Memory and Vaccines

Secondary Response X pool of effector pathogen specific cells capable of iX response Pathogen specific antibodies are X present in X IgX (or in mucosal sites IgX/IgX) are produced and have X affinity for pathogen (IgX, X, X > IgX) X threshold for activation = X pathogen burden Effector cells are present and X enter the tissue and proliferate Innate and adaptive immune responses work together X

Secondary Response Larger pool of effector pathogen specific cells capable of immediate response Pathogen specific antibodies are already present in serum IgG (or in mucosal sites IgA/IgE) are produced and have HIGH affinity for pathogen Low threshold for activation = low pathogen burden Effector cells are present and immediately enter the tissue and proliferate Innate and adaptive immune responses work together immediately

T-independent antigens include cX, lX, and nX aX. Will you get memory cells?

NO

1. As a naïve cell becomes an effector cell, IL-X receptor expression is decreased OR increased. This is important, as we discussed above when you activate T cells and they proliferate you eventually need them to die to conclude the immune response. So you need to make the activated T cells fairly X lived but you do need to maintain some for in case you ever encounter the antigen again. 2. Activated effector cells rely on IL-X for survival while memory cells rely on IL-X. As a naïve T cell is activated it reduces expression of IL-XR and increases expression of IL-X receptors because IL-X is not as plentiful as IL-X during an iX response. In this way the effector T cell becomes more dependent on IL-X than IL-X. 3. IL-X diminishes as the immune response ends and IL-X is again the predominant available survival cytokine. As the immune response ends, less IL-X will be available and what little IL-X there is will be taken up by T X cells that express significant amounts of IL-X receptor. Effectively, these cells will starve to death. However, memory cells are special. As they are induced they maintain high expression of IL-XR and have very little expression of IL-XR. This is enough to keep them alive during the immune response but does not make them reliant on IL-X long term. Therefore, when the immune response ends and IL-X is no longer plentiful they can return to relying on IL-X for survival which will allow them to proliferate for homeostatic turn over.

1. As a naïve cell becomes an effector cell, IL-7 receptor expression is decreased. This is important, as we discussed above when you activate T cells and they proliferate you eventually need them to die to conclude the immune response. So you need to make the activated T cells fairly short lived but you do need to maintain some for in case you ever encounter the antigen again. 2. Activated effector cells rely on IL-2 for survival while memory cells rely on IL-7. As a naïve T cell is activated it reduces expression of IL-7R and increases expression of IL-2 receptors because IL-7 is not as plentiful as IL-2 during an immune response. In this way the effector T cell becomes more dependent on IL-2 than IL-7. 3. IL-2 diminishes as the immune response ends and IL-7 is again the predominant available survival cytokine. As the immune response ends, less IL-2 will be available and what little IL-2 there is will be taken up by T regulatory cells that express significant amounts of IL-2 receptor. Effectively, these cells will starve to death. However, memory cells are special. As they are induced they maintain high expression of IL-7R and have very little expression of IL-2R. This is enough to keep them alive during the immune response but does not make them reliant on IL-2 long term. Therefore, when the immune response ends and IL-2 is no longer plentiful they can return to relying on IL-7 for survival which will allow them to proliferate for homeostatic turn over.

3 mechanisms of T regulatory cell mediated suppression of immune responses: 1. Secretion of iX/tX cytokines 2. Targeting X 3. Metabolic disruption of cell grown --> IL-X and aX starvation

3 mechanisms of T regulatory cell mediated suppression of immune responses: 1. Secretion of inhibitory/tolerogenic cytokines 2. Targeting APCs 3. Metabolic disruption of cell grown --> IL-2 and adenosine starvation

4 main functions of the Adaptive Immune Response: 1. Distinguish X from X: Through CX TX mechanisms 2. AX: Recall that T cells and B cells proliferate rapidly following antigen encounter. This is called CX EX. 3. EX Function: T helper cells have a variety of subsets that produce different X and other soluble factors that influence the type of immune response made to different pathogens, including the X of antibodies that will be made by differentiated B cells that have become antibody secreting plasma cells. 4. RX. After a pathogen has been defeated we need to stop the immune response to end the X and return to a state of hX. This is known as CX and is controlled by regulatory processes within the immune response. When these mechanisms fail the result is cX iX diseases like X disease and X. Regulation inhibits aX

4 main functions of the Adaptive Immune Response: 1. Distinguish Self from Non-self: Through Central Tolerance mechanisms 2. Amplification: Recall that T cells and B cells proliferate rapidly following antigen encounter. This is called Clonal Expansion. 3. Effector Function: T helper cells have a variety of subsets that produce different cytokines and other soluble factors that influence the type of immune response made to different pathogens, including the isotypes of antibodies that will be made by differentiated B cells that have become antibody secreting plasma cells. 4. Regulation. After a pathogen has been defeated we need to stop the immune response to end the inflammation and return to a state of homeostasis. This is known as Contraction and is controlled by regulatory processes within the immune response. When these mechanisms fail the result is chronic inflammatory diseases like autoimmune disease and allergies. Regulation inhibits autoimmunity.

Active can be: 1. IX a. killed X bacterium or virus b. X of bacterium or virus c. pX or pX d. tX (vaccines against toxins like X) e. VLP OR 2. Live-Hybrid virus a. AX mutants - less OR more pathogenic i. Limited X range ii. TX sensitive iii. CX-adapted iv. GX manipulated b. VX strains - not as pathogenic 3. DNA - pure, naked DNA

Active can be: 1. Inactivated a. killed whole bacterium or virus b. subunit/piece of bacterium or virus c. peptide or polysaccharide d. toxoid (vaccines against toxins like tetanus) e. VLP OR 2. Live-Hybrid virus a. Attenuated mutants - less pathogenic i. Limited host range ii. Temperature sensitive iii. Cold-adapted iv. Genetically manipulated b. Virulent strains - not as pathogenic 3. DNA - pure, naked DNA

Active immunity is induced X of natural infection.

Active immunity is induced outside of natural infection.

Active immunity: People are vaccinated with X or X virus. Live viruses can X. Inactivated vaccines or killed vaccines are viral vaccines in which the virus does X replicate. In this way a patient can receive the strength and X term protection associated with "X infection" with OR without getting sick. Vaccines should elicit an X response similar to that produced by the X infection including immunologic mX, without causing the X associated with the microbe. Protection usually occurs from production of antigen-specific X and X mediated immunity. You need to choose a strain that will give enough X to create a strong immune response, but not a strain that is so strong that the patient will get X. There is only one vaccination that we look at for X cell mediated immunity. This is a vaccine against M. X. It is OR is not given in the US but is prevalently given in S. In this case the vaccine is to a related organism Bacillus Calmette -Guerin (BCG). Remember that M. tuberculosis is an Xcellular organism, so antibodies will OR will not be very effective so instead we make a strong X cell response to BCG which can confer some T cell mX response that will be protective against M. tuberculosis. Strong T cell response means X are produced that contribute to macrophage X and control of tuberculosis.

Active immunity: People are vaccinated with live or inactivated virus. Live viruses can replicate. Inactivated vaccines or killed vaccines are viral vaccines in which the virus does NOT replicate. In this way a patient can receive the strength and long term protection associated with "natural infection" without getting sick. Vaccines should elicit an immune response similar to that produced by the natural infection including immunologic memory, without causing the illness associated with the microbe. Protection usually occurs from production of antigen-specific antibody and cell mediated immunity. You need to choose a strain that will give enough stimulation to create a strong immune response, but not a strain that is so strong that the patient will get sick. There is only one vaccination that we look at for T cell mediated immunity. This is a vaccine against M. tuberculosis. It is not given in the US but is prevalently given in Europe. In this case the vaccine is to a related organism Bacillus Calmette -Guerin (BCG). Remember that M. tuberculosis is an intracellular organism, so antibodies will not be very effective so instead we make a strong T cell response to BCG which can confer some T cell memory response that will be protective against M. tuberculosis. Strong T cell response means cytokines are produced that contribute to macrophage activation and control of tuberculosis

Anergy (CTLA-4) Cause: X Stimulation Signals received: Signal X in the absence of signal X OR engagement of X Timeline: X Proliferation: X Effector Function: X to X Primed Properly: Yes or No (signal X with no signal X or signal 2 replaced with X)

Anergy (CTLA-4) Cause: Suboptimal Stimulation Signals received: Signal 1 in the absence of signal 2 OR engagement of CTLA-4 Timeline: Days Proliferation: Low Effector Function: none to low Primed Properly: No

As you will see in the next session on hypersensitivity, these mechanisms can be used to inappropriate responses contracting immune after a pathogen has been cleared as we are discussing in this session. The table to the left describes how these peripheral tolerance mechanisms are used to distinguish between self-antigens, which the body should remain X to, and foreign antigens which it needs to be X.

As you will see in the next session on hypersensitivity, these mechanisms can be used to inappropriate responses contracting immune after a pathogen has been cleared as we are discussing in this session. The table to the left describes how these peripheral tolerance mechanisms are used to distinguish between self-antigens, which the body should remain tolerant to, and foreign antigens which it needs to attack.

Peripheral Immune Regulation At this point we have a fully developed immune response that is doing major damage against the pathogen and potentially our own cells. This will include recruitment of nX, activation of mX, cX proteins, trafficking and activation of X cells, and production of X by plasma cells within the X lymph node. How can we possibly stop this? The way to stop this is the X tolerance mechanisms. These mechanisms will first X the immune response then eventually lead to X of the majority of the cells that responded. There are three main mechanisms: 1. Clonal aX/eX 2. T X cells 3. Clonal X All of these work X to ensure the end of an immune response and will largely result in the X of most of the cells involved in combatting the pathogen.

At this point we have a fully developed immune response that is doing major damage against the pathogen and potentially our own cells. This will include recruitment of neutrophils, activation of macrophages, complement proteins, trafficking and activation of T cells, and production of antibodies by plasma cells within the draining lymph node. How can we possibly stop this? It's a little like trying to stop a train speeding down the track. The way to stop this is the peripheral tolerance mechanisms. These mechanisms will first slow the immune response then eventually lead to death of the majority of the cells that responded. There are three main mechanisms: Clonal anergy/exhaustion, T regulatory cells, and clonal deletion. All of these work together to ensure the end of an immune response and will largely result in the death of most of the cells involved in combatting the pathogen.

B Cell Peripheral Tolerance: Self-Antigen and B-cell there are 4 outcomes: 1. AX 2. Clonal X or X (kills off cells with X specificity) 3. IX receptors 4. Lymph Node X

B Cell Peripheral Tolerance: Self-Antigen and B-cell there are 4 outcomes: 1. Anergy 2. Clonal Death or apoptosis (kills off cells with same specificity 3. Inhibitory receptors 4. Lymph Node Sequestration

Both Memory T and B cell Responses Occur Quickly Upon Secondary Exposure and are Long Lasting On secondary exposure: 1. X lag time 2. X magnitude of response 3. Cells are X rapidly following clearance of antigen but there is always a X Memory B cells live for X years (X booster needed every 10 days) Memory T cells live X-X years

Both Memory T and B cell Responses Occur Quickly Upon Secondary Exposure and are Long Lasting On secondary exposure: 1. Shorter lag time 2. Higher magnitude of response 3. Cells are terminated rapidly following clearance of antigen but there is always a remnant Memory B cells live for 10 years (Tdap booster needed every 10 days) Memory T cells live 20-25 years

What are the chemokines normally used by B cells to get into the lymph node?

