Binding of ________ to _________ directs naive lymphocyte homing to lymphoid tissue
L-selectin/ vascular addressin
Tcell activation signal 1 requires recognition of _________.
TCR-MHC class II
The costimulatory signal in Tcell activation requires _________
The binding of ___________to __________ directs activated lymphocyte homing to infected site
Which is NOT involved in Tcell activation?
Activation of naive CD8 Tcells can be achieved by....
macrophage + activated CD4 Tcell
macrophage + naive CD4 Tcell
The development of either TH1 or TH2 cells from TH0 cells is determined by _______
T/F: Naive T cells enter lymph from blood by binding to HEV
T/F: Naive T cells can enter lymph nodes in afferent lymph as well as from the blood?
_______ is not required for activation of B cells by thymus independant Ag
_____, ______, & ______ are required for activation of B cells by thymus independant Ag
B cell receptor
B cell co-receptor
primary follical is found in ______
Afinity matruation happens in ______
Somatic hypermutation happens in ________
isotypic switching occurs in _________
Measels recovery results in _________ immunity
_______ activates complement, is an opsinon, & neutralizes
________ clear immunocomplexes from circulation in blood
______ clear immunocomplexes from circulation in liver and spleen
_________ is the classic C3 convertase
what movements are associated with hinge flexability
________ is a functionally monovalent Ab that can block IgE
Ab dependant cell mediated cytotosicity is dependant on _______ or _______
IgG ==> IVK cells
IgE ==> eosinophiles
at which anatomical sites do naive T cells encounter antigen?
secondary lymphoid tissue
in which sites would a pathogen or antigens end up and how if they intered the body through a small wound in the skin?
pathogen & dendridic cells that have ingested the pathogen are carried to the nearest lymph node in the afferent lymph
in which sites would a pathogen or antigen end up and how if they entered the body from the gut?
gut associated lymphoid tissues like pyers patches:
pathogens enter GALT via specialized M cells in the gut epithelium
in which sites would a pathogen or antigens end up and how if they got into the blood stream?
pathogens circulating in the blood enter the spleen directly from the blood vessels that feed it
Adaptive immune responses involving T celsl usually take several days... why?
1. Ag transported to secondary lymphoid tissue, processed, & presented by APC to Tc cells or Th cells to activate them
2. the number of T cells specific for a pathogen will only b around 1/10,000 or 1/100,000 so it takes time for relevant T cells circulating through the secondary lymphoid tissues to reach the tissue containing site where antigens can activate them
3. it takes several days for an activated T cell to proliferate and differentiate into a large clone of fully functional effector T cells
how do naive T cells arrive at sites of infection?
they are delivered to all secondary lymphoid organs from the blood.
they can also pass from one lymph node to another via lymphatic vesicles
do all T cells leave infected areas after priming?
after activation by Ag only CD8 T cells and Th1 cells exit the lymphoid tissue via efferent lymph which delivers them to the blood in search of infected tissues.
Ag activated Th2 cells remain in the lymphoid tissue where they provide help to antigen specific B cells
which selectins have a role in the circulation of T cells between the blood and lymphoid tissues?
T cells & B cells expriss L-selectin
which binds to sulfated carbohydrates of mucin-like vascular addressins in HEVs
3 types are involved:
GlyCAM-1 & CD34 expressed on lymphnode HEVs
MAdCAM-1expressed on mucosal endothelium
how do T cells migrate across lymph node high endothelial venules (HEVs) from blood?
1. chemokines made by endothelium and bound to its extracellular matrix induce T cells to express LFA-1
2. LFA-1 binds with high affinity to an intercellular adhesion molecule
3. ICAM-1 expressed on the endothelium
4. Tcell squeezes through the endothelium junctions (diapedesis)
5. gains entry into the lymphnode
Why are dendridic cells more efficent than macrophages at stimulatind naive T cells?
dendritic cells are migratory and transport antigen to neighboring secondary lymphoid tissue
which cell surface glycoprotein distinguishes professional APC from other cells and is involved in the co-stimulation of T cells
B7 (a co-stimulator molecule)
what receptors can it bind on the Tcell & what signal does it deliver in each case?
