Immuno Test 1 part 2 page 36 till end Flashcards
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.
locally
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?
TRUE
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?
YES
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?
transendothelial migration
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?
true
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?
chemokinesis
is chemotaxis a receptor mediated event?
yes
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?
chemokines
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?
Julius Cohnheim
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?
Polymorphonuclear neutrophils
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?
pseudopodia
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?
Connective tissue
Where are mesangial cells?
The kidneys
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?
blood monocytes
Name the parts of this diagram:
A: NADPH Oxidase
B: Superoxide dismutase
C: myeloperoxidase
What do Cytosolic and plasma moleculare “scavengers” of oxyradicals do?
Limit damage to cells and tissues.
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
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.
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
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
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 are the major sections of the Spleen?
White pulp
red pulp
marginal zone
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
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
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
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 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?
two domains
transmembrane segment and a cytoplasmic tail
in alpha1 and beta1 domains
On the Class II MHC molecules, what is the binding site for the T cell coreceptor, CD4?
a loop in the Beta2 domain
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 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.
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:
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).
CONSTITUITIVELY
dendritic cells are the most potent stimulators of native T cell responses
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
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 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
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
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
Inflammation is an overlapping series of events that form a continuum.
Name the progression of events.