CCR7 and CCL21

CTLA-4 (Cytotoxic T lymphocyte- associated protein 4): During an active immune response CDX binds to BX molecules on the antigen presenting cell to provide signal X and activate the X cell. B7 molecules are upX on antigen presenting cells that have encountered antigen making the amount of B7 molecules on APCs plentiful as long as X remains plentiful. However, as T cells become activated they also begin to express a molecule X. While ligation of CD28 by B7 molecules provides an X signal to the T cell telling it to respond, ligation of CTLA- 4 by B7 molecules actually provides an X signal to the T cell inducing X. CTLA-4 binds the B7 molecules with a X higher affinity than CD28 binds B7. Therefore, as B7 molecules become limiting X is more likely to engage B7 than CDX. Therefore, as antigen becomes limiting the X signal is more likely to be engaged than the X signal so the cell will be made X.

CTLA-4 (Cytotoxic T lymphocyte- associated protein 4): During an active immune response CD28 binds to B7 molecules on the antigen presenting cell to provide signal 2 and activate the T cell. B7 molecules are upregulated on antigen presenting cells that have encountered antigen making the amount of B7 molecules on APCs plentiful as long as antigen remains plentiful. However, as T cells become activated they also begin to express a molecule CTLA-4. While ligation of CD28 by B7 molecules provides an activating signal to the T cell telling it to respond, ligation of CTLA- 4 by B7 molecules actually provides an inhibitory signal to the T cell inducing anergy. CTLA-4 binds the B7 molecules with a 20x higher affinity than CD28 binds B7. Therefore, as B7 molecules become limiting CTLA-4 is more likely to engage B7 than CD28. Therefore, as antigen becomes limiting the inhibitory signal is more likely to be engaged than the activating signal so the cell will be made anergic.

Central Tolerance: 1. Location: X or X 2. X and X selection 3. Requires X 4. For antigens expressed in X lymphoid tissue --> this includes sX, very X expressed antigens

Central Tolerance: 1. Location: Thymus or bone marrow 2. Positive and negative selection 3. Requires MHC 4. For antigens expressed in central lymphoid tissue --> this includes soluble, very largely expressed antigens

Central memory cells do not have X function but are more X lived. Effector memory cells are capable of X response to the antigen but do not X as long as effector T cells. Memory cells are derived directly from activated X T cells or some effector cells may become qX memory cells that can be very long lived. The majority of effector T cells will X by the mechanisms discussed above in T cell peripheral tolerance. Central Memory T cells will remain in X tissue while effector memory cells will X in the tissues constantly surveilling for their pathogen of interest in case it ever shows its face again!

Central memory cells do not have effector function but are more long lived. Effector memory cells are capable of quick response to the antigen but do not survive as long as effector T cells. Memory cells are derived directly from activated naïve T cells or some effector cells may become quiescent memory cells that can be very long lived. The majority of effector T cells will die by the mechanisms discussed above in T cell peripheral tolerance. Central Memory T cells will remain in lymphoid tissue while effector memory cells will migrate in the tissues constantly surveilling for their pathogen of interest in case it ever shows its face again!

Checkpoint Therapy: Monoclonal antibodies drugs are made to interfere with X or X which will X the T cells to X an immune response.

Checkpoint Therapy: Monoclonal antibodies drugs are made to interfere with PD-1/PD-L1 or CTLA-4/B7, which will reinvigorate the T cells to elicit an immune response.

Children with mutations in Fas/FasL or caspases necessary to accomplish apoptosis all develop X diseases with X accumulation. These human diseases, collectively called aX lX syndrome, are rare OR common and the only known examples of defects in aX causing aX.

Children with mutations in Fas/FasL or caspases necessary to accomplish apoptosis all develop autoimmune diseases with lymphocyte accumulation. These human diseases, collectively called autoimmune lymphoproliferative syndrome, are rare and the only known examples of defects in apoptosis causing autoimmunity.

Clonal Anergy or Exhaustion: This is X-lived functional inX that occurs when self- reactive cells recognize antigen in the presence OR absence of adequate co- stimulation. This occurs in one of 2 ways: a. Co-stimulatory molecules are X present on the antigen presenting cell b. The antigen presenting cell displays X signals instead of X signals. The main signal for anergy is X. The main signal for exhaustion is X.

Clonal Anergy or Exhaustion: This is long-lived functional inactivation that occurs when self- reactive cells recognize antigen in the absence of adequate co- stimulation. This occurs in one of 2 ways: a. Co-stimulatory molecules are NOT present on the antigen presenting cell b. The antigen presenting cell displays inhibitory signals instead of activating signals. The main signal for anergy is CTLA-4. The main signal for exhaustion is PD-1.

Clonal Deletion: Apoptosis of mature lymphocytes in the periphery Thus far we have talked about X tolerance mechanisms that X the actions of T cells. However, the T cells themselves still exist. In some cases, recognition of self-antigens may trigger pathways of X that result in deletion of the self-reactive T cell. Alternatively, at the conclusion of an immune response there mechanisms can be utilized to X cells that are no longer needed now that the danger has passed.

Clonal Deletion: Apoptosis of mature lymphocytes in the periphery Thus far we have talked about peripheral tolerance mechanisms that inhibit the actions of T cells. However, the T cells themselves still exist. In some cases, recognition of self-antigens may trigger pathways of apoptosis that result in deletion of the self-reactive T cell. Alternatively, at the conclusion of an immune response there mechanisms can be utilized to kill cells that are no longer needed now that the danger has passed.

Ex- viral vaccines: After IM injection, viral particles rapidly move through the X network and reach their target tissues. The first requirement to elicit vaccine responses is to provide sufficient signals through vaccine antigens and/or adjuvants to trigger an inflammatory reaction mediated by the X immune system. Antigen presenting cells (APC), for instance, X cells (DC), are recruited into the vaccination site to eventually activate antigen-specific X and X cell responses. Following the administration of a live viral vaccine and its spread, dendritic cells are activated at X sites in the body, migrate towards the corresponding X lymph nodes and launch multiple foci of X and X cell activation. This is because the live vaccine can X in the body and spread. Therefore, the route of administration for a live vaccine is X important for eliciting an immune response than that of an X vaccine. This may contribute to the generally X immunogenicity of live over killed vaccines.

Ex- viral vaccines: After IM injection, viral particles rapidly move through the vascular network and reach their target tissues. The first requirement to elicit vaccine responses is to provide sufficient signals through vaccine antigens and/or adjuvants to trigger an inflammatory reaction mediated by the innate immune system. Antigen presenting cells (APC), for instance, dendritic cells (DC), are recruited into the vaccination site to eventually activate antigen-specific B and T cell responses. Following the administration of a live viral vaccine and its spread, dendritic cells are activated at multiple sites in the body, migrate towards the corresponding draining lymph nodes and launch multiple foci of T and B cell activation. This is because the live vaccine can migrate in the body and spread. Therefore, the route of administration for a live vaccine is less important for eliciting an immune response than that of an inactivated vaccine. This may contribute to the generally higher immunogenicity of live over killed vaccines.

Exhaustion (PD-1) Cause: EX cX stimulation Signals received: Persistent overstimulation via signals X and X AND and ligation of X by X Timeline: X Proliferation: X Effector Function: X to X Primed Properly: Yes OR No Overstimulation can occur in chronic X infections like HX and HX and even cancer

Exhaustion (PD-1) Cause: Excessive continuous stimulation Signals received: Persistent overstimulation via signals 1 and 3 AND and ligation of PD-1 by PD-L1 Timeline: Weeks Proliferation: Low Effector Function: Low to moderate Primed Properly: Yes Overstimulation can occur in chronic viral infections like HIV and HCV and even cancer

Exhaustion and Anergy have similar results in that the T cells will no longer X or make other X responses but induction of exhaustion and anergy is accomplished through different OR same mechanisms.

Exhaustion and Anergy have similar results in that the T cells will no longer proliferate or make other effector responses but induction of exhaustion and anergy is accomplished through different mechanisms.

Extrafollicular B cell responses to polysaccharide antigens. Polysaccharide vaccines do not invoke as strong a response as a X antigen as X cells are not engaged so class switching doesn't happen. Therefore, the predominant antibody produced after polysaccharide vaccination is IgX. There is no immune X created! All that is occurring is that IgX is secreted and will be available in the X. Therefore, repeated doses of a polysaccharide vaccine does not cause a X response, it just leads to starting the whole process over again to make IgX to be available in case the patient encounters the polysaccharide antigen. 1. Specific Ig surface receptors on B cells to bind to polysaccharides reaching the X zone of spleen/nodes. 2. Without antigen-specific T cell help, B cells are activated, proliferate and differentiate into plasma cells outside the X center and do not undergo X maturation. They do not generate X cells. 3. These plasma cells migrate towards the X pulp of the spleen where they survive for a few X/X, secreting low OR high levels of low affinity IgX.

Extrafollicular B cell responses to polysaccharide antigens. Polysaccharide vaccines do not invoke as strong a response as a proteins antigen as T cells are not engaged so class switching doesn't happen. Therefore, the predominant antibody produced after polysaccharide vaccination is IgM. There is no immune memory created! All that is occurring is that IgM is secreted and will be available in the serum. Therefore, repeated doses of a polysaccharide vaccine does not cause a booster response, it just leads to starting the whole process over again to make IgM to be available in case the patient encounters the polysaccharide antigen. 1. Specific Ig surface receptors on B cells to bind to polysaccharides reaching the marginal zone of spleen/nodes. 2. Without antigen-specific T cell help, B cells are activated, proliferate and differentiate into plasma cells outside the GC and do not undergo affinity maturation. They do not generate memory cells. 3. These plasma cells migrate towards the red pulp of the spleen where they survive for a few weeks/months, secreting low levels of low affinity IgM.

T/F There are memory cells for IgM

FALSE!!!!

Who has the Fas receptor and who has the Fas ligand?

Fas receptor = cell that wants to die FasL = CD8+ cell that will kill target cell

What is the most important mechanism of peripheral clonal deletion?