1. when B7 binds to DC28 the B7 receptor expressed earliest on Tcells an activation is delivered and T cells undergo clonal expansion and differentiation which requires that the Tcell receptor and CD4 co-receptor are engaged specifically with a peptide:MHC II complex
2. CTLA-4 binds B7 with 20fold higher affinity than does CD28 & an inhibitory signal is delivered to the T cell when B7 on the APC binds to CTLA-4. this mechanism regulates Tcell proliferation and supresses Tcell activation after immune response
what is the consequence of antigen recognition by T cells in the absence of this lycoprotein on the APC
if they engage antigen in the absence of B7 expression and co-stimulations then the Tcell becomes irreversibly anergic instead of activated. this is one mechanism by which T cell tolerance may be achieved
an adjuvant enhances the effectiveness of vaccines by inducing the expression of ______ on _______
costimulatory molecules on dendritic dells
Three main classes of effector T cells are specialized to deal with different classes of pathogens and produce cytokines. Name 3 classes, describe how antigen is recodnized & effector functions for each & give one example.
1. Cytotoxic T cells: recognize antigen on surface of a cell that is presenting antigen bound to MHC class 1 molecules. it responds by killing these target cells and inducing the apoptotic pathway. antigens are derived from proteins from pathogens replicating in the cytosol of the target cell
2. TH1: recognize antigen bound to MHC class II molecules on the surface of an APC. they respond by activating the macrophage to destroy intravesicular bacteria and increase the phagocytosis of extracellular bacteria it has taken up. typical antigens are proteins from bacteria that live in the vesicles of macrophages
3. TH2: recognize antigen bound to MHC class II molecules on surface of B cells . they respond by secreting cytokines that will activate B cells to differientiate into antibody producing plasma cells. antigens are derived from protein components of pathogens circulating in the blood or tissue fluids.
virus infected cells attacked and killed by effector cytotoxic T cells are often surrounded by healthy tissue which is spared from destruction. Explain the mechanism that ensures that cytotoxic t cells kill only target cells.
1. they focus their killing machinery on target cells through polarization.
2. the cytoskeleton and the cytoplasmic vesicle containing lytic granules are oriented toward an area on the target cell where MHC class I:peptide complexes are engaging T cell receptors.
3. in the T cell the microtubule-organizing center, golgi, and lytic granules (that contain cytotoxins) align toward target cells.
4. the lytic granules then fuse with the cell membrane releasing their contents into the small gap between the T cell and the target cell resulting in the deposition of cytotoxins on the surface of the target cell.
5. the cytotoxic t cell is not killed in this process & will continue to make cytotoxins for release onto other target cells which kills numerous target cells in a localized area.
what cytotoxins do Tc cells produce?
molecules that induce apoptosis (programmed cell death) of the target cell
what are some features of regulatory T cells?
1. T reg express CD8 and control effector cells by inducing apoptosis
2. By interacting with dendritic cells in secondary lymphoid tissue, T reg prevent the interaction and activation of naive T cells
3. T reg secrete TGF-B and supress effector T cell function
what is the roll of the CD3 complex in signal transduction pathway leading from the T cell receptor?
the CD3 subunits associated with antigen binding T cell receptor help transmit the signal from the T cell receptor peptide MHC interaction at the cell surface into the interior of the cell through ITAMs present on their sytoplasmic tails. These are phosphorylated by associated protein tyrosine kinases (like Fyn) when the antigen receptor is activated and in turn activate further molecules of the signaling pathway
what is the role of protein tyrosine kinase Lck in signal transduction pathway leading from the T cell receptor?
