Inflamation is defined as?
the reaction of vascularized living tissues to local injury. The vascular and cellular events that highlight actue inflammation serve to deliver mediators of host defenses to sites of microbial invasion and/or tissue injury.
Inflammation is always an evoked response set in motion by________
It occurs only in ____.
some kind of a stimulus, eg tissue injury. It occurs only in living tissue.
Cardinal signs of Acute Inflammation?
1.) Rubor- redness (heat not fever) 2.) tumor- swelling edema 3.) Calor- heat 4.) Dolor- pain 5.) Functio laesa- loss of function
The local inflammatory response is always accompanied by_____________.
systemic changes collectively called the acute phase response or the systemic inflammatory response syndrome.
Systemic responses to infection are due to the ?
actions of proinflammatory cytokines such as tumor necrosis factor, interleukin-1 and interleukin-6 secreted by activated macrophages, mast cells, etc.
What are some other cytokines that also participate in the acute phase response?
colony stimulating factors that stimulate the bone marrow to produce more white blood cells.
What does the acute phase include?
1.) Fever- heat doesn't allow replication 2.) Leukocytosis (hematopoiesis) more WBC 3.) Increased synthesis of acute phase proteins 4.) decrease in the plasma concentration of iron. High concentration of free iron enhances bacterial replication. (battle between us and microbes takes iron away) 5.)Decrease in appetite. May deprive pathogens of nutrients, especially minerals, needed for their proliferation 6.) increased secretion of many hormones, notably ACTH and cortisol
What are acute phase proteins ?
plasma proteins whose concentration change by at least 25% during inflammation.
Some proteins decrease in plasma concentration and are called?
negative acute phase proteins Ex: albumin
Where are acute phase proteins synthesized? What roles do they have?
mostly by the liver. The proteins play various roles in the innate immune response to infectious agents.
What are some acute phase proteins?
1.) complement proteins 2.) C-reactive protein- binds to bacteria and promotes their uptake by phagocytic cells, a process referred to as opsonization. 3.) Mannose- binding protein (more opsonization, also activation of classical pathway) 4.) iron binding proteins (haptoglobin, transferrin, lactoferin) 5.) lipopolysaccharide- binding protein (increased response to G- bacteria)
What does the microvasculature consists of? What follows after tissue injury?
the afferent arterioles, the capillary networks and the efferent venues. initiation of inflammatory response at the capillary and post capillary venules.
in acute inflammation what is the initial response of arterioles? What happens within a few minutes?
transient vasoconstriction, mediated by neurogenic and chemical stimuli. Vasodilation occurs a few minutes later, increasing blood flow to inflamed area.
What are post capillary venules?
the venules are the primary anatomic site for inflammation-related leakage. The junctions between the endothelial cells are more permeable than those in the capillaries, additionally the endothelial cells are more sensitive to vasoactive mediators.
What are chemical mediators of inflammation?
they are chemical messengers that enhance blood flow, increase vascular permeability, or induce the emigration of leukocytes from the blood stream to the site of tissue injury.
What are examples chemotactic factors? and what do they lead to?
*C5a *Leukotriene B4 *Formylated peptides *Chemokines IL-8 CXCL8 *PAF -lead to recruitment and stimulation of inflammatory cells
The inflammatory response may have 3 outcomes?
1.) elimination of the causative agent 2.) walling off of the inflammation from the rest of the body with subsequent healing of the lesion 3.) persistence of the causative agent, leading to chronic inflammation or spread throughout the body.
Cellular sources of chemical mediators of inflammation?
Platelets, connective tissue mast cells, basophils, neutrophils, endothelial cells, fibroblasts, monocyte/tissue macrophages, injured tissue.
Many mediators carry out their biologic activity by?
binding to specific receptors on target cells. Most functions can be elicited by multiple mediators and most mediators serve multiple functions.
Many mediators exert their effects______ and do not circulate systemically in high concentration except in unusual circumstances.
What system of checks and balances limit the extent of the inflammatory response and hence tissue injury?
Many mediators have short tissue half lives. They quickly decay or are inactivated by enzymes or inhibited.
LPS released from the cell wall of Gram-negative bacteria is recognized and bound by....?
lipopolysaccharide binding protein present in plasma. LBP enhances the efficiency of transfer and presentation of LPS to the CD14 receptor on macrophage cell membrane, resulting in macrophage activation.
The activated macrophage synthesizes and secretes vasoactive mediators of inflammation including???
IL-1 IL-6 CXCL-8 TNF alpha, PAF
Nitric oxide is an important mediator of inflammation. what does it cause?
it causes vasodilation by relaxing vascular smooth muscle, reduces platelet aggregation and adhesion, and is a potent microbicidal agent. It is produced by activated endothelial cells and activated macrophages.
What are the steps of leukocyte recruitment to the site of inflammatory response?
begins with local dilation of postcapillary venules, followed by 1.) leukocyte rolling 2.) activation 3.) margination/pavementing and 4.) transendothelial migration (chemotactic factors influence any subsequent movement through the extracellular matrix to the site of inflammation or injury)
What are the four major families of adhesion molecules?
1.) selectins- Lselectin P-selectin and E selectin 2.)Addressins GlyCAM1 CD34 PSGL-1 ESL-1 MAdCAM 3.)Integrins- VLA-4 CD11aCD18, CD11bCD18 etc 4.) Immunoglobulin superfamily ICAM-1 ICAM-2 ICAM-3 VCAM-1 PECAM**, CD2, CD58, etc
Selectins are a family of adhesion molecules expressed on?
platelets, leukocytes and endothelial cells that promote the initial localization and rolling of leukocytes along endothelium at sites of tissue injury.
What is P-selectin? When is it expressed on a cell?
is pre-formed and is stored within Weibel-Palade bodies of ECs and the alpha granules of platelets. When EC is activated by histamine etc., the granule fuses with the cell membrane and P-selectin is expressed on the cell surface.
Where do P-selectins bind?
to an addressin on neutrophil, monocyte and T- lymphocyte cell suraces called P-selectin glycoprotein Ligand-1 (PSGL-1)
In acute inflammation, what happens in the capillaries?
endothelial cells react to vasoactive mediators leading to EC retraction, gap formation and increased permeability
What are examples of vasoactive mediators? and what do they do?
histamine serotonin bradykinin nitric oxide leukotriene C4 D4 E4 Prostaglandins Platelet-Activating Factor Anaphylatoxins lipopolysaccharide cytokines -They lead to vasodilatation, increased vascular permeability and endothelial expression of adhesion molecules
How is selective adhesion of leukocytes to vascular endothelium achieved?
through a myriad of complementary cell adhesion molecules in endothelial cells and leukocytes. There are 4 major families of adhesion molecules.
What are selectin molecules composed of?
a single chain transmembrane glycoprotein with an extracellular lectin roman
E (endothelial)- Selectin is synthesized and expressed where and when? What are examples of E-selectin?
synthesized on and expressed by endothelial cells within 1-2 hours AFTER pro inflammatory cytokine activation (by IL-1 and TNF-alpha) ex: CD62E, ELAM-1
Where does E-selectin bind?
to E-selectin ligand-1 (ESL-1) on the surfaces of granulocytes, monocytes and T lymphocytes
L (Leukocyte)-selectin is expressed where? what is an example of L-selectin?
expressed on lymphocytes, granulocytes, monocytes and macrophages. EX: CD62L
Where does L-selectin bind?
binds to several receptors on ECs including CD34, glycan-bearing cell adhesion molecule-1 (GlyCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1)
Vascular addressins are ____-like molecules that posses carbohydrate regions that bind the ____ domain of selectins
mucin-like lectin domain
Where are vascular addressins expressed?
on the surfaces of leukocytes and endothelial cells
Is selectin-addressin binding strong? How does this affect the inflammatory response?