Fas/FasL induced apoptosis

FcγRII on B cells: 1. If bound to B cells, even if antigen is bound to B cell by another antibody, normal signals will still get X down 2. Inhibits antigen-presentation to X cells, which inhibits X switching 3. Helps with sX 4. Decreases OR increases antibody production 5. Induces apoptosis of plasma cells (related to X where you make antibodies to your X, which leads to antigen-antibody interaction and iX) 6. Also used in lymph node during somatic hypermutation on cells with X affinity BCR

FcγRII on B cells: 1. If bound to B cells, even if antigen is bound to B cell by another antibody, normal signals will still get shut down 2. Inhibits antigen-presentation to T cells, which inhibits class switching 3. Helps with sequestration 4. Decreases antibody production 5. Induces apoptosis of plasma cells (related to lupus where you make antibodies to your DNA, which leads to antigen-antibody interaction and inflammation) 6. Also used in lymph node during somatic hypermutation on cells with WEAK affinity BCR

Generation of the Primary Antibody Response at the Lymph Nodes Extrafollicular and germinal center responses to protein antigens. 1. X cells are activated in the lymph nodes responding with their surface immunoglobulins to vaccine antigens that have rX, sometimes in association with migrating DCs. 2 -4. In an Xfollicular reaction, B cells rapidly differentiate into plasma cells that produce X-affinity antibodies (of the IgX +/- IgX/IgX isotypes) that appear at X levels in the X within a few days after immunization. 5-8. Protein antigens activate both X and X cells, to induce a highly efficient X cell differentiation pathway through X centers (GCs). There antigen-specific B cells proliferate and differentiate into antibody-secreting X cells or X B cells. Activation of antigen-specific T cells by antigen-bearing dendritic cells triggers migration of some antigen-specific X cells towards X dendritic cells (XDCs) in GCs. There, B cells get additional signals from X T cells (X) and initiate massive X proliferation, switch from IgX towards IgX, IgX or IgX, undergo X maturation and differentiate into X cells secreting large amounts of antigen-specific antibodies. 9. At the end of the GC reaction, a few plasma cells migrate to X niches mostly located in the bX mX.

Generation of the Primary Antibody Response at the Lymph Nodes Extrafollicular and germinal center responses to protein antigens. 1. B cells are activated in the lymph nodes responding with their surface immunoglobulins to vaccine antigens that have relocated, sometimes in association with migrating DCs. 2 -4. In an extrafollicular reaction, B cells rapidly differentiate into plasma cells that produce low-affinity antibodies (of the IgM +/- IgG/IgA isotypes) that appear at low levels in the serum within a few days after immunization. 5-8. Protein antigens activate both B and T cells, to induce a highly efficient B cell differentiation pathway through germinal centers (GCs). There antigen-specific B cells proliferate and differentiate into antibody-secreting plasma cells or memory B cells. Activation of antigen-specific T cells by antigen-bearing dendritic cells triggers migration of some antigen-specific B cells towards follicular dendritic cells (FDCs) in GCs. There, B cells get additional signals from follicular T cells (Tfh) and initiate massive clonal proliferation, switch from IgM towards IgG, IgA or IgE, undergo affinity maturation and differentiate into plasma cells secreting large amounts of antigen-specific antibodies. 9. At the end of the GC reaction, a few plasma cells migrate to survival niches mostly located in the bone marrow

IDO: an enzyme that catabolizes X (which will become fX) IDO leads to: 1. Tryptophan starvation -- can be used to make X like CD73 or CD25 2. Expansion of TX 3. Induction of X Tregs (XTregs)

IDO: an enzyme that catabolizes tryptophan (which will become foxp3) IDO leads to: 1. Tryptophan starvation -- can be used to make proteins like CD73 or CD25 2. Expansion of Tregs 3. Induction of peripheral Tregs (iTregs)

IL-10: 1. Blocks macrophages = No IL-X = no ThX 2. Blocks NX cells 3. Blocks B cells by making the activation threshold for stimulation much X

IL-10: 1. Blocks macrophages = No IL-12 = no Th1 2. Blocks NK cells 3. Blocks B cells by making the activation threshold for stimulation much higher

IgX dominates during secondary immune responses IgX controls IgX levels during secondary immune responses when IgX engages the FX gamma receptor XB (FcγRXB) on IgX- expressing X-cells. This will ensure that X affinity IgX production is prevented from being produced and IgX expressing memory B-cells are induced to produce X affinity IgX molecules by the antigen. This process is similar to what was discussed above in B cell peripheral tolerance mechanisms and controls the X of the B cell pool that is specific for any given antigen. As this process also works with affinity and maturation and somatic hypermutation, it ensures that as antigen becomes more X only those B cells that have the X affinity for the antigen will be given survival signals. Therefore the concentration of X affinity antibodies and the affinity of the antibody pool over time goes X! Thus, your immune response gets stronger OR weaker.

IgG dominates during secondary immune responses IgG controls IgM levels during secondary immune responses when IgG engages the Fc gamma receptor IIB (FcγRllB) on IgM- expressing B-cells. This will ensure that low affinity IgM production is prevented from being produced and IgG expressing memory B-cells are induced to produce high affinity IgG molecules by the antigen. This process is similar to what was discussed above in B cell peripheral tolerance mechanisms and controls the size of the B cell pool that is specific for any given antigen. As this process also works with affinity and maturation and somatic hypermutation, it ensures that as antigen becomes more limiting only those B cells that have the highest affinity for the antigen will be given survival signals. Therefore the concentration of high affinity antibodies and the affinity of the antibody pool over time goes up! Thus, your immune response gets stronger OR weaker.

Immune memory is a property of the X immune system evolved to respond rX and with X magnitude to rX exposure to an antigen relative to an initial encounter with an antigen. Memory lymphocytes consist of both memory X and X cells produced by antigen stimulation of X lymphocytes. Memory cells survive in a functionally X (i.e., X) state for X after antigen is cleared. Memory lymphocytes mediate X and eX response to subsequent encounter with antigen. Primary response: X exposure and response to a specific antigen Secondary response: X re-X to specific antigen

Immune memory is a property of the adaptive immune system evolved to respond rapidly and with greater magnitude to repeated exposure to an antigen relative to an initial encounter with an antigen. Memory lymphocytes consist of both memory B and T cells produced by antigen stimulation of naïve lymphocytes. Memory cells survive in a functionally quiescent (i.e., inactive) state for years after antigen is cleared. Memory lymphocytes mediate rapid and enhanced response to subsequent encounter with antigen. Primary response: Initial exposure and response to a specific antigen Secondary response: subsequent re-exposure to specific antigen

Immunity to a single organism: We receive a flu shot each year. Each year there are different strains that are likely to cause the majority of the influenza cases we would see that year, the vaccine itself will contain components for both the influenza type X and type X strains that are likely to cause disease this year. You need components from X types because immunity to influenza type A will OR will not protect you against influenza type B and vice versa so you need to have protection to X type individually.

Immunity to a single organism: We receive a flu shot each year. Each year there are different strains that are likely to cause the majority of the influenza cases we would see that year, the vaccine itself will contain components for both the influenza type A and type B strains that are likely to cause disease this year. You need components from both types because immunity to influenza type A will not protect you against influenza type B and vice versa so you need to have protection to each type individually.

Immunity to closely related organisms: There are vaccines that are made of organisms that are similar to another disease causing organism. An example of this is the vaccine that protects against X X. SX pX is caused by the vX virus, however the vaccine is made from the vX virus which is the causative agent of cX pox. VX and VX viruses are very similar in that the X antigens on the vaccinia virus are so similar to the X antigens of the variola virus that immunity to vaccinia can confer some X against variola.

Immunity to closely related organisms: There are vaccines that are made of organisms that are similar to another disease causing organism. An example of this is the vaccine that protects against small pox. Small pox is caused by the variola virus, however the vaccine is made from the vaccinia virus which is the causative agent of cow pox. Variola and Vaccinia viruses are very similar in that the outer antigens on the vaccinia virus are so similar to the outer antigens of the variola virus that immunity to vaccinia can confer some protection against variola.

Immunogenic (foreign antigens) 1. Location: Presence in X and X tissues permits concentration in peripheral lymphoid organs 2. Costimulation: EX of co-stimulators; seen in mX; promotes lymphocyte sX and aX 3. Duration of antigen exposure: Short OR long exposure to microbial antigen reflects effective immune response

Immunogenic: 1. Location: Presence in blood and peripheral tissues permits concentration in peripheral lymphoid organs 2. Costimulation: Expression of co-stimulators; seen in microbes; promotes lymphocyte survival and activation 3. Duration of antigen exposure: Short exposure to microbial antigen reflects effective immune response

Immunological Tolerance: the specific X to mount a response to your X self-antigens. Not only your self-antigens --> also includes fX, fX, and commensal microbes If these mechanisms fail = X

Immunological Tolerance: the specific inability to mount a response to your OWN self-antigens. Not only your self-antigens --> also includes food, fetus, and commensal microbes If these mechanisms fail = autoimmunity

In both cases immunity is mediated by X. The X made to the vaccinia virus X antigens X-react with the X antigens on the variola virus. The antibodies made to influenza type A do OR do not cross-react to confer protection to influenza type B.

In both cases immunity is mediated by antibodies. The antibodies made to the vaccinia virus outer antigens cross-react with the outer antigens on the variola virus. The antibodies made to influenza type A do NOT cross-react to confer protection to influenza type B.

In life all good things must come to an end, and that is true for a good immune response as well. The immune response as we have seen in previous self-studies and sessions is deadly and inflammatory. Continued inflammation, known as cX inflammation, is damaging to the body and mediates pathology. Therefore, when a pathogen is defeated many of the cells that have proliferated or trafficked to the site of inflammation to combat that pathogen will die by X, thus returning the immune system to its normal or homeostatic state. This occurs largely because the microbes themselves that induced the immune response in the first place provide the sX signals that lymphocytes require to stay alive. Without their cognate antigen, they will not receive the necessary stimuli to survive. The only other potential outcome for a cell at the end of an immune response is that it will become a X cell. These cells typically do not play a role in the X immune response to the pathogen but are more X lived cells capable of surviving for longer periods of time with OR without antigen stimulation and will be involved in the immune response if we encounter the pathogen a second time.

In life all good things must come to an end, and that is true for a good immune response as well. The immune response as we have seen in previous self-studies and sessions is deadly and inflammatory. Continued inflammation, known as chronic inflammation, is damaging to the body and mediates pathology. Therefore, when a pathogen is defeated many of the cells that have proliferated or trafficked to the site of inflammation to combat that pathogen will die by apoptosis, thus returning the immune system to its normal or homeostatic state. This occurs largely because the microbes themselves that induced the immune response in the first place provide the survival signals that lymphocytes require to stay alive. Without their cognate antigen, they will not receive the necessary stimuli to survive. The only otheR potential outcome for a cell at the end of an immune response is that it will become a memory cell. These cells typically do not play a role in the active immune response to the pathogen but are more long lived cells capable of surviving for longer periods of time without antigen stimulation and will be involved in the immune response if we encounter the pathogen a second time.

Inactivated vaccine: Inactivated microorganisms or subunits containing protein may still contain pathogen recognition patterns that initiate X responses. Without microbial X, vaccine-induced activation is lX. Inactivated vaccines set off innate responses mostly at their X of injection, so that their route and site of administration X the vaccine response. Following engagement of the innate immune response the X immune response can be triggered by the innate immune response to create a X response. For inactivated vaccine, you only get the X immune response.

