflammatory response - sometimes referred to as M1 macrophages (killer macrophages") Ex. other chemicals cause macrophages to produce cytokines that lessen the inflammatory response and promote wound healing and tissue repair - sometimes referred to as M2 macrophages ("healing macrophages") - the differentiation of M! Vs. M2 macrophages is not fixed; a macrophage can change its role in response to environmental cues, so presenting the types as two polarized alternatives is not entirely accurate - the relative activities of macrophages seems to drive certain disease states (e.g., in type 2 diabetes, an over abundance of inflammation-promoting (M1) macrophages in the adipose tissue decreases the sensitivity of various tissues to insulin. In contrast, anti-inflammatory macrophages (M2) promote an environment where tissue cells respond to insulin

Activation of the complement system eventually leads to 3 major protective outcomes: Inflammatory Response

The complement component C5a is a potent chemoattractant, drawing phagocytes to the area where the complement system has been activated. -C3a and C5a induce changes in the endothelial cells that line the blood vessels, contributing to the vascular permeability associated with inflammation. They also cause mast cells to release various pro-inflammatory ctyokines

inflammatory response

a coordinated response that can result when various sensor systems detect infection or tissue damage. - As a result of this response, cells that line local blood vessels undergo changes that allow fluids to leak out into tissues; the fluids contain complement system components and other proteins. - Phagocytic cells also move from the bloodstream to the tissues

3 general components of the innate immune system: sensor systems

allow the immune system to recognize when the first-line of defenses have been breached. - any microbe that passes through the first-line of defenses and into tissue is perceived by the immune system as an invader. - certain host cells serve as sentinel cells positioned at strategic sites in the body to detect invading microbes in blood or tissue fluids.

fever

another innate response. causes a higher-than-normal body temperature. - fever interferes with the growth of some pathogens and can enhance the effectiveness of other pathogens.

Hematopoiesis

formation and development of blood cells - all blood cells, originate from the same cell type, the hematopoietic stem cell, found in the bone marrow. - hematopoietic cells are capable of long-term self-renewal, meaning they divide repeatedly. - hematopoietic stem cells are induced to develop into various types of blood cells by a group of proteins called colony-stimulating factors (CSFs) General categories of Blood Cells and their derivatives: - red blood cells/erythrocytes - carry O2 in the blood - platelets - fragments arising from large cells called megakaryocytes. they are imporant for blood clotting - white blood cells/leukocytes - important in all host defenses. Leukocytes can be divided into 3 broad groups: granulocytes, mononuclear phagocytes, and lymphocytes

sentinel cell (lookouts of guards)

host cells that are positioned at strategic sites in the body to detect invading microbes in blood or tissue fluids. - they recognize microbes by detecting their unique components such as peptidoglycan, using a special group of receptors called pattern recognition receptors (PRRs). - some PRRs are located on the surface of sentinel cells, allowing the cells to detect surrounding invaders - other PRRs are within the sentinel cells' endosomes or phagosomes, allowing the cells to determine what they have engulfed

antimicrobial substances: peroxidases

part of systems that form antimicrobial compounds, using hydrogen peroxide (H2O2O in the process. - microorganisms that produce the enzyme catalase are less susceptible to the lethal effects of peroxidase systems because they can potentially convert hydrogen peroxide to water and O2 before peroxidases have a chance to use it - peroxidase systems are found in saliva, milk, body tissues, and phagocytes

3 general components of the innate immune system: first-line defenses

prevents microbes and other foreign material from entering the body's tissues. - these defenses include: physical barriers provided by the skin and the mucous membranes, along with the antimicrobial substances that bathe them - members of the normal microbiota residing on the surfaces also provide protection - first-line of defense has direct contact with external environment (e.g., digestive tract begins at the mouth and ends at the anus. it is simply a hollow tube that runs through the body, allowing intestinal cells to absorb nutrients from food that passes through.

apoptosis

programmed cell death of "self" cells that does not cause inflammation - the dying cells undergo certain changes (e.g., shape of the cell changes, enzymes cut the DNA, pieces of the cell bud off, efficiently shrinking the cell). some changes appear to serve as signal to macrophages that the remains of the cell are to be engulfed without the events associated with inflammation

cytokines

proteins that function as chemical messengers, allowing cells involved in host defenses to communicate

macrophage

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

3 general components of the innate immune system: innate effector actions eliminate invaders

when one or more of the sensor systems detects an invading microbes, various effector mechanisms may be called into action. because the sensors typically recognize patterns associated with certain groups of microbes, the effector actions can be tailored to defend against those groups. - ex. when a host cell recognizes that it is infected by a virus, that cell produces an interferon (IFN). Neighboring cells react by preparing to shut down their biosynthetic activities if they too become infected. by doing so, the cells can deprive the virus of a mechanism to replicate.