No, it's like a post-it note in staying power. if inflammatory stimulus is weak, and integrin-mediated attachment of the cell does not occur, the cells breaks away after a few seconds or minutes and returns to circulation
Integrins are transmembrane adhesive proteins expressed on___. They are composed of ___ and ___ sub units arranged as ____dimers.
leukocytes alpha beta heterodimers
Each of the several subfamilies of integrins expresses a ____ Beta chain that is associated with ____
conserved beta chain (e.g. Beta1/CD29, B2/CD18, B3/CD61) different alpha chains
What are the major functions of integrins? Some integrins also bind to proteins that participate in the ___ response?
to mediate adhesion of leukocytes to endothelial cells, extracellular matrix proteins (cell migration), and adhesion of T cells to antigen-presenting cells. inflammatory response (e.g. complement proteins)
True or false: integrins are always present on the surface of leukocytes?
Although integrins are always present on the surface of leukocytes, how are they regulated?
quickly up-regulated in NUMBERS and ADHESIVENESS following activation of leukocytes by chemoattractants (CXCL8, etc) secreted by activated ECs and/or tissue cells [some tissue-derived mediators may diffuse from tissue into the blood vessels, bind to EC surfaces and directly contact the leukocyte]
How is adhesiveness of an integrin changed?
via a conformation change in the integrin; up-regulated sticky integrins on activated leukocytes bind to counterrecptors (ICAM-1 or ICAM-2) on ECs yielding STABLE ADHESION of the leukocytes to the endothelium (also called pavementing)
Are integrin proteins significant to leukocyte extravasation?
What is leukocyte adhesion deficiency disease characterized by?
recurrent bacterial infections
For integrin VLA-4: name the subunits, give the other name, what WBCs it affects, its counter receptor and functions
CD49dCD29 Beta1, alpha4 WBCs: Lymphocytes, Monocytes/macrophages, Eosinophils counter: VCAM-1, fibronectin fcns: leukocyte-EC adhesion, leukocyte-matrix adhesion
For integrin CD11aCD18: name the subunits, give the other name, what WBCs it affects, its counter receptor and functions
LFA-1 Beta2, alphaL ALL WBCs ICAM-1, -2, -3 leukocyte-EC adhesion, T cell-APC adhesion
Members of the immunoglobulin superfamily of proteins share partial _________ that were originally identified in immunoglobulin ___ and ___ chains.
partial amino acid sequence homology and tertiary structural features (15%+) heavy light
Where are some immunoglobulin proteins expressed? What do they help do?
some are expressed on cell surfaces of cytokine-stimulated endothelial cells and leukocytes help localize leukocytes to areas of tissue damage
ICAM-1 (CD54) is an immunoglobulin protein expressed where?
by pro inflammatory cytokine activated ECs, and other cells including B lymphocytes and monocyte/macrophages
ICAM-2 (CD102) is an immunoglobulin protein expressed where at and what levels?
expressed at low levels on some ECs and also expressed on monocyte/macrophages and some T cells
VCAM-1 (CD106) is an immunoglobulin protein expressed where?
by activated ECs, macrophages and other cells
PECAM-1 (CD31) is short for what? Where is it present? How does it work?
platelet-endothelial cell adhesion molecule present on neutrophils, platelets, monocytes, B cells found within the junctional complex of activated ECs. It binds to the PECAM-1 molecule on another cell (i.e. it displays homotypic binding)
What is diapedesis?
After margination, how is diapedesis enhanced?
by the binding of PECAM-1 on neutrophils to PECAM-1 on ECs close to the inter-endothelial cell jcn this signals the neutrophils to exit and they squeeze through gaps and crawl into the perivascular tissue
During diapedesis, how do leukocytes migrate once in the tissue? is the movement random or with preference?
by interacting their integrin proteins with the proteins of the extracellular matrix (collagen, laminin, fibronectin, etc) with preference towards gradients of chemotaxins formed within the tissue
True or false: leukocyte aggregation at the site of inflammation follows a fairly predictable pattern?
In a bacterial infection, when do neutrophils predominate?
the first 6 to 24 hours of the inflammatory response
Neutrophils are the most numerous WBCs in circulation except in which two species?
pigs and cattle
Of the WBCs, which responds the quickest to chemotactic agents?
neutrophils. This is why the predominate during the first 6-24 hours of the inflammatory response
After an inflammatory reaction, when do monocytes and lymphocytes generally predominate? Is there an exception to this?
24-48 hours except in IMMEDIATE HYPERSENSITIVITY reactions and PARASITIC infections when eosinophils predominate
When do T cells predominate after an inflammatory response?
36-48 hours (based on the chart on page 45)
What is chemotaxis?
the energy dependent, unidirectional migration of cells toward increasing concentrations of a soluble chemotactic agent
What is a random, excited movement of cells?
is chemotaxis a receptor mediated event?
Chemotactic agents are ___ molecular-weight soluble compounds that are generated in ___ concentrations at sites of tissue injury with a __________.
low-molecular-weight high concentrations decreasing gradient away from the injured tissue
What is haptotaxis?
a fixed chemotactic gradient sometimes created by chemotactic agents that bind to the extracellular matrix protein
Over what distance is chemotaxis effective? What makes this so great?
up to 100 micrometers away from inflamed tissue almost no tissue is more than 50 micrometers away from a capillary, so the chemotactic signal easily brings hordes of leukocytes to the inflamed area.
What are the two basic types of leukocyte chemoattractants?
classical leukocyte attractants and chemokines
What do classical leukocyte attractants act on? what are some examples?
act broadly on several cell types including monocytes, macrophages and neutrophils *bacterial chemotaxins, N-formylated peptides *dead cells (necrotaxis), mitochondrial N-formylated peptides *plasma-derived: C5a/C3a/C5b67 and fibrinopeptides *Platelet-activating factor *leukotriene B4 (LTB4)
What are the most important group of chemotactic agents?
What are the two types of chemokines and what do they work on?
*CXC chemokines - potent attractants and activators or neutrophils; the most significant is CXCL8 (IL-8) *CC chemokines - attract various leukocytes BUT NOT NEUTROPHILS
What is phagocytosis? what cells are capable of phagocytosis?
the process by which certain cells of the innate immune system, including macrophages and neutrophils (professional phagocytes) engulf large particles (>0.5 micrometers in diameter) such as bacteria, fungi, protozoa, etc
What did Elie Metchnikoff discover in 1882?
the russian zoologist is credited with discovering phagocytosis.
What type of cells was Metchnikoff studying in 1882? What happened with the thorn?
mobile cells in the transparent starfish larva when a sharp thorn was introduced into the body of the larva, mobile cells surrounded the foreign body and attacked it
In later experiments, what did Metchnikoff discover?
that mobile cells were able to ingest and destroy foreign matter, including bacteria
Name the scientist credited with seeing white blood cells migrate from tissue capillaries to form pus at sites of injuries?