Inactivated vaccine: Inactivated microorganisms or subunits containing protein may still contain pathogen recognition patterns that initiate innate responses. Without microbial replication, vaccine-induced activation is limited. Inactivated vaccines set off innate responses mostly at their site of injection, so that their route and site of administration influence the vaccine response. Following engagement of the innate immune response the adaptive immune response can be triggered by the innate immune response to create a memory response. For inactivated vaccine, you only get the X immune response.

Inactivated vaccines: whole cell or fractionated (subunit) Inactivated vaccines are produced by growing the bacterium or virus in X media, then inactivating it with X and/or X (usually X). Inactivated vaccines are OR are not alive and cannot X. These vaccines can OR cannot cause disease from infection, even in an X person. The immune response to an inactivated vaccine is mostly X. Little or no X immunity is generated.

Inactivated vaccines: whole cell or fractionated (subunit) Inactivated vaccines are produced by growing the bacterium or virus in culture media, then inactivating it with heat and/or chemicals (usually formalin). Inactivated vaccines are not alive and cannot replicate. These vaccines cannot cause disease from infection, even in an immunodeficient person. The immune response to an inactivated vaccine is mostly humoral. Little or no cellular immunity is generated.

Induced Tregs vs. Natural Tregs Induced Tregs are in the X and natural Tregs are in the X. Induced Tregs protect the environment, but both Tregs work the X. iTregs = T cells with sX activity that are induced in the periphery (lX nX, MX, GX, etc.) Think about the brain, which is in an enclosed space. We want to make sure that the few T cells that migrate there are X so that they do not cause damage. There is X in T cells. Under normal conditions, in your gut you will express IL-X, which makes TX cells. But if you get food poisoining, your cytokine environment switches to IL-X and IFNX, which makes ThX cells.

Induced Tregs vs. Natural Tregs Induced Tregs are in the periphery and natural Tregs are in the thymus. Induced Tregs protect the environment, but both Tregs work the same. iTregs = T cells with suppressive activity that are induced in the periphery (lymph nodses, MALT, GALT, etc.) Think about the brain, which is in an enclosed space. We want to make sure that the few T cells that migrate there are iTregs so that they do not cause damage. There is plasitcity in T cells. Under normal conditions, in your gut you will express IL-10, which makes Treg cells. But if you get food poisoining, your cytokine environment switches to IL-12 and IFNgamma, which makes Th1 cells.

Initiation of a vaccine response to attenuated vaccines -innate participation 1. IX 2. Vaccine antigen pathogen associated signals attract dX cells, mX and nX patrolling throughout the body using X recognition. 3 -4. If enough signals are sensed, monocytes and dendritic cells are activated, changing their X receptors. 4-5.Activation induces cell migration along lymphatic vessels to the X lymph nodes where the activation of X and X lymphocytes will take place.

Initiation of a vaccine response to attenuated vaccines -innate participation 1. Injection 2. Vaccine antigen pathogen associated signals attract dendritic cells, monocytes and neutrophils patrolling throughout the body using PRR recognition. 3 -4. If enough signals are sensed, monocytes and dendritic cells are activated, changing their surface receptors. 4-5.Activation induces cell migration along lymphatic vessels to the draining lymph nodes where the activation of T and B lymphocytes will take place.

Like T cells, mature B cells need to be X at the end of an immune response. This is accomplished in three ways: 1. AX: Just like T cells, if a B cell recognizes antigen without either X cell help, either because the X cell has become aX itself or eliminated, or without accessory signals from CDX or IgX/X then the cell will become aX. An anergic B cell will not X into a plasma cell and will not secrete X. 2. SX: A B cell that has not been X may leave the lymph node follicle to try seek out its antigen in another lymph node. The same is true of aX B cells, however non-activated B cells and anergic B cells lack expression of most X receptors. Without expression of these homing beacon receptors they will not be able to X the lymph node or lymph node follicle to the environment of the lymph node where they can be more X lived. In this case the B cells will X because they do not receive X stimuli that are typically found in the lymph node follicles. 3. Inhibition (i.e.X feedback): IgX produced by a plasma cell can be recognized by the FcγRX on X cells. Engagement of FcγRX on plasma cells delivers an X signal to the plasma cell, terminating production of X. FcγRII on B cells binds to the X portion of IgG.

Like T cells, mature B cells need to be removed at the end of an immune response. This is accomplished in three ways: 1. Anergy: Just like T cells, if a B cell recognizes antigen without either T cell help, either because the T cell has become anergic itself or eliminated, or without accessory signals from CD21 or Igα/β then the cell will become anergic. An anergic B cell will not differentiate into a plasma cell and will not secrete antibody. 2. Sequestration: A B cell that has not been activated may leave the lymph node follicle to try to leave the lymph node and seek out its antigen in another lymph node. The same is true of anergic B cells, however non-activated B cells and anergic B cells lack expression of most chemokine receptors. Without expression of these homing beacon receptors they will not be able to get back into the lymph node or lymph node follicle to the environment of the lymph node where they can be more long lived. In this case the B cells will die because they do not receive survival stimuli that are typically found in the lymph node follicles. 3. Inhibition (i.e.antibody feedback): IgG produced by a plasma cell can be recognized by the FcγRII on B cells. Engagement of FcγRII on plasma cells delivers an inhibitory signal to the plasma cell, terminating production of antibody. FcγRII on B cells binds to the Fc portion of IgG.

Live attenuated vaccines give the X response as natural infection but often as sX and more X lasting with OR without the illness

Live attenuated vaccines give the SAME response as natural infection but often as stronger and more long lasting WITHOUT the illness

Live attenuated -- capable of X, which is needed for immune response Characteristics of live-attenuated vaccines (attenuated = X pathogenic) Live vaccines are derived from "X" or X-causing, viruses or bacteria. o Small pox variolation: Prior to the small pox vaccine originally created by Edward Jenner in 1796, there was a practice of "variolation" or X where live small pox was taken from a pustule on an X person with a relatively X case of small pox and then placed in an open wound of a X person. This person would become ill X-X days later and then often would recover from a much X severe case of small pox than they might have been exposed to. However, this practice was OR was not 100% and many people X but it was form of early X vaccination. o Pox Parties: Today and prior to the introduction of the X vaccine that protects against chicken pox, parents would intentionally expose their children to children who are recovering from an infectious disease. Most commonly this has been done with fX, mX, and X pox. In this way their child will be exposed to the illness with OR without vaccination.

Live attenuated-- capable of replication, which is needed for immune response Characteristics of live-attenuated vaccines (attenuated = less pathogenic) Live vaccines are derived from "wild" or disease-causing, viruses or bacteria. o Small pox variolation: Prior to the small pox vaccine originally created by Edward Jenner in 1796, there was a practice of "variolation" or inoculation where live small pox was taken from a pustule on an infected person with a relatively mild case of small pox and then placed in an open wound of a healthy person. This person would become ill 7-8 days later and then often would recover from a much less severe case of small pox than they might have been exposed to. However, this practice was not 100% and many people died but it was form of early live vaccination. o Pox Parties: Today and prior to the introduction of the varicella vaccine that protects against chicken pox, parents would intentionally expose their children to children who are recovering from an infectious disease. Most commonly this has been done with flu, measles, and chicken pox. In this way their child will be exposed to the illness without vaccination.

Markers of Memory T cells: Differentiating a memory B cell from a naïve B cell is easy. Naïve B cells express IgX and IgX on their surface while memory B cells have class switched to IgX, X, or X. For T cells the marker CDX is used for differentiation. CDX is expressed on nX, eX, and mX T cells. However, it can be alternatively X to cleave out segments. These different appearances of CDX are termed CDXRX and CDXRX. A good way to remember this is that, CD45RA has X of its subunits and is expressed on X T cells. MX and eX T cells have cleaved X segments from the CD45RA exons to form the CD45RX isoform. In this way we can identify by CD markers whether or not we are looking at a X T cell or and eX/mX T cell. There are two general types of T memory cells: CX memory cells and EX memory cells. CD45RX have A, B, C exons and CD45RX do not.

Markers of Memory T cells: Differentiating a memory B cell from a naïve B cell is easy. Naïve B cells express IgD and IgM on their surface while memory B cells have class switched to IgG, A, or E. For T cells the marker CD45 is used for differentiation. CD45 is expressed on naïve, effector, and memory T cells. However, it can be alternatively spliced to cleave out segments. These different appearances of CD45 are termed CD45RA and CD45RO. A good way to remember this is that, CD45RA has All of its subunits and is expressed on nAive T cells. MemOry and effectOr T cells have cleaved Out segments from the CD45RA exons to form the CD45RO isoform. In this way we can identify by CD markers whether or not we are looking at a naïve T cell or and effector/memory T cell. There are two general types of T memory cells: Central memory cells and Effector memory cells. CD45RA have A, B, C exons and CD45RO do not.

Memory B cell development requires X cell help Memory B cells require X cell help to be developed. This occurs at the activation of the B cell in the lX nX. T cells, tell the B cell to undergo X switching, pX, and dX. You do OR do not get memory B cells for T-independent antigens. There is no such thing as an IgX producing memory B cell or for an antigen that cannot be recognized by T cells. ThX/ThX/TX cells engage B cells at the X zones of secondary lymphoid tissue but only TX cells interact with B cells within the X centers. Specialized Dendritic Cells (XDCs) and TX cells interact with B cell in the X center through the BCR. This activation is X important for differentiation of memory B cells. B cells in the germinal center with the X affinity for antigen receive X signals and begin to proliferate after receiving signals from XDCs and TX. So in the lymph node, you have B cells being activated by protein antigen, they get help from TX cells that induce class switching, sX hX, and X affinity antibody. They also receive survival signals from XDCs. If you do NOT get Tfh or FDC interaction the B cells will be X lived and while they may OR may not recognize antigen they will OR will not not survive very long.

Memory B cell development requires T cell help Memory B cells require T cell help to be developed. This occurs at the activation of the B cell in the lymph node. T cells, tell the B cell to undergo class switching, proliferate, and differentiate. You DO NOT get memory B cells for T-independent antigens. There is no such thing as an IgM producing memory B cell or for an antigen that cannot be recognized by T cells. Th1/Th2/Tfh cells engage B cells at the marginal zones of secondary lymphoid tissue but only Tfh cells interact with B cells within the germinal centers. Specialized Dendritic Cells (FDCs) and Tfh cells interact with B cell in the germinal center through the BCR. This activation is most important for differentiation of memory B cells. B cells in the germinal center with the highest affinity for antigen receive survival signals and begin to proliferate after receiving signals from FDCs and Tfh. So in the lymph node, you have B cells being activated by protein antigen, they get help from Tfh cells that induce class switching, somatic hypermutation, and high affinity antibody. They also receive survival signals from FDCs. If you do NOT get Tfh or FDC interaction the B cells will be short lived and while they may recognize antigen they will not survive very long.