associates with tails of CD4 and CD8 coreceptors. when they participate in binding to peptide:MHC complexes, Lck is activated and phosphorylates ZAP-70
what is the role of CD45 in the signal transduction pathway leading from the T cell receptor
cell surface protein phosphatase that helps activate Lck and other kinases by removing inhibitory phosphate groups from their tails
what is the role of ZAP-70 in the signal transduction pathway leading from the T cell receptor
when phosphorylated it inds to phosphorylated ITAMS of (zi) chain which initiates the signal transduction cascade by activating phospholipase C-gamma and guanine-exchange factors
what is the role of IP3 in the signal transduction pathway leading from the T cell receptor
once produced by the action of PLc gamma on membrane inositol phospholipids it causes an increase in intracellular Ca levels which leads to the activation of the protein calcineurin
what is the role of calcineurin in the signal transduction pathway leading from the T cell receptor
activates NFAT by removing an inhibitory phosphate group. activated NFAT enters the nucleus and together with NfkB and AP-1 it will initiate the transcription of genes that lead to Tcell proliferation and differentiation
antigen recognition by T cells in the absence of co-stimulation results in ________
what is the morphology of a granuloma? what type of infection leads to granuloma formation? why is it actually beneficial to the host?
1. center macrophages and giant multinucleated cells created by macrophage fusion infected with bacteria that are replicating intracellulary. epitheloid cells surround the core which consists of non-fused macrophages. epithelioid cells are surrounded by activated CD4 Tcells
2. chronic infections that are resistant to macrophage killing mechanisms
3. granulomas surrounded by CD4 T cells cut off infection from blood supply and the cells in the granuloma core will die from oxygen deprivation and toxic products of the macrophages (ie. tuburculosis)
B cells are activated by CD4 TH2 cells only if both cell types recognize the same antigen. The same epitope does not need to be shared...why?
Many bacteria are surrounded by a polysaccharide capsule & in some cases Ab against the capsular polysaccharides give protective immunity against the pathogen which are generally restricted to the IgM isotype because the help needed to switch to IgG is provided by T cells which recognize only peptide antigens.
Adult humans make effective immune responses to polysaccharides of encapsulated bacteria & their antibody responses are polysaccharide-specific T cell independant and involve antibodies of the IgM isotype.
children do not make effective immune responses to polysaccharides alone & cannot be immunized with such vaccines.
if the polysaccharide is conjugated to protein then peptides from the protein part of the molecule activate specific Th2 cells. B cells specific for polysaccharide will bind & internalize the antigen via their receptors, process it & present its peptides on their surface. T cells specific for these peptides interact with B cell delivering the necessary cytokines and CD40-CD40-ligand signal required for isotype switching. The B cell with then produce igG anti-polysaccharide antibodies.
what is an example of a conjugated vaccine used to stimulate the synthesis of IgG antibody against H. influenzae B polysaccharide?
conjugate vaccine is composed of capsular polysaccharide conjugated to tetanus or diphtheria toxoid. The Ab response is polysaccharide specific, T cell dependant, & comprises igG that protects children from the meningitis caused by this microorganism.
cross-linking of immunoglobulin by antigen is essential but not always sufficent to initiate the signal cascade for Bcell activation. stimulation of additional receptors is also necessary for the full activation and differientiation of naive B cells. Describe these receptors and their ligands & outline how they help activate the B cell.
B-cell coreceptor made of CD21, CD19, and CD81 cooperate with Bcell receptor and B cell activation and increases the sensitivity of the B cell to antigen 1,000-10,000 fold. This becomes important when concentrations are low. CD21 binds to complement components that have been deposited on the surface of pathogens. CD19 provides the long cytoplasmic tail involved in signaling. When the co-receptor and Bcell receptor and co-receptor are both ligated by antigen and C3d. Lyn is a protein tyrosine kinase bound to the ITAMs of Iga which phosphorylates CD19 when it is nearby. The phosphorylated CD19 tail will initiate activation signals that complement those generated by the Bcell receptor complex.
Depending on the characteristics of the antigen an additional signal provided by CD4 Th2 cells may be needed for Bcell activation. Th2 cells express CD40 ligand on their surface which binds to CD40 on B cell and delivers a stimulatory signal. They also secrete cytokines IL-4, IL-5, and IL-6. By binding to specific receptors these help stimulate B cells to proliferate and differientiate into plasma cells
explain the difference between thymus dependant (TD) and thymus independent (TI) antigens
TD antigens can only induce the generation of antibodies by B cells when T-cell help is available
they induce immnological memory as well as affinity maturation after somatic hypermutation
TI antigens are able to induce antibodies in the absence of Tcell help even in patients who lack a thymus
because of the absence of tcell cytokines in the response to antigens these antigens do not induce isotype switching or somatic hypermutation to any great extent
TI antibody response does not undergo affinity maturation
immunological memory is also not produced
give an example of a type 1 thymus independant antigen and type 2 (TI-1 & TI-2) and describe how such antigens bypass the requirement for Tcell help.