Metchnikoff used Cohnheim's observations and his own to conclude what? What did he receive in 1908?
that inflammation served as an important defense reaction of the body and played a major part in recovery from bacterial infections. The nobel prize
What are the 7 steps of phagocytosis?
1) chemotaxis and adherence of microbe to phagocyte 2) ingestion of microbe by phagocyte 3) formation of a phagosome 4) fusion of phagosome with a lysosome to form a phagolysosome 5) digestion of ingested microbe by enzymes 6) formation of residual body containing indigestible material 7) discharge of waste materials
PMNs stands for what?
What percent of total blood leukocyte population do neutrophils make up in most animal species? what are the exceptions?
40-70% swine and cattle -- lymphocytes are the predominate peripheral blood cells
Where are the majority of PMNs stored? When are they released?
PMNs are stored in the bone marrow and released when pro inflammatory mediators reach the bone marrow via the bloodstream, act on the marrow capillaries and on stored PMNs to mobilize them into circulating blood.
Once released into the blood stream, what ability to neutrophils lose?
ability to divide and give rise to new cells (terminally-differentiated cells)
How many neutrophils does an adult human produce in a day?
over 1 x 10^11
how long do neutrophils normally circulate in the blood? How long can they survive in tissues?
4-8 hours in blood before migrating to tissue may survive in tissue up to 4 or 5 days
True or false: a neutrophil can re-enter the bloodstream once it enters a tissue?
FALSE once it enters a tissue a neutrophil cannot return to the blood stream
What happens to circulating PMNs that are not recruited to inflammation sites?
undergo programmed cell death and are usually phagocytosed by resident macrophages in the LIVER or SPLEEN
What are the dimensions of neutrophils in circulations? during diapedesis?
spherical shaped and 10-12 micrometers in diameter can reduce width to 1 micrometer during diapedesis
What are heterophils? What animals are they found in?
large, reddish staining cytoplasmic granules found in neutrophils of certain animals found in chickens, rabbits and guinea pigs
Neutrophils carry many cell surface receptors including those that mediate attachment to ____ cells and ______.
endothelial cells opsonization
What does a neutrophil do when it encounters a microbe? how is this mediated?
it must BIND to it attachement is mediated by the interaction between cell surface receptors and ligands on the microbe
How do neutrophils and macrophages recognize microbes? What are some examples?
by their conserved microbial structures that are invariant within a pathogen class PAMPs (pathogen-associated molecular patterns): LPS, lipoteichoic acid, peptidoglycan, mannose-rich oligosaccharides, etc
What are the receptors on phagocytes that recognize PAMPs?
pattern recognition receptors (PRRs)
What is an example of PRRs binding to PAMPs?
the mannose receptor on a macrophage binds terminal mannose and fucose residues of glycoproteins and glycolipids, which are typically found on microbial cells walls
What are opsonins?
naturally occurring (NON-SPECIFIC) or acquired (SPECIFIC) substances that coat microbes and render them more susceptible to phagocytosis
Opsonins carry what kind of charge? What does this help them neutralize?
they are positively charged proteins this helps neutralize the negative charges on foreign particles by enabling them to bind to negatively charge phagocytes
What is an example of a specific opsonin? How does it work?
IgG Fab portions bind to epitopes on the microbe; Fc portion binds to the Fcgamma receptor on phagocyte
Name 6 examples of nonspecific opsonins. Are nonspecific opsonins more or less efficient than specific ones?
Complement proteins C3b, iC3b, C4b and a number of plasma reactive proteins including fibronectin, mannose-binding lectin (MBL) and C-reactive protein less efficient than IgG coating BUT it can enhance phagocytosis early in the course of infection before specific antibodies are produced.
Following attachment to a phagocyte, the adherent particle stimulates the formation of what on the cell membrane?
What step of phagocytosis are pseudopodia involved in? Describe what they do
they are involved in engulfment. they meet each other on opposite sides and fuse, creating an enclose chamber surrounding the phagocytosed particle.
What is a phagocytic vesicle? how is it formed?
a free-floating chamber in the cytoplasm containing a phagocytosed particle. (also called a phagosome) formed when the chamber created by fused pseudopodia breaks away from the cell membrane
After engulfment during phagocytosis, what do lysosomal granules do?
migrate through the cytoplasm and fuse with the phagolysosome to form a phagolysosome
what happens inside a phagolysosome? How long does it take?
microbicidal molecules and proteolytic enzymes stored in lysosomes destroy the phagocytized microbe. It occurs within 10 to 30 minutes.
Give examples of primary lysosomal granules of neutrophils
defensins -- disrupt the plasma membrane myeloperoxidase - respiratory burst neutral and acid hydrolyses - degrade bacterial products lysozyme - destroys bacterial cell walls
Give examples of secondary granules
lysozyme (also a primary) - destroys bacterial lactoferrin - binds iron collagenase - degrades connective tissue
Phagocytosis stimulates a series of ____-dependent biochemical events occurring at the plasma membrane and within the phagolysosome, promoting _____ of the ingested particle. This is known as what?
O2 destruction Respiratory burst
What are the 3 characteristics of a respiratory burst?
1) 2-3 fold increase in O2 consumption by the cell 2) increased glucose oxidation via the hexose monophosphotase shunt 3) generation of microbicidal reactive oxygen intermediates (ROIs; also called reactive species oxygen species--ROS): superoxide anion 02-, hydrogen peroxide H2O2, hypochlorous acid HOCl, hydroxyl radical OH, and singlet oxygen O2
What system in the most potent microbicidal system in neutrophils?
The H202-myeloperoxidase-halide system
Killing of microbes can also occur by oxygen-independant mechanisms via what?
the action of chemicals in phagocyte granules
What kind of environment (i.e. basic or acidic) prevails in the phagolyosome? Does this affect the activity of chemicals?
acidic (pH 4-5) enhances the activities of chemicals
What is a lysozyme?
A mucopeptidase found in serum, sweat, tears, saliva, mucous, nasal secretions, phagocytes and tissue fluids
How does a lysozyme work?
Breaks down bacterial cell wall peptidoglycan by hydrolyzing the glycosidic bond between the monosaccharides of the peptidoglycan backbone. This renders the bacteria susceptible to osmotic lysis.
What type of bacteria are susceptible to lysozyme?
Works on Gram positive bacteria
What are defensins?
(cationic peptides) a group of small peptides found in phagocytes and certain intestinal cells.
What do defensins form?
They form ion-permeable channels in microbial cell membrane, resulting in escape of essential metabolites
What bacteria are susceptible to defensins?
they can kill or inactivate a wide variety of bacteria, fungi, and some enveloped viruses
Where do bactericidal permeability increasing proteins (BPIs) bind?
(primary granules) bind specifically to the outer membrane of gram-negative bacteria
What does BPI induce? Why is this important?
induces phospholipase activation, phospholipase degradation and increased permeability in the outer membrane of the bacterium. Even though the inner membrane is intact, any bacteria exposed to BPI (even for just a few seconds) lose their ability to replicate (irreversible)
Do lysosomal enzymes have direct bactericidal activity?
NO. Most are digestive and function after killing a microbe
What do neutral and acid hydolases do? what are they examples of?
degrade and digest killed bacteria within the phagolysosome. Examples of lysosomal enzymes.
What organelle do neutrophils lack? How does this affect them?
mitochondria they have a limited supply of energy which cannot be replenished
What happens to neutrophils immediately following phagocytosis?
rapid apoptotic cell death and ingestion by macrophages.