Memory X cell role in vaccination (boosting): The main goal of vaccination is to create memory X cells which will be capable of producing X should they ever encounter the pathogens. Memory X cells do not produce antibodies and are not pX. Memory X cells can be activated with X amounts of antigen independently of CDX T cell help during the secondary immune response. In vaccination strategy, the activity of memory X cells is more of a consideration for X or X vaccines. Generally, secondary responses to live attenuated viral vaccines are mX, since pre-existing antibodies may nX the vaccine strains prior to in vivo replication.

Memory B cell role in vaccination (boosting): The main goal of vaccination is to create memory B cells which will be capable of producing antibodies should they ever encounter the pathogens. Memory B cells do not produce antibodies and are not protective. Memory B cells can be activated with lower amounts of antigen independently of CD4+ T cell help during the secondary immune response. In vaccination strategy, the activity of memory B cells is more of a consideration for killed or subunit vaccines. Generally, secondary responses to live attenuated viral vaccines are minimal, since pre-existing antibodies may neutralize the vaccine strains prior to in vivo replication.

Memory T cells Memory T-cells are produced during encounter with specific peptide antigens (from the pathogens) that are presented by X molecules on antigen presenting cells. In addition to effector cells some memory cells are generated during T-cell pX. Effector cells will significantly X-number the amount of memory cells that are produced. For a T helper cell, the effector cells are those that secrete X for a CTL are the cells that X cells, the cells that X something. The memory cells are instead much more X lived, present in X numbers, and have X effector function.

Memory T cells Memory T-cells are produced during encounter with specific peptide antigens (from the pathogens) that are presented by MHC molecules on antigen presenting cells. In addition to effector cells some memory cells are generated during T-cell priming. Effector cells will significantly out-number the amount of memory cells that are produced. For a T helper cell, the effector cells are those that secrete cytokine for a CTL are the cells that kill cells, the cells that DO something. The memory cells are instead much more long lived, present in smaller numbers, and have limited effector function.

Memory T-cell responses are OR are not like memory B-cell responses. During secondary challenge to antigen, effector T-cell responses have X lag time and have a X magnitude of response. The differences between memory T-cells and memory B-cells are that memory X-cell responses are terminated rapidly following clearance of antigen and affinity of the XCR for peptide antigen does not X. You can see that frequency of effector T cells and titer of antibody peaks around X weeks after infection. This period between the time the patient was infected and this peak is known as the "X phase". As you eliminate the pathogen eX cells decline over the course of months with antibody lasting much X than effector T cells. However, a small population of memory B and T cells will survive for X. Memory B cells will survive for approximately X years, this is part of why it is recommended that you receive a tetanus booster shot every X years! Memory T cells are able to live even X, how long however is unclear. They can live in the body for at least X-X years or longer!

Memory T-cell responses are like memory B-cell responses. During secondary challenge to antigen, effector T-cell responses have shorter lag time and have a higher magnitude of response. The differences between memory T-cells and memory B-cells are that memory T-cell responses are terminated rapidly following clearance of antigen and affinity of the TCR for peptide antigen does not increase. You can see that frequency of effector T cells and titer of antibody peaks around 2 weeks after infection. This period between the time the patient was infected and this peak is known as the "lag phase". As you eliminate the pathogen effector cells decline over the course of months with antibody lasting much longer than effector T cells. However, a small population of memory B and T cells will survive for years. Memory B cells will survive for approximately 10 years, this is part of why it is recommended that you receive a tetanus booster shot every 10 years! Memory T cells are able to live even longer, how long however is unclear. They can live in the body for at least 20-25 years or longer!

Metabolic Disruption of Cell Growth: IL-X and AX Starvation: T regulatory cells constitutively express the IL-2X chain, CDX. This is the high OR low affinity receptor for IL-X on T cells which is only expressed on X-T regulatory cells following activation. As T regulatory cells express X levels of CD25 X of the time they are better OR worse able to bind up IL-2 in the area effectively X other cells in the area of IL-2. Additionally, they express high levels of CDX which is the aX receptor. Again, without adenosine T cells are unable to replicate. Adenosine is needed for X replication.

Metabolic Disruption of Cell Growth: IL-2 and Adenosine Starvation: T regulatory cells constitutively express the IL-2Rα chain, CD25. This is the high affinity receptor for IL-2 on T cells which is only expressed on non-T regulatory cells following activation. As T regulatory cells express high levels of CD25 all of the time they are better able to bind up IL-2 in the area effectively starving other cells in the area of IL-2. Additionally, they express high levels of CD73 which is the adenosine receptor. Again, without adenosine T cells are unable to replicate. Adenosine is needed for DNA replication.

Natural Infection Natural infection "may" provide a X lasting infection or "X" protection. Ideally, the first time you encounter a pathogen, you receive the "X-type" strain or the strain that is actively X in the population. Recovery from an infectious disease confers Xlong immunity to that disease in a healthy individual, this is because the X of the memory pool of cells created is typically larger OR smaller following a natural infection. If you are re- exposed to the antigen this induces the memory cells to begin replication X and re- establish the memory X cell response as well as aX circulating in the X and memory X cells. This is why many vaccines require X over time to expand the dwindling memory pool.

Natural Infection Natural infection "may" provide a longer lasting infection or "stronger" protection. Ideally, the first time you encounter a pathogen, you receive the "wild-type" strain or the strain that is actively circulating in the population. Recovery from an infectious disease confers lifelong immunity to that disease in a healthy individual, this is because the size of the memory pool of cells created is typically larger following a natural infection. If you are re- exposed to the antigen this induces the memory cells to begin replication quickly and re- establish the memory T cell response as well as antibodies circulating in the serum and memory B cells. This is why many vaccines require boosters over time to expand the dwindling memory pool.

Normally, T cells get signal 1 (X) and signal 2 (X). However, in an X environment, APC will NOT express B7. Therefore, there will OR will not be no co-stimulation. An example of this would be an APC presenting your pancreatic islet cells. Thus X will be expressed to make the cell X.

Normally, T cells get signal 1 (MHC/TCR) and signal 2 (CD28/B7). However, in an tolerogenic environment, APC will NOT express B7. Therefore, there will be no co-stimulation. An example of this would be an APC presenting your pancreatic islet cells. Thus CTLA-4 will be expressed to make the cell anergic.

Other assessments of a successful long-term vaccine efficacy may include: 1. the X of antibody responses induced, e.g., their aX. This refers to the X of the interaction of antibody binding to a specific eX at the X of an antigen. The aX is the X of the epitope specific aX for a given antigen. 2. the X of vaccine antibodies and/or the X of immune memory cells capable of rapid and effective reactivation upon subsequent microbial exposure to confer X-term protection

Other assessments of a successful long-term vaccine efficacy may include: the quality of antibody responses induced, e.g., their avidity. This refers to the strength of the interaction of antibody binding to a specific epitope at the surface of an antigen. The avidity is the sum of the epitope specific affinities for a given antigen. the persistence of vaccine antibodies and/or the generation of immune memory cells capable of rapid and effective reactivation upon subsequent microbial exposure to confer long-term protection

What are the 2 different immunization strategies?

Passive and Active

Passive can be: 1. Immune serum globulin (hX or eX) 2. Specific X 3. MX antibodies

Passive can be: 1. Immune serum globulin (human or equine) 2. Specific Igs 3. Monoclonal antibodies

Passive immunity: A X-lived, tX immunity provided through administration of protective usually pX antibodies specific for a X microbe to a person that has OR has not had prior exposure to that microbe. These antibodies are produced by one human or other X and transferred to another, usually of the different OR same species. If the antibodies are generated in a different species (horse, rabbit, etc) then a person can only receive antibodies from that species X. This is because the human immune system will recognize these antibodies as X and make their own antibodies to the X regions. This will result in a condition known as "SX SX" which is a form of X that can be very dangerous for patients. Protection will end when these antibodies X during a period of X to X. The most common form of passive immunization is the antibodies (IgX) from mother to infant when antibodies cross the placenta during the last X-X months of pregnancy. A full-term infant will have a full complement of IgX X antibodies from its mother that have crossed the placenta. These can be protective against some diseases for up to a X. Additionally, IgX can be transferred from mother to child during breastfeeding protecting the infant from mucosal and gastrointestinal infections. Breastfeeding can contribute antibodies, mainly IgX.

Passive immunity: A short-lived, transient immunity provided through administration of protective usually polyclonal antibodies specific for a single microbe to a person that has not had prior exposure to that microbe. These antibodies are produced by one human or other animal and transferred to another, usually of the same species. If the antibodies are generated in a different species (horse, rabbit, etc) then a person can only receive antibodies from that species ONCE. This is because the human immune system will recognize these antibodies as foreign and make their own antibodies to the constant regions. This will result in a condition known as "Serum Sickness" which is a form of hypersensitivity that can be very dangerous for patients. Protection will end when these antibodies breakdown during a period of weeks to months. The most common form of passive immunization is the antibodies (IgG) from mother to infant when antibodies cross the placenta during the last 1-2 months of pregnancy. A full-term infant will have a full complement of IgG maternal antibodies from its mother that have crossed the placenta. These can be protective against some diseases for up to a year. Additionally, IgA can be transferred from mother to child during breastfeeding protecting the infant from mucosal and gastrointestinal infections. Breastfeeding can contribute antibodies, mainly IgA.

Passive means you are given X (X) vs active means you are vaccinated with X or X virus.

Passive means you are given immunoglobulins (Ig) vs active means you are vaccinated with live or inactivated virus.

What is the lag phase?

Period between the time the patient was infected and this peak of T cell and antibody titer

Peripheral Tolerance: 1. For antigens X expressed in central lymphoid tissue 2. Occurs X cells have left thymus or bone marrow 3. Relies on several mechanisms 4. Uses T X cells (both nX and X)

Peripheral Tolerance: 1. For antigens NOT expressed in central lymphoid tissue 2. Occurs AFTER cells have left thymus or bone marrow 3. Relies on several mechanisms 4. Uses T regulatory cells (both natural and induced)

Peripheral Tolerance: Any mechanism occurring X the central lymphoid organs that limits OR expands the activity of an immune response

Peripheral Tolerance: Any mechanism occurring outside the central lymphoid organs that limits the activity of an immune response

Polysaccharide Vaccines: Polysaccharide vaccines are an inactivated X vaccine made of long OR short X chains found in the X capsule of certain bacteria. Pure polysaccharide vaccines are available for three diseases: pX disease, mX disease, and SX Typhi.

Polysaccharide Vaccines: Polysaccharide vaccines are an inactivated subunit vaccine made of long sugar chains found in the surface capsule of certain bacteria. Pure polysaccharide vaccines are available for three diseases: pneumococcal disease, meningococcal disease, and Salmonella Typhi.