TI-1 antigens are bacterial LPS of gram-neg bacterial cell walls and DNA
they not only engage the B cell receptor and coreceptor but also bind to other activating cell surface receptors like TLR and thus provide additional activating signals that drive Bcells to proliferate & differentiate into plasma cells
in the absence of Tcell cytokines needed for isotype switching only igM antibodies are made
TI-2 antigens are highly repetitive protein or carb epitopes on the surface of pathogens.
Bcells respondinto to TI-2 antigen are often B-1 cells & both IgM and IgG antibodies can be produced
predominately IgM is made
TI-2 antigens by-pass the requirement for T-cell help because the number of Bcell receptors occupied by these antigens is very high and cross linking is efficent
generating strong signals from Bcell receptor
Some molecules seem to act as TI-1 antigens when part of a bacterial surface but need Tcell help if purified & administered on their own... explain...
A B-cell might bind one component of the bacterial cell surface antigen A with its B-cell receptor and another component like LPS with a TLR
together the signals from the receptors activate the B-cell to differentiate into plasma cells producing antibody against antigen A
if antigen A is administered on its own the signal from the TLR will be absent and the Tcell help would be needed to provoke the production of anti-A antibody
T/F: Plasma cells produce secreted antibody, proliferate and undergo somatic hypermutation to produce antibodies with a higher affinity for antigen
False: a plasma cell is a terminally differientated Bcell that is not dividing and cannot change its Ab specificity
somatic hypermutation & selection of B cells with higher-affinity immunoglobulin receptors occur in activated B cells before they differentiate into plasma cells
T/F: An immunodeficency called hyper IgM syndrome is characterized by lack of CD40 ligand expression on Tcells
T/F: Antibody dependant cell mediated cytotoxicity (ADCC) is mediated by NK cells which use their Fc receptors to bind to antibody-coated target cells which they kill through inducing apoptosis
T/F:TI-2 polysaccharide antigens are commonly used in vaccines administered to infants bc they stimulate strong Ab responses
False: T1-2 polysaccharide antigens activate only mature B cells
often the Bcells are B-1 cells that do not aquire full function until a child is 5yrs old
TI-2 antigens therefore do not stimulate efficent antibody responses to infants
What is the main effector function of IgM? why is it efficent in preventing blood born infections & fixing complement but less efficent than other Ab classes in inducing phagocytosis of immune complexes?
CD40 ligand on Tcells binds to CD40 on Bcells signaling B cells to activate NfkB
NFkB is a transcription factor that upregulates the expression of ICAM-1 (adhesion molecule) on Bcell surface
ICAM-1 prolongs interaction btw the Bcell and Tcell which traps the Bcell in the Tcell zone
causes a primary focus of proliferating Bcells to form
What are characteristics of follicular dendritic dells in the primary follicals of secondary lymphoid tissue
1. They provide a stable depository of intact antigens able to bind to Bcell receptors
2. They have a large surface area as a result of forming dendrites
Explain why poly-Ig receptor transports dimeric IgA antibodies across cellular barriers and what type of barriers are involved?
what are the final locations of the transported material?
dimeric IgA is made in MALT and is transported across the barrier of the mucosal epithelium:
1. the dimeric IgA binds to the poly-Ig receptor on the basolateral surface of an epithelial cell
2. uptake through receptor mediated endocytosis into an endocytotic vesicle
3. on reaching the opposite face of the cell the the vesicle fuses with the membrane
4. here the poly-Ig receptor is cleaved proteolytically btw the membrane-anchoring & the IgA-binding regions
5. releases IgA into the mucous layer on the surface of the epithelium
6. Dimeric IgA remains attached to a small piece of the poly-Ig receptor (secretory component) which holds the IgA at the epithelial surface through interactions with molecules in the smucus
7. The rest of the poly-Ig receptor is degraded and serves no further purpose
Dimeric IgA is released into the lumen of the GI, GU, and respiratory tract, onto the surface of the eyes, into the nose & throuat, & into breast milk
what is the main effector function of IgM?