The Monocyte-macrophage system (MMS) consist of?
monocytes, mobile macrophages and resident or fixed tissue macrophages.
when monocytes are released from the bone marrow what do they do?
they circulate in the blood for 10-20 hours before migrating into tissues, where they undergo maturation to become tissue macrophages.
A large portion of monocytes, after becoming macrophages, what happens to them?
they become attached to the tissues and remain attached for months to years; they form the basis of the tissue macrophage sytem.
Where are resident macrophages and macrophage-like cells located?
they are strategically placed at all the sites where microorganisms may gain entry into the host, thereby providing a continuing defense in the tissues against infection ( they serve as the first line of defense when microorganisms breach the physical barriers).
Where are histocytes?
Where are mesangial cells?
Where are microglial cells?
Central nervous system
All species have alveolar macrophages but ruminants, cats, and pigs In addition to alveolar macrophages also have_____?
PIMs- pulmonary intravascular macrophages
Where are Free macrophages derived from?
What makes up the majority of macrophages at inflammatory sites?
free macrophages derived from blood monocytes.
________ have been referred to as the most dynamic and gifted of the leukocytes.
Macrophages play a central role in _____________________?
In innate and adaptive immunity and are important effector cells for the elimination of microorganisms.
How long can macrophages live?
They can live for months to years unless they are destroyed by performing phagocytic functions.
Macrophages do not possess _____ and ____ granules, however the lysosomal contents of macrophages are similar in many ways to those of neutrophils.
1* and 2* granules
Unlike neutrophils, macrophage lysosomes also contain large amounts of_________, which digest the thick lipid membranes possessed by some bacteria.
Similar to neutrophils macrophages possess several cell membrane receptors, including____________?
Cytokine receptors, complement receptors, antibody receptors, and integrins.
Mannose-binding receptors on cell membrane bind to _______ or _______ in the capsule or LPS of invading bacteria, allowing macrophages to bind directly to nonopsonized bacteria.
mannose or flucose residues.
Macrophages respond to the same chemoattractants as________.
neutrophils, but in addition, they respond to CC chemokines, cationic peptides released by dead and dying neutrophils, and lymphokines released by activated T cells, eg. migration inhibition factor and macrophage chemotactic factor
Unlike ________, macrophages are sluggishly motile.
Macrophages are more powerful phagocytes than _________, capable of sustained, repeated phagocytic activity.
Macrophages have the ability to engulf much larger particles, such as _____,______,.
Red blood cells, neutrophils, necrotic debris, etc.
Compared to neutrophils, a macrophage is capable of phagocytizing as many as _________ bacteria.
Activated macrophages can synthesize ____ ____, a very powerful microbicidal agent.
How do macrophages eventually disappear?
either by dying or making their way into the circulatory system via the lymphatic system
In chronic inflammation, macrophage accumulation will persist, this is mediated by multiple mechanisms such as:
1.) recruitment of monocytes from the circulation
2.) Macrophage proliferation. Unlike neutrophils, macrophages are not terminally differentiated cells and can proliferate in situ at sites of chronic inflammation and form still more macrophages.
3.) immobilization of macrophages. Some cytokines, eg, migration inhibition factor, complement fragment Bb, etc. can immobilize macrophages at the site of inflammation.
When stimulated, macrophages may increase in size and form clusters of ______________.
Epithelloid cells ( resemble epithelial cells) or several may fuse to form multinucleated giant cells.
Multinucleated giant cells and epitheliod cells are found only in ___________ conditions, such as chronic inflammatory reactions.
Activated macrophages are major secretory cells, able to synthesize over 100 products including:
Several immunoinflammatory mediators, such as complement proteins, cytokines, proteinases, etc and lipid mediators of inflammation ( leukotrienes, prostaglandins, PAF, etc)
Macrophages playt a crucial role in_____________ and ___________
tissue reorganization and wound healing.
What do macrophage proteinases ( elastases, collagenases) do?
they degrade connective tissue, the cellular debris is then phagocytized.
Macrophage proteinases also synthesize and secrete many growth factors that promote the proliferation of _______ and the growth of new blood vessels ( angiogenesis factor)
Name the functions of Macrophages:
1.) antigen presentation
2) tissue reorganization and wound healing
3.) secretion of cytokines, enzymes and other factors
4.) tumor cell destruction
5.) phagocytosis and destruction of bacteria.
When neutrophils and macrophages engage in phagocytosis, they can injure normal host tissues by release of ______ and ________
ROI and lysosomal enzymes
What are antiproteinases?
synthesized by the liver, leukocytes, and connective tissue cells, present in plasma and tissue eg alpha 2 macroglobulin and alpha 1 antitrypsin, inhibit leukocyte proteinases, thereby preventing and/ or minimizing tissue damage.
Name the parts of this diagram:
A: NADPH Oxidase
B: Superoxide dismutase
What do Cytosolic and plasma moleculare "scavengers" of oxyradicals do?
Limit damage to cells and tissues.
What "scavengers" of oxyradicals limit damage to cells and tissues?
Cytosolic and plasma molecular scavengers
What enzymes convert escaped H202 to H20 and O2?
Are these enzymes present in cells?
catalase and glutathione peroxidase
yes, both are present in cells
What type of substances can damage the membrane of a phagolysosome?
ex: bacterial leukocidin, urate crystals
What happens when a membranolytic substance damages the membrane of a phaygolysosome?
the potent hydrolytic enzymes spill out, killing the leukocyte and releasing these enzmes into tissues
When large numbers of bacteria are present, enhanced feeding may result in what?
What does this give lytic enzymes access to?
The fusion of the lysosome with the developing phagosome prior to the complete closure of the phagosome
This causes lytic enzymes in the lysosome to have direct access to the extracellular environment
What happens when a phagocyte encounters a phaygocytic stimuli that is too large to be internalized?
What are examples of these stimuli?
the pahgocyte releases lysosomal enzymes into the surrounding environment, leading to tissue injury (vasculitis)
Examples: helminth larvae, bacteria immobilized against a fibrin meshwork, antigen-antibody immune complexes fixed against a basement membrane or endothelium or joint surface, etc
Where are the cells of the adaptive immune response located? Name the cells
localized and concentrated in organs and tissues of the lymphoid system
(lymphocytes, accessory cells, antigen-presenting cells)
Where are foreign antigens transported and concentrated?
in the organs and tissues of the lymphoid system
Where are lymphoid stem cells produced in the young fetus?
In the older fetus and neonates?
By the yolk sac mesoderm and fetal liver in the very young fetus, in the bone marrow of the older fetuses and neonates
How are lymphoid tissues and organs classified?
based on the 1) level to which they participate in the maturation of lymphocytes and 2) provision of a suitable environment for the interaction between foreign antigen and antigen-sensitive T and B lymphocytes.
Where are central lymphoid organs and tissues located?
What do they regulate?
located in the thymus, bone marrow, peyer's patches, and bursa of fabricius
regulate production and maturation of lymphocytes--generate lymphocytes that are individually different to meet the threat posed to an animal or individual by the large number of microbial pathogens, the concept being "ONE CELL, ONE SPECIFICITY"
Central lymphoid organs develop early in embryonic life and involute after puberty, except for which organ?
What do mature lymphocytes acquire?