Primary Antibody Response for Polysaccharide (PS) vaccines The immune response to a pure polysaccharide vaccine is typically T-cell X. These vaccines can stimulate B cells with OR without needing T-helper cells. The vaccines do not work consistently in children younger than X years of age, probably because of X of the immune system (not good at activating X cells yet). Polysaccharide vaccines are OR are not as efficacious as protein antigen. The antibody induced with polysaccharide vaccines has X functional activity. The predominant antibody produced after most polysaccharide vaccination is IgX. Polysaccharide antigens that fail to activate T cells do not trigger X centers. They elicit wX and sX antibody responses, and no immune mX. Repeat doses of polysaccharide vaccines usually do OR do not cause a booster response. Repeated doses are need for more X production, but you are starting the process all over again each time you get a shot and you only get IgX.

Primary Antibody Response for Polysaccharide (PS) vaccines The immune response to a pure polysaccharide vaccine is typically T-cell independent. These vaccines can stimulate B cells without needing T-helper cells. The vaccines do not work consistently in children younger than 2 years of age, probably because of immaturity of the immune system (not good at activating B cells yet). Polysaccharide vaccines are not as efficacious as protein antigen. The antibody induced with polysaccharide vaccines has less functional activity. The predominant antibody produced after most polysaccharide vaccination is IgM. Polysaccharide antigens that fail to activate T cells do not trigger germinal centers, They elicit weaker and shorter antibody responses, and no immune memory. Repeat doses of polysaccharide vaccines usually do not cause a booster response. Repeated doses are need for more antibody production, but you are starting the process all over again each time you get a shot and you only get IgM.

Primary Response X number of naïve pathogen specific cells requiring priming X Phase: Significant X before specific antibodies are produced IgX antibody is produced from plasma cells upon B cell differentiation (IgX > IgX (blood) or IgX/X in mucosa) X threshold required for activation = X pathogen burden DX before effector T cells are generated and traffic to tissues X response bridges the gap until X is generated

Primary Response Small number of naïve pathogen specific cells requiring priming Lag Phase: Significant delay before specific antibodies are produced IgM antibody is produced from plasma cells upon B cell differentiation (IgM > IgG (blood) or IgA/E in mucosa) High threshold required for activation = high pathogen burden Delay before effector T cells are generated and traffic to tissues Innate response bridges the gap until adaptive is generated

Program death (PD-1) molecule: PD-1 is induced on the X of cells that have been X activated for short OR long periods of time. It is a marker of X. This is evident in chronic X infections where CDX T cells that are specific for the virus no longer produce X, pX, or release gX and pX even though there is plenty of antigen around. These cells are said to be exhausted and express X. PDX engages PD-X or PD-X on the surface of X which instructs the T cell of its exhausted state and X it from making these responses. It can also be used as a X tolerance mechanism to X the function of autoreactive T cells which are mediators of pathology in X diseases. The repeated activation can be repeated signals X and X.

Program death (PD-1) molecule: PD-1 is induced on the surface of cells that have been repeatedly activated for long periods of time. It is a marker of exhaustion. This is evident in chronic viral infections where CD8+ T cells that are specific for the virus no longer produce cytokines, proliferate, or release granzymes and perforin even though there is plenty of antigen around. These cells are said to be exhausted and express PD-1. PD-1 engages PD-L1 or PD-L2 on the surface of APCs which instructs the T cell of its exhausted state and inhibits it from making these responses. It can also be used as a peripheral tolerance mechanism to inhibit the function of autoreactive T cells which are mediators of pathology in autoimmune diseases. The repeated activation can be repeated signals 1 and 3.

Survival and induction of Memory T cells IL-X is required to induce memory T-cell survival. Moreover, IL-X is important in maintaining memory T-cells when antigen is X. As was mentioned early when we discussed T cell development, IL-X receptors are expressed on X and dX T- cells and IL-X is necessary to maintain survival for the X T-cells.

Survival and induction of Memory T cells IL-7 is required to induce memory T-cell survival. Moreover, IL-7 is important in maintaining memory T-cells when antigen is absent. As was mentioned early when we discussed T cell development, IL-7 receptors are expressed on naïve and developing T- cells and IL-7 is necessary to maintain survival for the naïve T-cells.

Reasons for B cell Peripheral Tolerance: 1. Stop X secretion or stop X B cells 2. B cells recognize a bunch of antigens that T cells cannot therefore we need a X mechanism to shut them down

Reasons for B cell Peripheral Tolerance: 1. Stop antibody secretion or stop new B cells 2. B cells recognize a bunch of antigens that T cells cannot therefore we need a different mechanism to shut them down

Secondary Immune Response: when you get a second infection both the effector T cells and antibodies peak VERY X but they do OR do not stick around just as the effector cells and plasma cells in the primary response did not stick around for very long. Some effector cells become quiescent and become long lived memory cells.

Secondary Immune Response: when you get a second infection both the effector T cells and antibodies peak VERY rapidly but they do not stick around just as the effector cells and plasma cells in the primary response did not stick around for very long. Some effector cells become quiescent and become long lived memory cells.

T regulatory cells and tolerogenic mediators: T regulatory cells can be induced in the X where they are referred to as XT regulatory cells (XTregs) or induced by X in the pX as part of X tolerance. When they are induced in the thymus it is as part of X selection. This occurs when thymic generated Tregs are specialized self-antigen specific cells that respond strongly OR weakly to self-antigen but are OR are not deleted by apoptosis. Instead, they are either tolerized by X selection or X to be tolerogenic. This means they will be able to X the responses of all other immune cells.

T regulatory cells can be induced in the thymus where they are referred to as Natural T regulatory cells (nTregs) or induced by cytokines in the periphery as part of peripheral tolerance. When they are induced in the thymus it is as part of negative selection. This occurs when thymic generated Tregs are specialized self-antigen specific cells that respond strongly to self-antigen but are not deleted by apoptosis. Instead, they are either tolerized by negative selection or induced to be tolerogenic. This means they will be able to inhibit the responses of all other immune cells.

Secretion of Inhibitory/Tolerogenic Cytokines (IL-X, TGF-X, IL-X,) The X environment plays a role in the type of response that occurs. If the cytokines produced in the area are tX instead of iX the cell's effector function will be X. IL-X and TGF-X are associated with some X Th subsets (ThX and ThX respectively) but only when paired with other cytokines that are considered truly pro-X. For Th2 this would IL-X and IL-X and for Th17 the cytokine combination is TGF-X and IL-X. When IL-X and TGF-X are the predominant cytokines that are being produced in the area. The result is a X environment. This indicates an environment that X inflammatory responses, a homeostatic or quiescent environment. T regulatory cells are capable of producing both IL-X and TGF-X.

Secretion of Inhibitory/Tolerogenic Cytokines (IL-10, TGF-β, IL-35,) The cytokine environment plays a role in the type of response that occurs. If the cytokines produced in the area are tolerogenic instead of inflammatory the cell's effector function will be inhibited. IL-10 and TGF-β are associated with some inflammatory Th subsets (Th2 and Th17 respectively) but only when paired with other cytokines that are considered truly pro-inflammatory. For Th2 this would IL-4 and IL-10 and for Th17 the cytokine combination is TGF-β and IL-6. When IL-10 and TGF-β are the predominant cytokines that are being produced in the area. The result is a tolerogenic environment. This indicates an environment that impedes inflammatory responses, a homeostatic or quiescent environment. T regulatory cells are capable of producing both IL-10 and TGF-β.

Situations where passive immunization may be used: 1. To prevent disease after a X exposure (e.g., X injury with blood that is contaminated with hepatitis B virus) 2. To X the symptoms of an X disease (e.g. Health care workers that were exposed to Ebola during the epidemic received X from patients who recovered) 3. To protect X individuals (Severe primary immunodeficiencies eg. X) 4. To block the action of bacterial X and prevent the diseases they cause.

Situations where passive immunization may be used: 1. To prevent disease after a known exposure (e.g., needlestick injury with blood that is contaminated with hepatitis B virus) 2. To lessen the symptoms of an ongoing disease (e.g. Health care workers that were exposed to Ebola during the epidemic received antibodies from patients who recovered) 3. To protect immunodeficient individuals (Severe primary immunodeficiencies eg. XLA) 4. To block the action of bacterial toxins and prevent the diseases they cause.

Subunit vaccines (fractional): To make fractional vaccines, only those components of the organism which are most OR least likely to elicit an immune response in the population are included in the vaccine (ex: the X capsule of pneumococcus [a bacteria] or the X subunit of influenza virus) are separated and purified for use as a vaccine instead of using the whole bacterium or viral particle. HA is a X on surface of influenza that changes every year.

Subunit vaccines (fractional): To make fractional vaccines, only those components of the organism which are most likely to elicit an immune response in the population are included in the vaccine (ex: the polysaccharide capsule of pneumococcus [a bacteria] or the HA subunit of influenza virus) are separated and purified for use as a vaccine instead of using the whole bacterium or viral particle. HA is a glycoprotein on surface of influenza that changes every year.

T regulatory cells rely on X (aX rX genes), which express the X-antigen genes used for X selection. T regulatory cells are T cells that responded X strongly to self-antigen in the X but were allowed to survive anyway and leave the X and now they can be used to X the immune response.

T regulatory cells rely on AIRE (autoimmune regulatory genes), which express the self-antigen genes used for negative selection. T regulatory cells are T cells that responded TOO strongly to self-antigen in the thymus but were allowed to survive anyway and leave the thymus and now they can be used to stop the immune response.

TGF-β --> always think tX and shutting down immune response 1. Promote IgX but inhibits X cells 2. Inhibits X cell proliferation but keeps them alive 3. Inhibits ThX/X 4. Makes TX in the periphery

TGF-β --> always think Tolerance and shutting down immune response 1. Promote IgA but inhibits B cells 2. Inhibits T cell proliferation but keeps them alive 3. Inhibits Th1/2 4. Makes Tregs in the periphery

T/F If ONE cell produces both Fas/FasL, then suicide will occur.

TRUE

Targeting antigen presenting cells: When T regulatory cells interact with antigen presenting cells like dendritic cells they X the ability of the DC to be a good antigen presenting cell and induce the DC to secrete of IX 2,3 diX (also known as IDO). CX binding plays a role in this as it triggers the DC to produce X which X T cell growth by starving them of X. Furthermore, T X cell interaction with APCs will induce the APC to express X ligands on their surfaces. These ligands, PDX, induce an X phenotype on effector X cells that the APC might interact with in the area. Tregs ALWAYS express X!

Targeting antigen presenting cells: When T regulatory cells interact with antigen presenting cells like dendritic cells they inhibit the ability of the DC to be a good antigen presenting cell and induce the DC to secrete of Indolamine 2,3 dioxygenase (also known as IDO). CTLA-4 binding plays a role in this as it triggers the DC to produce IDO which limits T cell growth by starving them of tryptophan. Furthermore, T regulatory cell interaction with APCs will induce the APC to express inhibitor ligands on their surfaces. These ligands, PD-L1, induce an exhausted phenotype on effector T cells that the APC might interact with in the area. Tregs ALWAYS express CTLA-4!