The main effector function of IgM is complement activation but it can also neutralize pathogens and toxins
why is IgM efficent at preventing blood borne infections?
IgM is the first Ab to be produced by plasma cells during a primary Ab response & is secreted as a pentamer that circulates in the blood
large size of pentamer causes it to not penetrate effectively into infected tissue
most effective against pathogens in the blood stream
why is IgM efficent in fixing complement?
in the classical pathway of complement activation, at least two Fc regions are needed to bind C1 which is the first complement component in pathway
a single pentameric molecule of IgM can initiate complement activation
two IgG antibodies in close proximity to each other are needed to bind C1
Why is IgM less efficent than other antibody classes in inducing phagocytosis of immune complexes?
phagocytotic cells carry both complement receptors and Fc receptors for IgG and IgA
there are no Fc receptors for IgM
immune complexes of IgM and Ag alone cannot be taken up by macrophages through Fc receptor mediated endocytosis
IgM:Ag:C3b complex can be phagocytosed by a macrophage after binding to complement receptors but is not as efficent as having both complement and Fc receptors cooperating to induce phagocytosis
Explain how the receptor FcRn transports IgG antibodies across cellular barriers, the type of barrier involved, & the final location of the transported material
IgG antibody binds to FcRn in the membranes of endothelial cells in blood capillary walls and is transported by receptor mediated transcytosis from the blood into the extracellular spaces in tissues
IgG binds two FcRn molecules on the aical side of the endothelium in the lumen of the capillary
followed by receptor-mediated endocytosis into an endocytic vesicle
on reaching the basal surface of the endothelial cell, the vesicle fuses with the membrane and IgG is released into the extracellular space
IgG is transported into infected tissues and is also transported across placenta into the fetal circulation during pregnancy
What are the similarities between the activation of mast cells and NK cells via FceRI and Fc(gamma)RIII?
1. activation of both mast cells and NK cells occurs only when their Fc receptors are bound to antigen:antibody complexes
2. when cross-linking occurs both mast cells and NK cells release the contents of granules through exocytosis which involves the fusion of vesicles containing preformed proteins within the cell membrane
What are the differences between mast cells and NK cells via FceRI and Fc(gamma)RIII?
1. mast cells bind IgE whereas NK cells bind IgG
2. exocytosis of granules from mast cells occurs at random around the cell membrane
exocytosis of granules from NK cells is highly polarized focusing on the target cell to minimize damage to neighboring cells
3. IgE binds to FceRI with high affinity in the absence of antigen & mast cells become activated when antigen becomes available and binds to the receptor bound IgE
NK cells bind IgG with low affinity and bind IgG effectively when it is already bound to multivalent antigen
4. Activated mast cells release inflammatory mediators that affect other cells
activated NK cells release apoptosis-inducing compounds that kill target cells directly
5. AB dependent cell mediated cytotoxicity (ADCC) carried out by NK cells could be induced in newborn infants by maternal IgE aquired transplacentally
IgE cannot be transferred across the placenta and so newborn babies cannot activate mast cells via maternal IgE
***Decribe the course of events that results in the swolen lymph nodes characteristic of many infections:
B lymphocytes that have bound specific antigen and encountered their cognate T cells in the Tcell area of a lymph node are activated and start to proliferate forming a primary focus.