What do they learn to discriminate between?
acquire specific antigen receptors and other phenotypic characteristics
learn to discriminate between self-peptides (which are tolerated) and foreign antigens (which are not) [self vs nonself]
True or false: maturation and differentiation of lymphocytes depends upon antigenic stimulation?
FALSE; maturation and differentiation are INDEPENDENT of foreign antigenic stimulation
If central/primary organs are removed early in life, what happens to lymphocytes?
(this is on page 57, make sure I understood this correctly)
There is a loss of lymphocytes, resulting in loss of immune responsiveness
What is the thymus the site of?
T cell development and maturation
Where is the thymus located? Are there any exceptions?
located in the anterior mediastenal space
yes; in horses, pigs, sheep, cattle and chickens the thymus can extend up the neck as far as the thyroid gland
What is the thymus organized into? What are these separated by?
organized into lobules, separated by connective tissue septae
The thymus has a ____ _____ supply and _____ ______ vessels that drain into ______ lymph nodes
rich blood supply
efferent lymphatic vessels
mediastinal lymph node
How was the role of the thymus in a host immune response determined?
What was the result?
following a neonatal thymectomy of day-old mice
there was a dramatic decrease in circulating T lymphocytes [lymphopenia] and total loss of the cell-mediated immune response
What are the two compartments of the thymus?
Cortex (outer compartment) and medulla (inner compartment)
The cortex of the thymus contains what percentage of total thymocytes?
What is a thymocyte?
An immature lymphocyte in the thymus
What do thymocytes acquire as they mature in the cortex?
Where do they migrate as they mature?
antigent receptors (TCRs) and other functional and phenotypic characteristics of mature T cells.
migrate to the medulla
The medulla of the thymus is sparsely populated with what?
Mostly mature lymphocytes
A network of what three cells are found throughout the thymus, especially at the corticomedullary junction?
1) epithelial cells
3) dendritic cells
What do the epithelial cells, macrophages and dendritic cells provide to assist the proliferation and maturation of thymocytes?
the stimuli, including cytokines (especially IL-7) thymic hormones (thymosin, thymic hormon factor, thymopoietin, thymulin, etc) and major histocompatibility comples (MHC) molecules that are REQUIRED for proliferation and maturation of thymocytes
Developing thymocytes, also called pre ___, acquire TCRs via what?
True or false: TCRs are selected for either self-MHC restriction or self-tolerance
False: TCRs are selected for BOTH self-MHC restriction AND self-tolerance
What is self-tolerance?
the ability to distinguish between self and nonself by MHC self peptide complexes expressed on THYMIC STROMAL CELLS
What does the thymus do to thymocytes whose TCRs cannot recognize antigen-MHC complexes or whose TCRs react strongly with self antigen-MHC complexes?
induces death by apoptosis
What percent of developing thymocytes die by apoptosis?
In humans, thymic involution begins when and ends when?
begins at puberty and continues throughout adulthood (doesn't end)
Where does thymic involution begin? what happens to cells stored there?
begins within the cortex, which may disappear completely while the medullary remnants persist
immature cortical thymocytes from the cortex are lysed--cortical atrophy is related to corticosteroid sensitivity (lysis) of these cells
When was the bursa of fabricius first described? by whom?
first described in the 16th century by Hieronymus Fabricius
What is the bursa of fabricius? What does it look like?
It is a lymphoepithelial organ found in birds BUT NOT IN MAMMALS; it is a sac-like structure dorsal to the cloaca
Describe the development of the bursa of fabricius
reaches maximum size 1-2 weeks after hatchin, followed by gradual involution; by the time the bird reaches sexual maturity (6 months) only atrophied vestiges remain of the BF and the thymus
How was the function of the bursa of fabricius determined? What happened?
following a bursectomy of day-old chicks
there was only a slight drop in the numbers of circulation lymphocytes, but there was a dramatic decline in antibody immune response
Describe B cell differentiation and maturation
Similar to the T cells, the majority of B cells (90-95%) die through apoptosis because of negative selection of self-reactive B cells.
Mature B cells begin to migrate from the bursa to the peripheral lymphoid organs a few days prior to hatching
Bone marrow is a site for what? What type of lymphoid organ is it considered in mammals?
the site of generation of all circulating blood cells (hematopoeisis) and a fat depot (as the animal ages more than 50% of the marrow will become filled with fat)
in mammals it is a primary and secondary lymphoid organ
What are the two compartments of bone marrow?
What does the hematopoietic compartment of bone marrow contain?
what does it do?
the hematopoietic compartment contains precurses of all the blood cells (self-renewing stem cells) as well as stromal cells, macrophages and lymphocytes
hematopoietic cytokines produced by these cells stimulate proliferation and maturation of precursor cells
In most mammals the bone marrow is a site of early events of what?
B cell development
What do the stromal cells of bone marrow do?
1) secrete various cytokines required for B cells development
2) selection of immature B cells (B cells that acquire self-reactive antigen receptors are allowed to die)
How long do the numerous plasma cells in bone marrow product antibodies for?
Where are these plasma cells produced?
for many months or years
Plasma cells are also produced in peripheral lymphoid organs as a result of antigenic stimulation of B Cells and then migrate into the bone marrow
What are Peyer's Patches aggregations of? Where are they located?
aggregations of lymphatic nodules
found in the walls of all three segments of the small intestine
There are two types of Peyer's patches. Describe the first.
What do they contain?
How long do they last?
Numerous discrete lymphatic follicles that function as peripheral lymphatic organs.
They contain B cells, T Cells, APC's, etc
they persist throughout the life of the individual or animal
Describe the second type of Peyer's Patches.
What specific animals are these type located in?
What is it the site of?
When does it undergo involution?
In ADDITION to the discrete lymphatic follicles in te jejunum, there is a single large ileal Peyer's Patch that functions as a primary lymphatic organ
Exists in ruminants, pigs and dogs
it si the site of early B cell development (populated by IgM+ immature B cells)
undergoes involution by 1.5 years of age
When do peripheral lymphoid organs arise? how long do they persist for?
arise late in fetal life
persist through adulthood
What happens when peripheral (secondary) lymphoid organs are removed?
there is not any significant reduction to an individual's immune capacity
What is the role of peripheral (secondary) lymphoid organs (i.e. what develops there)
sites where mature lymphocyte responses to foreign antigens are initiated and develop
Lymph nodes are the only lymphatic organ with what type of lymph vessels?
only organ with BOTH afferent and efferent lymph vessels
What are lymph nodes the site of?
How are antigens carried to the nodes?
Sites where immune responses to antigens entering the body via the skin and mucos, or from parenchymal organs and connective tissues are initiated
carried by lymphatic fluid
All lymph nodes eventually drain into ________ and back to the ______
thoracic duct system
back to the peripheral blood
What are the main parts of lymph nodes?
efferent lymphatic vessels
what happens in the cortex of lymph nodes?
B cells are organized into primary and secondary follicles
What is a primary follicle?
what does it contain?
where is it located?
follicles without germinal centers
contain mostly resting mature B cells, follicular dendritic cells (FDCs) and macrophages
located in the cortex of lymph nodes
What is a secondary follicle?
How do they develop?
What happens to B cells here?
Where are secondary follicles located?
primary follicles WITH germinal centers (GCs)
GCs develop in response to antigenic stimulation of B cells
B cell proliferation, selection of B cells producing high affinity antibodies, and generation of memory B Cells occurs in GCs
located in cortex of lymph nodes
What does the paracortex of lymph nodes contain?