The dX/mX of immune memory induction, as well as the relative contribution of X antibodies and of immune memory protection against specific diseases are important to X-term vaccine efficacy. Long-term immunity is produced as a result of X of antigen-specific immune eX and/or the induction of immune mX cells that are efficiently and quickly reactivated into immune effectors following pathogen exposure.

The determinants/mechanisms of immune memory induction, as well as the relative contribution of persisting antibodies and of immune memory protection against specific diseases are important to long-term vaccine efficacy. Long-term immunity is produced as a result of maintenance of antigen-specific immune effectors and/or the induction of immune memory cells that are efficiently and quickly reactivated into immune effectors following pathogen exposure.

The make-up of the vaccine directly influences the tX and aX of immune effectors that participate to generate protection. Vaccines can be administered by different routes: IntraX, oX, intraX, and sX.

The make-up of the vaccine directly influences the type and activity of immune effectors that participate to generate protection. Vaccines can be administered by different routes: Intramuscular, oral, intradermal, and subcutaneous.

Types of vaccines: There are two basic types of vaccines: X attenuated and X (killed). The characteristics of live and inactivated vaccines are same OR different; these characteristics determine the features of immunity developed to the vaccine.

Types of vaccines: There are two basic types of vaccines: live attenuated and inactivated (killed). The characteristics of live and inactivated vaccines are different; these characteristics determine the features of immunity developed to the vaccine.

The organism Clostridium tX produces a highly potent Xtoxin that is one of the most Xtoxins in the world. This neurotoxin induces rigid X in patients. Within approximately X-X days of exposure to the bacteria, patients will begin to experience paralysis of the X muscles leading to tX or "X" as it is more commonly called. Eventually this paralysis will X leading to exhaustion and paralysis of the X muscles causing X failure. There is a X% mortality associated with C. tetani if the patient is not treated. Tetanus disease is entirely mediated by the Tetanus X the organism produces. Lucky for us, we are capable of making X in response to the toxin. Unfortunately for us, the symptoms of tetanus exposure can occur at any time between a few X to a few X after the bacteria have entered our bodies. Average incubation period is X-X days. We won't begin to make antibody until this point which means our antibody response is too little too late. So what can be done? 1. Tetanus X: The tetanus toxin has been isolated and has been fixed with X to form tetanus X. This is basically X tetanus toxin which will now X cause disease. Toxin = dX, Toxoid = pX. If we have been immunized with tetanus X we will make antibodies to tetanus X that will bind and nX tetanus toxin should we be exposed before it can enter our cells. Tetanus toxoid has been conjugated to DX and PX for the X and X vaccines which will confer to protection to all X organisms. 2. Administration of Tetanus anti-X: Tetanus antiX is hX tetanus X. In other countries and some rural areas of the US, the tetanus antiX is made in X and referred to as X tetanus antiX. This is important as it will bind up toxin in a patient whose vaccination history is X while the body works toward making an immune response to the X. Anti-toxin is X immunity and will not confer X term protection. Therefore administration of X will allow them to make an immune response that will confer X term protection. Tetanus toxoid is fixed with X.

The organism Clostridium tetani produces a highly potent neurotoxin that is one of the most potent toxins in the world. This neurotoxin induces rigid paralysis in patients. Within approximately 7-10 days of exposure to the bacteria, patients will begin to experience paralysis of the masseter muscles leading to trismus or "lockjaw" as it is more commonly called. Eventually this paralysis will descend leading to exhaustion and paralysis of the chest muscles causing respiratory failure. There is a 30% mortality associated with C. tetani if the patient is not treated. Tetanus disease is entirely mediated by the Tetanus Toxin the organism produces. Lucky for us, we are capable of making antibodies in response to the toxin. Unfortunately for us, the symptoms of tetanus exposure can occur at any time between a few days to a few weeks after the bacteria have entered our bodies. Average incubation period is 7-10 days. We won't begin to make antibody until this point which means our antibody response is too little too late. So what can be done? 1. Tetanus Toxoid: The tetanus toxin has been isolated and has been fixed with formalin to form tetanus toxoid. This is basically inactivated tetanus toxin which will now NOT cause disease. Toxin = disease, Toxoid = protection. If we have been immunized with tetanus toxoid we will make antibodies to tetanus toxoid that will bind and neutralize tetanus toxin should we be exposed before it can enter our cells. Tetanus toxoid has been conjugated to Diphtheria and Pertussis for the Tdap and DTap vaccines which will confer to protection to all three organisms. 2. Administration of Tetanus anti-toxin: Tetanus antitoxin is human tetanus immunoglobulin. In other countries and some rural areas of the US, the tetanus antitoxin is made in horses and referred to as equine tetanus antitoxin. This is important as it will bind up toxin in a patient whose vaccination history is unclear while the body works toward making an immune response to the toxoid. Anti-toxin is passive immunity and will not confer long term protection. Therefore administration of Toxoid will allow them to make an immune response that will confer long term protection. Tetanus toxoid is fixed with formalin.

The properties of antibodies in the primary and secondary immune response can be correlated to antibody responses in immunized (vaccinated) or unimmunized (non- vaccinated) individuals: Source of B cells: Non-immunized individual Primary Response Frequency of antigen specific B cells: 1 in 10X-10X Isotype of Antibody Produced: IgX> IgX (or IgX/IgX) Affinity of Antibodies: Low or High Somatic Hypermutation: Low or High Immunized individual Secondary Response Frequency of antigen specific B cells: 1 in 10X-10X Isotype of antibody produced: IgX, IgX, IgX> IgX Affinity of antibodies: Low or High Somatic hypermutation: Low or High

The properties of antibodies in the primary and secondary immune response can be correlated to antibody responses in immunized (vaccinated) or unimmunized (non- vaccinated) individuals: Source of B cells: Non-immunized individual Primary Response Frequency of antigen specific B cells: 1 in 104-105 Isotype of Antibody Produced: IgM> IgG (or IgA/IgE) Affinity of Antibodies: Low Somatic Hypermutation: Low Immunized individual Secondary Response Frequency of antigen specific B cells: 1 in 102-103 Isotype of antibody produced: IgG, IgA, IgE> IgM Affinity of antibodies: High Somatic hypermutation: High

There are two mechanisms of peripheral clonal deletion: 1. Cell death caused by antigen recognition X co-stimulation: This occurs when a T cell is activated X strongly without co-stimulation. This is akin to what occurs in the tX during cX tX except now it is occurring in the X lymph node. In this case it is a way of keeping X created naïve T cells from becoming X as their responses is no longer necessary. 2. Cell death caused by engagement of death receptors: FX/FX: This is the X important mechanisms of peripheral clonal deletion. In this mechanism, a cell decides to X-sacrifice. The cell that has decided to die will OR will not kill itself but instead will rely on the killers of the immune system to do the killing for them. The target cell will express the receptor X on its surface as signal to nearby CDX X T cells that it would like to be killed. The CDX T cell expresses the ligand to Fas, which is creatively called Fas X, or FX. When FasL binds to Fas the X domain in the Fas molecule is engaged which leads to the activation of the X cascade and eventually X of the cell. In the figure both cells are expressing Fas and FasL so they are killing each other but that is not always the way the relationship works. Sometimes a CDX T cell will kill a target cell and remain intact.

There are two mechanisms of peripheral clonal deletion: 1. Cell death caused by antigen recognition WITHOUT co-stimulation: This occurs when a T cell is activated VERY strongly without co-stimulation. This is akin to what occurs in the thymus during central tolerance except now it is occurring in the draining lymph node. In this case it is a way of keeping newly created naïve T cells from becoming activated as their responses is no longer necessary. 2. Cell death caused by engagement of death receptors: Fas/FasL: This is the most important mechanisms of peripheral clonal deletion. In this mechanism, a cell decides to self-sacrifice. The cell that has decided to die will not kill itself but instead will rely on the killers of the immune system to do the killing for them. The target cell will express the receptor Fas on its surface as signal to nearby CD8+ cytotoxic T cells that it would like to be killed. The CD8+ T cell expresses the ligand to Fas, which is creatively called Fas ligand, or FasL. When FasL binds to Fas the death domain in the Fas molecule is engaged which leads to the activation of the caspase cascade and eventually apoptosis of the cell. In the figure both cells are expressing Fas and FasL so they are killing each other but that is not always the way the relationship works. Sometimes a CD8+ T cell will kill a target cell and remain intact.

There are ways to increase immunogenicity, this means vaccine developers will use these mechanisms to make X immune responses occur. For example, as we just discussed polysaccharides are OR are not good immunogens, but they can be used with other things that are good immunogens to develop a better immune response. CX: Increased immunogenicity of polysaccharide vaccines can be achieved by cX linking the polysaccharide to a X. This process is called cX. Conjugation changes the immune response from T-cell X to T-cell X, so that the vaccine is more immunogenic in X and antibody X response to multiple doses of vaccine can take place. ---------------------------------- Adjuvants are agents that X stimulation of the immune system by enhancing antigen pX and/or by providing co-X signals that function as immunomodulators. AX salts are most often used in today's vaccines. Adjuvants may be separated into two categories: 1. delivery systems that prolong the antigen X at site of injection which recruits more X cells and extends the duration of X and X cell activation 2. immune modulators that provide additional dX and aX signals to mX and dX cells.

There are ways to increase immunogenicity, this means vaccine developers will use these mechanisms to make stronger immune responses occur. For example, as we just discussed polysaccharides are not good immunogens, but they can be used with other things that are good immunogens to develop a better immune response. Conjugation: Increased immunogenicity of polysaccharide vaccines can be achieved by chemically linking the polysaccharide to a protein. This process is called conjugation. Conjugation changes the immune response from T-cell independent to T-cell dependent, so that the vaccine is more immunogenic in infants and antibody booster response to multiple doses of vaccine can take place. Adjuvants are agents that boost stimulation of the immune system by enhancing antigen presentation and/or by providing co-stimulation signals that function as immunomodulators. Aluminium salts are most often used in today's vaccines. Adjuvants may be separated into two categories: 1. delivery systems that prolong the antigen deposit at site of injection which recruits more DCs and extends the duration of B and T cell activation 2. immune modulators that provide additional differentiation and activation signals to monocytes and DCs.