the B cells move from the primary foci into primary follicles whicha re primarily B cell areas where they become centroblasts (large metabolically active dividing cells)
as centroblasts accumulate and proliferate the primary folical enlarges and changes morphologically into a germinal center
centroblasts undergo somatic hypermutation while dividing in the germinal center producing centrocysts with mutated surface Ig
only cells with mutated surface Ig that can take up antigen efficently through receptor-mediated endocytosis and present it to Th2 cells will be selected to differentiate into plasma cells or memory cells
antigen will be encountered at the surface of follicular dendritic cells as an immune complex
if B cells do not encounter their specific antigen they will undergo apoptosis and then be ingested and cleared by tingible body macrophages
this process takes around 7 days after an infection begins and the increase in cell numbers due to lymphocyte proliferation accounts for swolen lymph nodes
What is meant by the term "passive immunity" and how is it achieved?
the transfer of preformed immunity from one immune subject to a nonimmune subject
can be achieved by transfering whole serum, purified Ab, monoclonal Ab, or intact effector or memory lymphocytes
What are the isotype of antibodies involved in placental transfer? and why are they important?
IgG antibodies transported transplacentally provide protection in the bloodstream and extracellular spaces of tissues until the baby can begin making its own antibodies...then maternal IgG levels decrease
IgG1 is the isotype that is transported most effectively
What are the isotype of the antibodies involved in transfer into breast milk? and why are they important?
IgA is transfered into the infants GI tract in breast milk and protects the GI epithelia from colonization and ivasion by ingested microorganisms
is it possible for a pregnant mother with an autoimmune disease to transfer autoreactive antibodies to the developing fetus?
its possible for auto reactive antibodies to be transfered passively to a fetus via the placenta if the isotype is IgG
any reaction will persist only for as long as the antibodies are present
maternal antibodies can be removed by plasmapheresia (procedure that involves replacing blood plasma and consequently the removal of maternal immunoglobulins)
they will eventually be degraded by serum proteins
What is the origin of the secretory component and its significance after the release of dimeric IgA from the apical face of the gut epithelium?
During transcytosis the poly-Ig receptor is cleaved by a protease leaving a small piece of the original receptor (secretory component) still bound to the J chain during disulfide bonds
Once dimeric IgA is released at the apical face the carbohydrate moieties of the secretory component anchor the antibody to mucins of the mucus which enables the antibodies to bind to microbes in the mucus and inhibit the ability of microbes
instead the microbe is expelled from the body via mucosal secretions in the feces
How does IgE induce the forcible ejection of parasites and toxic substances from the respiratory and gastrointestinal tracts?
when IgE binds to antigen it leads to crosslinking of FceRI on mast cells in connective and mucosal tissues
mast cells rapidly release chemicals that activate smooth muscle to contract
muscle activity leads to vomiting, coughing and sneezing in the respiratory tract, diarrhea in the GI tract, which helps to expel the offending pathogen or toxic material
Why would it be inadvisable for a mother who has recently given birth to move with her newborn to a foreign country where there are endemic diseases not prevalent in her homeland?
Maternal IgG is passed transplacentaly and dimeric IgA is passed through breast milk
if an endemic infection develops in the newborn the IgG in the infants bloodstream may not have the appropriate specificity for the foreign antigens because the mother would not have encountered these antigens previously
therefore the newborn would not have immunity
without maternal IgG infants are particularly suceptible during the first 6 months of life because their immune system is unable to produce IgG
infections that breach mucosal surfaces may be more likely to develop during this time because dimeric IgA against the pathogen will not be formed in the breast milk until about a week after the mothers exposure
How does bispecificity arise in IgG4? and what is the consequence of the product?
One heavy chain and one light chain of IgG4 molecule can exchange with a similar module from a different IgG4 molecule
creates an antibody that has two different Ag binding sites
This Ab is monovalent for its specific antigens
functions that require two identical Ag-binding sites are comprised
Although IgG4 is able to neutralize pathogens to some extent its function also seems to be to interfere with certain immune responses and help to reduce their serverity
how do secondary lymphoid tissues of the mucosa simular to secondary lymphoid tissues elsewhere in the body?
Mucosal secondary lymphoid tissues have the same general microanatomy and organization as secondary lymphoid areas in other locations
they have distinct B and T cell zones
Both have sites where naive lymphocytes are activated by antigen and adaptive immune responses are initiated
how do secondary lymphoid tissues of the mucosa different from secondary lymphoid tissues elsewhere in the body?