How does the paracortex affect lymphocytes?
mostly T cells, some macrophages and dendritic cells.
lymphocytes enter the node from the circulation through the high endothelial venules (HEVs) in the paracortex
What does the medulla of the lymph node contain?
Contains mostly macrophages, antibody-secreting plasma cells and some lymphocytes
What does lymph leaving via an efferent lymphatic vessel contain?
contains newly secreted antibodies, effector lymphocytes (due to clonal expansion of T cells) and mostly naive lymphocytes that migrated from the blood into the lymph node through the paracortical HEVs
What type of lymphoid organ is the spleen?
What is so important about the spleen?
It's the largest secondary lymphoid organ
because it is the largest, it is the major organ in the body in which antibodies are produced
The spleen is the major site of immune response to what specific type of antigen?
what does a splenectomy lead to?
increase in blood-borne microbial infections
What are the major sections of the Spleen?
Describe the White Pulp of the spleen.
Where are T cells found?
Where are B cells organized and what do these areas contain?
The lymphoid tissue of the white pulp is organized around the central arteriole to form the periarteriolar lymphoid sheath (PALS)
T cells are mostly around the central arteriole
B cells are organized into primary and secondary follicles. The follicles also contain macrophages and follicular dendritic cells (FDCs). The follicles are anatomically and functionally the same as in lymph nodes
What cells does the red pulp of the spleen contain?
What happens in the red pulp (and spleen) as a result of these cells?
contains macrophages, some activated B cells and plasma cells. It is a storage site for erythrocytes, platelets and granulocytes
macrophages in the red pulp phagocytose old platelets and RBCs and also clear the blood of microorganisms and other particles--thus the spleen is the major site for phagocytosis of antibody-coated (opsonized) microbes
What is the marginal zone of the spleen? what does it contain?
separates the white pulp from the red pulp
contains macrophages and some lymphocytes
What is MALT?
What are the cells of MALT?
Mucosal-Associated Lymphoid Tissue
comprises all lymphoid cells present as either solitary or aggregated nodules in epithelia, lamina propria and submucosa of the gastrointestinal tract
What are the main sites of MALT?
Gut-associated lymphoid tissues (GALT)
Bronchial-associated lymphoid tissues (BALT) and genitourinary tract
Cutaneous immune system
Where is GALT located?
Lymphoid tissues in the lamina propria of the intestines, Peyer's pathces, appendix and tonsils
What does the cutaneous immune system contain?
lymphocytes and accessory cells in the epidermis and dermis that respond to environmental antigens
What is lymphocyte recirculation?
the continuous movement of lymphocytes from one lymphatic organ or tissue to another via the blood and lymph, and, if activated, to peripheral inflammatory sites
True or false: naive lymphocytes specific for any given antigen account for a high percentage of lymphocytes?
FALSE; account for about 1 in every 10^5 lymphocytes
What two things does lymphocyte recirculation ensure?
1) ensures that an antigen-specific lymphocyte will come in contact with that antigen no mater where in the body the antigen is located.
2) ensures that activated (effector) lymphocytes are delivered to the particular tissue where they are required for elimination of the antigen
How often does a lymphocyte recirculate from blood to the tissues and lymph and back again?
as often as 1-2 times per day
What are the predominant lymphocytes in blood?
What are HEVs?
What happens at HEVs?
Where are they located?
modified postcapillary venules within the paracortex of lymph nodes - High endothelial Venules
extravasation of native lymphocytes from blood into a peripheral lymph node
HEVs are present in each secondary lymphoid organ (peyer's patches, tonsils, etc) BUT NOT IN THE SPLEEN
What type of endothelial cells are in HEVs?
What do they contain that other cells in ordinary venules do not have?
cuboidal (plump) endothelial cells
cytokine-activated--allows them to express a variety of adhesion molecules no found on flat resting endothelial cells of ordinary venules
What do the adhesion molecules on HEV endothelial cells have to do with the recirculation of T lymphocytes?
recirculation patterns of native T lymphocytes is government by the combination of adhesion molecules (eg, L-selectin) and chemokine receptors (eg CCR7) that they express
What happens to the normal, continuous lymphocyte movement through nodes when an antigen enters the nodes?
What does this allow to happen?
temporary shut down in lymphocyte traffic
allows antigen-specific lymphocyte to be activated and change into effector cells or memory cells
What happens to naive T cells that do no encounter antigen?
They exit through an efferent lymphatic vessel, re-enter the circulation and home in on another lymph node
Where do mature B lymphocytes reside?
do they recirculate?
why would it not matter much if they do or do not recirculate?
Do other types of B cells recirculate?
reside mainly in follicles of peripheral lymphoid organs
recirculate, migrate from one peripheral lymphoid organ to the next
because only a small fraction of blood lymphocytes are B cells
yes; memory B cells, some activated B cells, and some plasma cells also recirculate
What is MHC?
What functions does it perform in the immune response?
Major Histocompatability Complex; a cluster of genes located in close proximity that encode the MHC proteins (molecules)
Functions: 1) positive selection of T cells in the thymus, 2) presentation of antigenic peptides to T cells, 3) encodes some complement proteins, some cytokines, and proteins invloved in antigen processing 4) class I and class II MHC proteins are the most important antigens recognized in the graft rejection process
True or false: all mammals and birds have an MHC complex?
TRUE; the structure and function are basically the same
How does naming work for MHC complexes?
initial of the species, followed by LA for leukocyte antigen (because proteins are readily detected by blood leukocytes)
What is HLA?
Human MHC complex
What is DLA?
Dog MHC complex; chromosome 12
What is ELA?
Equine MHC complex; chromosome 20
What is OLA?
Ovine MHC complex; chromosome 20
What is BoLA?
Bovine MHC complex; choromsome 23
What is CLA?
Caprine MHC complex, chromosome 23
What is SLA?
Swine MHC complex, chromosome 7
What is B locus?
Chicken MHC complex, chromosome 16
Where are human MHC genes located?
Does the MHC always look the same in the human genome?
on a segment of the short arm of chromosome 6.
It is the most polymorphic gene cluster in the human genome, with large numbers of alleles (variants of polymorphic genes) at several different loci
How is MHC polymorphism usually detected?
What are MHC proteins often referred to as?
major histocompatability complex proteins
What is an MHC haplotype?
How many are within a family?
the set of MHC alleels present on each chromosome
there are only 4HLA haplotypes within a family
How are haplotypes from both parents inherited and expressed?
codominantly; each individual expresses the MHC alleles on both chromosomes that are inherited from both parents
True or false: because MHC proteins are so polymorphic, they are not specific for any species?
FALSE; MHC proteins are HIGHLY SPECIFIC for each individual species, hence MHC proteins are considered as species or strain markers
What do Class I MHC molecules consist of?
Where are these expressed?
Are there any exceptions?
two noncovalently linked polypeptide chains that are constituitively expressed on the cell membranes of most nucleated cells except primitive cells in early embryonic life, sperms, neurons and erythrocytes of most mammals
How is MHC class I expression enhanced?
by exposure to cytokines such as interferons alpha, beta and gamma
Each individual expresses how many different class I molecules on EVERY cell?
What do they contain?