These X viruses or bacteria become attenuated, or X in a laboratory setting through X appearing after repeated culture. Effective live attenuated vaccines contain organisms that must X in the vaccinated person enough to stimulate an X response. Live attenuated vaccines produce immunity in most recipients with X dose, except those administered X. The immune response to a live attenuated vaccine is the X as that produced after natural infection. The immune system can OR cannot distinguish an infection with an X strain or the X-type strain. If a vaccine is given through an X or X route, IgX may be produced in the vaccinated host. The more similar a vaccine strain is to the disease- causing form of the organism, the X the immune response to the vaccine. Their role in vaccine efficacy is through an antigen-driven pX and dX process in response to subsequent and/or repeated encounters with the microbes or antigens that originally stimulated their production. The antigen-driven activation of memory X cells causes them to proliferate quickly and differentiate into X cells generating large amounts of X-affinity antibodies, higher OR lower than after primary immunization. Some live oral vaccines: XMist protecting against influenza and X a polio vaccine. Because active immunity is often induced by vaccination of "inactivated" or "attenuated" organisms, this protection may X over time. Individuals may be more susceptible to exposure to the organism they were immunized against if their antibody levels X. o Ex: X outbreaks in the US in 2015 in college students. These students had been vaccinated but it had been ~X years since contact with mumps, therefore, their memory X cells had died out. They were given X shots.

These wild viruses or bacteria become attenuated, or weakened in a laboratory setting through mutations appearing after repeated culture. Effective live attenuated vaccines contain organisms that must replicate in the vaccinated person enough to stimulate an immune response. Live attenuated vaccines produce immunity in most recipients with one dose, except those administered orally. The immune response to a live attenuated vaccine is the same as that produced after natural infection. The immune system cannot distinguish an infection with an attenuated strain or the wild-type strain. If a vaccine is given through an oral or mucosal route, IgA may be produced in the vaccinated host. The more similar a vaccine strain is to the disease- causing form of the organism, the better the immune response to the vaccine. Their role in vaccine efficacy is through an antigen-driven proliferation and differentiation process in esponse to subsequent and/or repeated encounters with the microbes or antigens that originally stimulated their production. The antigen-driven activation of memory B cells causes them to proliferate quickly and differentiate into plasma cells generating large amounts of higher-affinity antibodies, higher than after primary immunization. Some live oral vaccines: FluMist protecting against influenza and Sabin a polio vaccine. Because active immunity is often induced by vaccination of "inactivated" or "attenuated" organisms, this protection may wane over time. Individuals may be more susceptible to exposure to the organism they were immunized against if their antibody levels decline. o Ex: Mumps outbreaks in the US in 2015 in college students. These students had been vaccinated but it had been ~15 years since contact with mumps, therefore, their memory B cells had died out. They were given booster shots.

Tolerogenic vs. Immunogenic Tolerogenic cytokines: FX/FX TGFX IL-X CX/PDX IX High OR Poor co-stimulation FcX receptor Immunogenic cytokines: TNFX IFNX IL-X IL-X IL-X CDX/CDXL CDX/BX High OR Poor co-stimulation Normally, these two are in X. When there is a pathogen, there is an X in the immunogenic cytokines, BUT if this increased is sustained for too long, then you will run out of X and start attacking X

Tolerogenic vs. Immunogenic Tolerogenic cytokines: Fas/FasL TGFbeta IL-10 CTLA-4/PD-1 IDO Poor co-stimulation Fcgamma receptor Immunogenic cytokines: TNFalpha IFNgamma IL-1 IL-6 IL-12 CD40/CD40L CD28/B7 High co-stimulation Normally, these two are in balance. When there is a pathogen, there is an increase in the immunogenic cytokines, BUT if this increased is sustained for too long, then you will run out of pathogen and start attacking yourself

Tolerogenic (self-antigens) 1. Location: Presence in X organs that induces X selection and other mechanisms of cX tX 2. Costimulation: DX of co-stimulators may lead to T cell aX or aX, development of T X cells or sensitivity to suppression by T X cells 3. Duration of antigen exposure: X-lived persistence (throughout X); prolonged OR short TCR engagement may induce anergy and apoptosis

Tolerogenic: 1. Location: Presence in generative organs that induces negative selection and other mechanisms of central tolerance 2. Costimulation: Deficiency of co-stimulators may lead to T cell anergy or apoptosis, development of Treg cells or sensitivity to suppression by Treg 3. Duration of antigen exposure: Long-lived persistence (throughout life); prolonger TCR engagement may induce anergy and apoptosis

Tolerogenic: X immune response vs. Immunogenic: X an immune response

Tolerogenic: Shut down immune response vs. Immunogenic: Causes an immune response

Tregs require the transcription factor X to develop. Mutations in foxp3 lead to a systemic Xorgan X disease, called iX dX pX, eX, X-linked syndrome, or X for short. This highlights the importance of T regulatory cells in maintaining self-tolerance.

Tregs require the transcription factor foxp3 to develop. Mutations in foxp3 lead to a systemic multiorgan autoimmune disease, called immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or IPEX for short. This highlights the importance of T regulatory cells in maintaining self-tolerance.

Vaccines ultimately prime the aforementioned activities to happen more X when your body encounters the pathogen for the second time.

Vaccines ultimately prime the aforementioned activities to happen more quickly when your body encounters the pathogen for the second time.

Vaccination is the process of generating pX aX immune responses against microbes by exposure to pathogenic OR nonpathogenic forms or component of the microbes. The key to successful vaccines is to trigger the X immune response to develop X cells, which act quickly when encountering a pathogen or develop antibodies with X affinity to a pathogen, with OR without allowing the person to experience symptoms or get sick. Vaccines can be administered X injection (IM), oX, X (ID) and X (SQ). For currently available vaccines, X protective efficacy is primarily assessed and determined by the induction of antigen-specific antibodies, measured by "X".

Vaccination is the process of generating protective adaptive immune responses against microbes by exposure to nonpathogenic forms or component of the microbes. The key to successful vaccines is to trigger the adaptive immune response to develop memory cells, which act quickly when encountering a pathogen or develop antibodies with greater affinity to a pathogen, without allowing the person to experience symptoms or get sick. Vaccines can be administered intramuscular injection (IM), orally, intradermally (ID) and subcutaneously (SQ). For currently available vaccines, early protective efficacy is primarily assessed and determined by the induction of antigen-specific antibodies, measured by "titer".

Vaccine-induced immune effectors include: CELL MEDIATED cytotoxic CD8+ T lymphocytes (CTL) : act to reduce OR increase, control and clear Xcellular pathogens by directly X infected cells (release of pX, gX, etc.) or indirectly killing infected cells through antimicrobial X release CD4+ T cells: act to reduce OR increase, control and clear X- and Xcellular pathogens by: 1. producing IFN-X, TNF-X/- X, IL-X and IL-X and supporting activation and differentiation of X cells, CDX T cells and macrophages (ThX cells) 2. producing IL-X, IL-X, IL-X, IL-X and IL-X and supporting X cell activation and differentiation (ThX cells)

Vaccine-induced immune effectors include: CELL MEDIATED cytotoxic CD8+ T lymphocytes (CTL) : act to reduce, control and clear intracellular pathogens by directly killing infected cells (release of perforin, granzyme, etc.) or indirectly killing infected cells through antimicrobial cytokine release CD4+ T cells: act to reduce, control and clear extra- and intracellular pathogens by: producing IFN-γ, TNF-α/- β, IL-2 and IL-3 and supporting activation and differentiation of B cells, CD8+T cells and macrophages (Th1cells) producing IL-4, IL-5, IL-13, IL-6 and IL-10 and supporting B cell activation and differentiation (Th2 cells)

Vaccine-induced immune effectors include: HUMORAL AX: produced by differentiated B lymphocytes that have class switched to IgX, IgX, or IgX secreting plasma cells. These antibodies are capable of binding specifically to a tX or a pathogen and able to "nX" or block the toxin or microbe from attaching to a host cell. The antibodies induced in response to vaccination also promote oX and pX, as well as activate cX just as they would if they were induced due to iX by the pathogen or exposure to the toxin. Toxin is produced by X and is able to act at sites X away from the site of infection. Antibody does 3 things: 1. Blocks the penetration of microbe through X barrier 2. Blocks binding of microbe and X of cells 3. Blocks binding of X to cellular receptor

Vaccine-induced immune effectors include: HUMORAL Antibodies: produced by differentiated B lymphocytes that have class switched to IgG, IgA, or IgE secreting plasma cells. These antibodies are capable of binding specifically to a toxin or a pathogen and able to "neutralize" or block the toxin or microbe from attaching to a host cell. The antibodies induced in response to vaccination also promote opsonization and phagocytosis, as well as activate complement just as they would if they were induced due to infection by the pathogen or exposure to the toxin. Toxin is produced by bacteria and is able to act at sites far away from the site of infection. Antibody does 3 things: 1. Blocks the penetration of microbe through epithelial barrier 2. Blocks binding of microbe and infection of cells 3. Blocks binding of toxin to cellular receptor

Vaccines Summary: The type of vaccine given, as well as its composition, affects the activation of X immunity and level of vaccine responses. The strongest antibody responses are generally elicited by X vaccines able to activate more robust X reactions to better support the induction of X immune effectors. Very few X-live vaccines generate high long-lived antibody responses after administration of a X vaccine dose, even in X young adults. Scheduling strategies for primary immunization usually entail at least X vaccine doses, optimally repeated at least X-X weeks apart to generate successive waves of X cell and X center responses. Vaccine antibodies elicited by primary immunization with killed or subunit types of vaccines eventually X.

Vaccines Summary: The type of vaccine given, as well as its composition, affects the activation of innate immunity and level of vaccine responses. The strongest antibody responses are generally elicited by live vaccines able to activate more robust innate reactions to better support the induction of adaptive immune effectors. Very few non-live vaccines generate high long-lived antibody responses after administration of a single vaccine dose, even in healthy young adults. Scheduling strategies for primary immunization usually entail at least two vaccine doses, optimally repeated at least 3-4 weeks apart to generate successive waves of B cell and GC responses. Vaccine antibodies elicited by primary immunization with killed or subunit types of vaccines eventually wane.

Vaccines: Recall from our initial studies on immunology that immunity is the ability to dX and tX the presence of "X-antigens" from foreign or "X-self" antigens that must be eliminated. Protection from infectious disease occurs because most microbes are identified as X by the immune system. Immunity in an individual is generally X to a single strain of a X organisms or to a group of closely X organisms.

Vaccines: Recall from our initial studies on immunology that immunity is the ability to distinguish and tolerate the presence of "self-antigens" from foreign or "non-self" antigens that must be eliminated. Protection from infectious disease occurs because most microbes are identified as foreign by the immune system. Immunity in an individual is generally specific to a single strain of a single organisms or to a group of closely related organisms.

What are the differences between tolerogenic and immunogenic antigens? 1. SX vs. fX 2. LX of antigens 3. CX 4. DX of antigen exposure For location, think placenta and BBB where there is a X in place to keep out antigens For co-stimulation, think about monoclonal antibodies, which X co-stimulation to produce AX to start OR stop patients' autoimmune disease

What are the differences between tolerogenic and immunogenic antigens? 1. Self vs. foreign 2. Location of antigens 3. Costimulation 4. Duration of antigen exposure For location, think placenta and BBB where there is a barrier in place to keep out antigens For co-stimulation, think about monoclonal antibodies, which inhibit co-stimulation to produce ANERGY to stop patients' autoimmune disease

What are 2 ways to increase immunogenicity?

conjugation and adjuvants