In the systemic immune system: adaptive immune responses are activated in secondary lymphoid tissues that are distinct from the site of the infection
in mucosal immune system: the adaptive immune response is initiated at secondary lymphoid tissues at the site of the infection
Why do children that have their tonsils or adenoids removed respond less effectively to the oral polio vaccine than children who still have these tissues?
Tonsils and adenoids are located in the oral cavity and are composed of extensive secondary lymphoid tissue making up Waldeyers ring
they are responsible for the production of secretory IgA specific for infectious material entering the gut and airways
oral polio vaccine elicits the most effect protective immunity through the production of secretory IgA including the secondary lymphoid tissues of Waldeyers ring
What are two ways that dendritic cells capture antigen from the intestine for presentation to T lymphocytes?
1. M-cell dependent capture relies on transcytosis of microorganisms across the gut epithelium into pockets containing dendritic cells
dendritic cells then process and present antigens to T lymphocytes in either the T cell area of Pyers patches or the mesenteric lymph node
2. M-cell independant capture occurs in the lamina propria as a result of dendritic cells extending cytoplasmic process between intracellular enterocyte junctions
Antigen is taken up by these and processed, and the dendritic cell then presents antigens to T cell in GALT or mesenteric lymph nodes
How are macrophages in the intestinal mucosa similar to macrophages in other areas?
intesinal macrophages are able to phagocytose and kill bacterial pathogens
How are macrophages in intestinal mucosa different from macrophages in other places?
Macrophages do not stimulate inflammatory responses because they lack TLRs and signaling receptors required for activation pathways leading to inflammatory cytokine production.
What is the route that peyers patch-activated T lymphocyte follows beginning in a high endothelial venule and ending in the lamina propria?
1. Chemokines CCL21 & CCL19 is synthesized in Peyer's patches bind to CCR7 on naive T cells and recruit them into the lymphoid tissue across a high endothelial venule
2. T cells bearing appropriate antigen-specific receptors are stimulated by dendritic cells and undergo proliferation and differentiation within the peyers patches
3. Activated T cells then leave the peyers patch and enter the lymph, travel to mesenteric lymph nodes before arriving at the thoracic duct & then enter the bloodstream
4. homing process is mediated by expression of appropriate integrin and chemokine receptors
5. they cross the vascular endothelium into the lamina propria
6. cytokine secretion and mediate killing
What are four locations where secretory IgA can bind to antigens in mucosal tissue and what is their fate upon binding?
1. lamina propria: transcytosis to mucosal layer
2. endosomal compartment: neutralization of endocytoses antigen
3. Mucosal layer: neutralization of antigen at mucosal surfaces
4. M-cell surface: transport to secondary lymphoid tissue
What enables breast milk to contain antibodies against microorganisms encountered in the gut or other mucosal tissues?
B cells activated in the gut or mucosal tissue can home to the lactating mammary glands and secrete dimeric IgA into breast milk
lymphocytes activated in one mucosal tissue can recirculate to another one as well as to the tissue that they were activated in
because lymphocytes activated in mucosal tissue carry integrins that bind to the vascular addressin MAdCAM-1 which is expressed on the walls of blood vessels serving different types of mucosal tissues
Why do individuals who have selective IgA deficency not succumb to repeated infection through mucosal surfaces?
What are four actions of Th2 effector cells that provide protection from intestinal helminths and lead to expulsion of the parasites from the GI tract.
1. IL-13 enhances epithelial cell turnover and sloughing of parasitized epithelial cells
stimulates goblet cells to produce mucus which then interferes with adhereance of helminths to mucosal surfaces
2. IL-5 attracts eosinophils and activates them to secrete major basic protein which is cytotoxic to helminths
eosinophils can attack parasites directly when their Fc receptors are cross linked by parasites that have become coated with antibody (especially IgE)
eosinophil pours out toxic granule contents directly onto the parasite surface
3. IL-4 is produced when they interact with target B cells, stimulates B cells to switch to production of IgE
antiparasite IgE antibodies produced bind to high-affinity Fce receptors on mast cells
cross linking of bound IgE by parasite antigens activates mast cells to release chemical mediators that help to eliminate the parasite
histamine: causes contraction of smooth muscle
TNF- alpha: activates epithelium and enables recruitment of additional effector leukocytes
matrix metalloproteinase: helps reodel the mucosa
4. IL-3 & IL-9 attract mast cells to site of parasite infection
What are 2 reasons why memory B cells respond more quickly than naive B cells to antigen?