6 different class I molecules
contain alpha chains derived from the two alleles of HLA-A, HLA-B and HLA-C genes that are inherited from both parents
What does the alpha chain of class I MHC molecules contain?
three external domains (alpha1, alpha2, alpha3 domains), a transmembrane segment and a cytoplasmic tail
What is located on the MHC class I molecules between domains alpha1 and alpha2? What does it bind? When/how many can it bind?
the peptide-binding cleft or groove
binds peptides containing 8-11 amino acids
a single class I molecule can bind several different antigenic peptides BUT IT CAN ONLY BIND ONE AT A TIME
What does the alpha3 segment of MHC Class I molecules contain? what does it serve for?
contains a loop
serves as the binding site for the T cell coreceptor, CD8
Where are the polymorphic amino acid residues confined to in Class I MHC molecules?
confined to alpha1 and alpha2 domains
What is Beta2M?
Where is it encoded?
Is it invariant or variant?
B2M is a non-MHC-encoded protein that associates noncovalently with the alpha3 domain of the alpha chain. It is
encoded by a gene on chromosome 15
it is invarient (nonpolymorphic)--i.e. all B2M chains of Class I molecules are the same
How does the assemblying of class I MHC molecules begin?
What does it form and how is it stabilized?
What is the name of the completed complex?
Where is it transported?
begins with the folding heavy chain first interacting with Beta2M
the 'empty' dimeric molecular complex is then stabilized by the binding of a peptide (self peptide or foreign peptide)
trimolecular complex (alpha chain, Beta2M
transported to the cell membrane
What happens to Class I MHC cells in the absence of Beta2m?
The class I heavy chain is NOT EXPRESSED on the cell surface
What is the function of MHC Class I proteins?
the presentation of peptides derived from proteins in the cytosol, eg, viral proteins, to CD8+ T cells.
What do Class II MHC molecules consist of?
How and where are they expressed?
How is expression enhanced?
two nonidentical protein chains (alpha and beta chains)
constituitively expressed on the cell membranes of dendritic cells and B lymphocytes and on activated macrophages
enhanced by interferon-gamma
What three regions are Class II molecules encoded by?
How many Class II molecules does each individual possess?
HLA-DP, HLA-DQ, HLA-DR
6-12 class II molecules
Each chain of MHC Class II molecules has how many domains?
what are they?
Where are the polymorphic amino acid residues located?
transmembrane segment and a cytoplasmic tail
in alpha1 and beta1 domains
What is the peptide binding groove on Class II molecules formed by?
What does it bind and how many?
formed by interaction of the alpha1 and beta1 domans,
binds peptides containing 10 to 30 amino acids.
a single class II molecule can bind several different peptides (but only ONE peptide at a time)
On the Class II MHC molecules, what is the binding site for the T cell coreceptor, CD4?
a loop in the Beta2 domain
What is the invariant chain (Ii) of Class II molecules?
What is it associated with?
a nonpolymorphic protein
associated with newly synthesized class II molecules (plays a role in antigen presentation)
What is the function of MHC Class II proteins?
present peptides derived from protein antigens degraded in cellular vesicles (phagosome or endosome) to CD4+ T cells
What does the stable expression of Class II molecules depend on?
just like class I molecules a fully assembled class II molecule consists of an alpha chain, beta chain and a bound peptide
stable expression on cell surfaces requires the presence of all 3 components
What is located within the locus of Class II molecules?
Name the three.
genes that encode several proteins important in antigen processing
HLA DM is one of the genes found in the Class II locus.
What does HLA DM do?
facilitates removal of invariant chain-derived CLIP protein and the binding of endosomal peptide to class II MHC molecules
Proteasome is one of the genes found in the Class II locus. What does it do?
a cytoslic protease complex that cleaves proteins into small peptide fragments that are subsequently presented by class I MHC molecules
TAP is one of the genes found in the Class II locus. What does it stand for? and what does it do?
transporter associated with antigen processing
transports peptides from the cytosol into the endoplasmic reticulul where the peptides associate with newly synthesized Class I molecules
Describe the structural differences between Class I MHC and Class II MHC
Class I: alpha chain and Beta2m
Class II: alpha and beta chains
Describe the distribution differences between Class I MHC and Class II MHC
Class I: most nucleated cells
Class II: Professional APCs (B cells, dendritic cells, macrophages)
Describe the sites of polymorphic resides for Class I and Class II MHC
Class I: alpha1 and alpha2 domains
Class II: alpha1 and Beta1 domains
Describe the peptide binding cleft of Class I and Class II MHC
Class I: closed; binds peptides of 8-11 amino acids
Class 2: open; binds peptides of 10-30 amino acids
Describe the sources of peptides for Class I and Class II MHC
Class I: cytosol
Class II: endosome
Describe the peptide presented to for Class I and Class II MHC?
Class I: CD8+
Class II: CD4+ T Cells
Describe the outcome for Class I and Class II MHC
Class I: T cell-mediated cytotoxicity
Class II: T cell-mediated help
What does the Class III MHC region contain?
genes that code for several complement proteins, cytokines such as tumor necrosis factor, etc
What is MHC restriction?
The concept that a given T cell will recognize antigen ONLY after it is processed and the ensuing antigenic peptide is bound to a particular class I or II MHC molecule.
During T cell development in the thymus, a pre-T cell acquires TCR that is specific for what?
both an antigenic peptide and a self-MHC molecule
What do CD8+ T Cells recognize?
what are these cells also called?
recognize peptide antigen ONLY in association with PARTICULAR SELF-MHC class I molecules
What do CD4+ T Cells recognize?
what are these cells also called?
recognize peptide antigen associated with particular Self-MHC CLASS II MOLECULES
helper T cells
What is associated with possesion of certain MHC haplotypes?
certain diseases, such as various allergies, some viral infections and certain auto immune diseases
What are the four hypotheses that attempt to explain the relationship with MHC and disease susceptibility?
1) the absence of an MHC molecule that can bind and present an antigenic peptide
2) the absence of TCRs that can recognize the complex of antigenic peptide MHC molecule
3) the MHC allelic gene may encode molecules that are recognized as RECEPTORS by bacterial toxins or viruses
4) within a species, a reduction in MHC polymorphism may predispose that species to infectious diseases, eg cheetahs and the Florida panther
What is antigen processing and presentation defined as?
the series of events that result in the conversion of protein antigens to self-MHC-associated peptide fragments that are then presented to antigen-sensitive T lymphoctes.
T lymphocytes respond only to what?
processed protein antigens
What does the high degree of polymorphism of MHC class I and II molecules concentrated at the peptide-binding region ensure?
What is the limiting factor?
that a particular species has the potential to effectively respond to and eliminate any antigen it encounters
no single individual expresses as finite number of MHC molecules; no single individual is capable of responding vigorously to each and every pathogen requiring a T cell response for elimination
When a peptide binds to an MHC molecule, how long may it stay bound for?
What does this allow?
hours to several days
peptide-MHC complexes persist long enough on the cell membranes of antigen-presenting cells and target cells to ensure productive interaction with antigen-specific T cells
MHC molecules bind to and present what kinds of peptides to T cells?
both self-peptides and foreign peptides
In a normal, healthy cell, why do Class I molecules display self peptides?
a result of normal turnover of self proteins
if the cell is infected by a virus or viral particles self peptides will be displayed by class I MHC molecules, but the T cells usually respond ONLY to FOREIGN PEPTIDES
What are the phases of Naive T cell responses?
antigen recognition, lymphocyte activation, clonal expansion, differentiation and effector functions
Fill in the chart:
A cell is divided into what two compartments?
In which can microorganisms replicate?