1. In a secondary immune response there are 10-100 times more antigen specific memory B cells participating in the immune response
these B cells have undergone isotype switching and somatic hypermutation and so they have higher affinity B cell receptors that respond to lower levels of antigen
activated memory B cells differentiate into plasma cells more quickly than naive B cells do
they can produce antibodies as soon as 4 days after antigen is encountered
2. Memory B cells make stronger cognate interactions with class II and B7 co-stimulatory molecules on the memory B cell surface
What are two reasons why memory T cells respond more quickly than naive T cells to antigen?
1. they have different recirculation patterns from naive T cells
they can enter peripheral tissues without the need for previous activation in secondary lymphoid organs & can enter peripheral tissues without the need for previous activation in secondary lymphoid organs and can be activated at sites of infection in peripheral
2. they do not require co-stimulation via CD28-B7 interaction to differentiate into effector T cells
do not need to wait for activation of antigen presenting cells and production of co-stimulatory molecules before coming activated
Why do only memory B cells participate in secondary immune responses to particular pathogens and why is it advantagous?
Naive B cells carry the inhibitory Fc receptor Fc(gamma)RIIB1.
Complexes composed of antigen and IgG produced in the primary response or by reactive memory cells
cross link Fc(gamma)RIIB1 and B cell receptor supresses naive B-cell activation
Memory B cells do not carry the Fc(gamma)RIIB1 receptor and so they are not inhibited in this way
Supression of Naive B cells means that only reactivated memory B cells that have already undergone isotypic switching and somatic recombination make antibodies
All antibodies are high affinity and primarily IgG, IgA, or IgE isotypes.
Supression of naive B cells estimates repetition of the events that took place in the primary immune response
If not inhibited this could lead to the production of low affinity IgM antibodies rather than high affinity
isotype-switched antibodies are more effective in removing pathogens
***Why is supression of naive B cells in secondary immune responses advantageous for fighting measles but not for fighting influenza?
The measles virus is a relatively invariant pathogen with little antigenic change
Antibodies made by memory B cells will be more effective because of isotype switching and somatic recombination
Influenza virus is highly mutable
Memory response and suppression of naive B cells restrict antibody production to only epitopes shared by infecting strain and origional strain.
over time influenza viruses expresses a limited number of epitopes that are able to activate memory B cells and new epitopes will lack the capacity to stimulate naive B cells
How does immunological memory operate in short term and long term?
Short-Term: immunological memory operates shortly after an adaptive immune response has cleared the infection in an individual and while the pathogen is still present in the community
if the individual is reexposed and reinfected then antibodies generated in the first round of infection can bind immediately to pathogen which blocks its activation by neutralizing and mediating its removal and destruction by complement fixation and phagocytosis
Any remaining effector T cells or activated B cells can respond right away to antigen presence.
this ensures that infection wont reestablish itself and also generate a new supply of antibodies and effector cells
Long term: mediated through long lived memory lymphocytes which are generated in the primary immune response
these cells can be rapidly stimulated by reexposure to the same antigen to produce a strong and effective immune response that rapidly clears the pathogen.
Describe the ligand for NK cell receptor CD94:NKG2A and why is the concentration of this ligand on the target cell an effective measure of the presence or absence of classical MHC class 1 molecules?
The ligand for CD94:NKG2A is nonclassical MHC class molecule HLA-E bound to conserved peptides derived from the leader sequence of the heavy chains of classical MHC class 1 molecules HLA-A, -B, & -C
The ligand will be produced only if there is a steady supply of HL-A, -B, & -C heavy chains in the cell.
If the supply of these proteins is interupted then leader peptides will not be provided in the lumen of the ER for binding to HLA-E so it will be retained in the ERand its levels on the cell surface will decrease