2) vesicular system, including the endosome, ER, lyososomes, etc
microorgs can replicate in either compartment
What happens to cytosolic antigens?
antigenic peptides are presented in association with class I MHC molecules to CD8+ T cells
What happens to endosomal antigens?
antigenic peptides are presented in association with Class II MHC molecules to CD4+ T cells
The MHC Class II processing pathway occurs for what type of antigen?
What are the cells called that present peptides assoicated with Class II MHC molecues to helper T cells
professional antigen-presenting cells (APCs)
What do APCs express on their cell membranes?
What are the best defined APCs?
express both class I and class II MHC molecules on cell membranes
macrophages, B cells, and dendritic cells
Where do dendritic cells arise from?
where are they found?
What do they possess that gives them their name?
arise from hematopoeitic stem cells in the bone marrow
found in the t cell areas of lymphatic tissues
possess long thin cytoplasmic processes called dendrites
What do dendritic cells express?
How do they express them?
How important are dendritic cells regarding stimulation?
express many monlecules associated with naive T cell activation, eg class I and II MHC molecules, the costimulatory B7 molecules, and the cell adhesion molecules ICAM-1, ICAM-2, LFA-1, and LFA-3 (CD58).
dendritic cells are the most potent stimulators of native T cell responses
Besides their main expressors, what else do dendritic cells express at a high level?
What do dendritic cells secrete and what does it do?
dendritic cell-specific adhesion molecule DC-SGN
chemokine called CD-CK (CCL 18) that specifically attracts naive T cells
What are immature dendritic cells called?
where are they found?
What do they do?
Do they express co-stimulatory molecules?
Langerhans cells (LCs)
found in nonlymphoid tissues such as the skin and mucous membranes
they are actively phagocytic
they do no express co-stimulatory molecules
Describe what LCs do when a protein antigen invades skin or mucosa?
LCs bind the antigen to their surfaces,
endocytose it into vesicles and process it,
migrate as "veiled cells" via the afferent lymphatics into the paracortex of the draining lymph nodes where they mature and become interdigitating dendritic cells (IDCs; mature nonphagocytic cells)
What does the migration of LCs provide a mechanism for?
for transporting antigens from the skin and mucosa to the T cells located in the lymph nodes
What happens to most of the antigen ingested by macrophages?
What happens to some of the antigens?
Most are degraded and eliminated by exocytosis
some peptide products form complexes with MHC class II molecules and are displayed on the cell surface and presented to TH cells
Macrophages do not express MHC class II proteins unless what?
unless they are activated by phaocytosing microorganisms
What are macrophages beneficiaries of?
TH cell effector functions, i.e. cytokines secreted by activated TH cells activate macrophages to kill phagocytosed microbes
B cells bind to antigens using what?
What do B cells do to the bound antigens?
What do cytokines do to B cells?
B cell receptors (BCRs)
endocytose them and present processed peptides from the antigens to TH cells.
cytokines produced by effector TH cells stimulate B cells to produce antibodies against protein antigens
What happens to extracellular protein antigens?
They are phagocytosed or endocytosed into vesicles
the vesicles fuse with lysosomes containing acidic proteases
partial degradation of the antigen occurs int he acidic endosomes, leading to the generation of short peptide fragments of 10-20 amino acid residues
Describe the 5 stages of uptake of extracellular proteins through expression of MHC
1) uptake of extracellular proteins into vesicular compartments of APC
2) processing of internalized proteins in endosomal/lysosomal vesicles
3) biosynthesis and transport of class II MHC molecules to endosomes
4) association of processed peptides with class II MHC molecules in vesicles
5) expression of peptide-MHC complexes on cell surface
What do newly synthesized class II MHC molecules in the ER associate with?
a MHC class II-assocation trimeric invariant chain (Ii, CD74)
What happens when Ii chaiin bind to the class II molecule?
What does this promote?
What happens to Class II molecules witout Ii?
Where does Ii direct newly formed class II molecules?
part of the Ii polypeptide chain lies within the peptide-binding cleft, ensuring that class II molecules cannot bind and present peptides they encounter in the ER
promotes the folding and assembly of Class II MHC molecules.
in its absence, many class II molecules remain in the eER as complexes and misfolded proteins
directs newly formed class II molecules to the specialized endosomal compartment called MIIC (MHC class II Compartment) where peptide loading takes place.
Name the specialized MHC class II-like molecule that is found in the MIIC and facilitates the loading of class II molecules with peptides?
What is the main function of the HLA-DM in the MIIC?
in the MIIC the Ii chain is cleaved by proteases to leave a fragment bound to the peptide groove called CLIP (CLass II-associated Invariant chain Peptide). HLA-DM catalyzes the release of CLIP
What are two secondary functions of HLA-DM in the MIIC
1) stabilizes the empty class II molecules so they do not aggregate; catalyzes the binding of peptides to the empty peptide groove
2) facilitates the release of weakly bound peptides from the peptide grooves and allows other peptides to replace them. This ensures that the peptide-MHC II complexes on the cell surface of teh APC will survive long enough to enounter the antigen-specific TH cell
What happens to individuals with mutations in the HLA-DM genes?
demonstrate defective antigen presentation. The class II molecules assemble correctly with the Ii chain howver the MHC molecules fail to bind endosome-derived peptides and are displayed at the cell surface still bound to the CLIP peptide
What happens to Class II molecules with bound peptides?
If an APC is not processing a foreign antigen, what will happen to MHC class II molecules?
transported to the surface of an APC where they are displayed for recognistion by CD4+ helper T cells.
they are displayed at the cell surface with bound self peptides
True or false: the presentation of antigen (signal 1) to a naive helper T cell by an MHC class II molecule on an APC is, BY ITESELF, enough to trigger an immune response
FALSE; it is insufficicent to trigger an immune response
the T cell must also be exposed to co-stimulating molecules (signal 2) such as cytokines and cell membrane proteins, produced by the APC
What are examples of co-stimulatory molecules for helper T cells?
cytokine interleukin 1 (IL-1) and the cell membrane proteins B7-1 (CD80) and B7-2 (CD86)
Describe the events of costimulation of T cells related to signal 1
Signal 1 leads to the induction of various transcription factors, some of which bind to the promoter regions of the IL-2 and IL2R genes, enhancing their transcription in the T cell
Delivery of the co-stimulatory signal increases the half-life of IL-2 mRNA, resulting in IL-2 production (T cell autocrine growth factor)
This leads to the proliferation and differentation of naive T helper cell into effector T cells and memory T cells
What does signal 2 induce during co-stimulation of T cells?
induces the synthesis of anti-apoptotic proteins
What happens in the absence of the co-stimulatory signal?
IL-2 mRNA is rapidly degraded, preventing the synthesis of IL-2.
as a result the activation process is terminated and the naive T cell either fails to respond and dies by apoptosis or enters a state of unresponsiveness called anergy
The inflammatory response may have three outcomes. Name them.
1) elimination of the causative agent,
2) "walling off" of the inflammation from the rest of the body (delays the spread of bacteria or toxic products) with subsequent healing of the lesion, and
3) persistence of the causative agent, leading to chronic inflammation or spread throughout the body
Inflammation is an overlapping series of events that form a continuum.
Name the progression of events.
What are the two main categories of sources of chemical mediators of inflammation?
exogneous - bacterial lipopolysaccharide (LPS), etc
endogenous - from plasma and host cells