Immune Responses to Pathogens Flashcards
Do dendritic cells participate in innate or adaptive immune responses?
Both.
Dendritic cells that participate in part of the innate responses are responsible for triggering the adaptive immune responses.
Dendritic cells present peptides derived from pathogens to naïve T cells to alert the naïve T cells of an infection, and then provide a co-stimulatory signal to fully activate the naïve T cells and initiate the adaptive immune response.
Is adaptive immunity independent of innate immunity?
Adaptive immunity is much more effective than, but not independent of innate immunity.
What is an extracellular bacterial infection?
Those infections where the bacteria do not invade the cells of the host.
What is the most appropriate form of an adaptive immune-response for extracellular bacterial infection?
Production of antibodies would be the most appropriate form of an adaptive immune response.
The antibodies would function to neutralize the pathogen, or opsonize the pathogen to make phagocytosis more efficient, or activate complement to kill the pathogen.
Describe the immune response prior to adaptive immunity activation if you cut your finger on a piece of glass contaminated with bacteria.
The first line of defense (intact skin) has been breached.
At the site of tissue damage, the mast cells that reside in the tissues release histamine that increase the blood flow to the area, resulting in inflammation (redness, swelling, increased local temperature).
During the early innate responses, complement proteins from the blood enter the tissues and can kill many types of bacteria via the alternate pathway.
Resident macrophages recognize pathogen-associated molecular patterns (PAMPs) with their pattern recognition receptors (PRRs including Toll-like receptors, TLRs) and phagocytose bacteria, and produce alarm cytokines to start the induced innate responses.
The resident macrophages release substances that help recruit neutrophils and monocytes to the site of infection.
During the induced innate responses, neutrophils arrive at the site of infection within minutes and immediately begin ingesting bacteria by phagocytosis.
After several hours, the monocytes that have entered the tissues differentiate into macrophages. Macrophages are very efficient phagocytic cells and also secrete bactericidal substances.
However, if there are large numbers of bacteria, the bacteria could overwhelm the innate responses.
The bacteria could multiply and spread to other sites in the body.
The adaptive immune system would be activated as a last line of defense.
What do complement proteins do during the early innate response?
Complement proteins from the blood enter the tissues and can kill many types of bacteria via the alternate pathway
How do resident macrophages start the induced innate responses?
They recognize pathogen-associated molecular patterns (PAMPs) with their pattern recognition receptors (PRRs including Toll-like receptors, TLRs), phagocytose bacteria, and produce alarm cytokines.
What do resident macrophages recruit?
The resident macrophages release substances that help recruit neutrophils and monocytes to the site of infection
During the induced innate responses, how soon do neutrophils arrive at the site of infection?
Within minutes and immediately begin ingesting bacteria by phagocytosis.
How many hours do monocytes take to differentiate into macrophages during the induced innate responses?
After several hours, the monocytes that have entered the tissues differentiate into macrophages.
Macrophages are very efficient phagocytic cells and also secrete bactericidal substances.
Describe why dendritic cells are one of the most important links between innate and adaptive immunity.
Immature dendritic cells in the skin engulf the bacteria, process (digest) it and display its antigenic peptides on MHC class II proteins on the cell surface.
The dendritic cells migrates from the skin to a nearby lymph node where they “presents” the antigenic peptide fragments to a T helper cell.
They take a “snapshot” of what is happening on the frontlines of the infection and bring the information to the lymph node to activate the specific lymphocytes (T cells, B cells) that will be useful in fighting that particular pathogen.
The pathogen itself may also enter the lymphatic system and be carried to nearby lymph nodes.
What cells recognize antigenic determinants on intact pathogens?
In the lymph nodes are B cells with B cell receptors (BCRs) that can recognize antigenic determinants on the unprocessed and intact pathogens.
Describe the activation of a T helper cell.
The T cell receptor (TCR) of the T helper cell binds to the MHC class II-peptide complex on the dendritic cell.
The CD3 complex of the T helper cell sends a signal to the nucleus (“signal 1” of T cell activation).
The CD28 protein on the T cell interacts with the B7 co-stimulatory protein on the dendritic cell (“signal 2” of T cell activation).
The T helper cell secretes IL-2 and binds it (“signal 3” of T cell activation) triggering proliferation and differentiation into effector cells and memory cells.
The T helper cell starts to express CD40L on its cell surface.
How does a pathogen travel to a lymph node?
The pathogen is pushed from the tissue and into the lymphatic vessel by blood pressure, where it eventually enters a lymph node.
Describe T-dependent B cell activation.
Bacteria bind to and cross-link the BCR resulting in a signaling cascade initiated by Igα/Igβ co-stimulatory proteins (“signal 1” of B cell activation).
The B cell starts to express the co-stimulatory B7 proteins on its cell surface.
The antigen is internalized and processed inside an endosome so that peptide fragments can be displayed on MHC class II proteins.
The TCR of the T helper cell binds to the MHC class II-peptide complex on the B cell, and the CD28 of the T cell binds to the B7 of the B cell.
The CD40 protein on the B cell binds to the CD40L of the T helper cell (“signal 2” of B cell activation), and the T helper cell provides the B cell with cytokines (“signal 3” of B cell activation) resulting in the complete activation of the B cell.
Cytokines secreted by the activated T helper cell also cause the activated B cell to divide, class switch to a different isotype of antibody and differentiate into plasma cells or memory B cells.
Plasma cells increase their production of ribosomes and endoplasmic reticulum in preparation for becoming “antibody factories.”
Memory B cells differentiate are important for future responses if there is a re-infection with the same pathogen.
Activated T helper cells and B cells divide many times. What do they differentiate into?
The activated T helper cells and B cells divide many times.
The lymphocytes differentiate into effector cells and memory cells.
The large increase in the number of T and B cells increases the size of the lymph node and results in “swollen glands.”
Why can you have antibodies in your blood that recognize antigens that you encountered many years ago?
The plasma cells generated during a T cell-dependent antibody response can migrate to the bone marrow and produce specific antibodies for long periods of time (many years). This explains why you may have antibodies in your blood that recognize antigens that you encountered many years ago.
What type of antibody do plasma cells produce during a T cell-independent response?
The plasma cells generated during a T cell-independent response are short-lived and produce only low affinity IgM antibodies.
How long does the primary response take for production of antibodies?
After approximately 5–7 days (for a primary response), the plasma cells start making and secreting antibodies.
Antibodies secreted by the plasma cells enter the blood and travel all over the body including the site of infection. How do the antibodies function?
The antibodies will bind to the bacteria and both neutralize it (i.e., prevent it from attaching to surfaces, IgM and IgG), opsonize it to improve the efficiency of phagocytosis (IgG), and activate complement to kill the bacteria (IgM and IgG).
Antibodies secreted into mucus will neutralize the bacteria (IgA).
What are toxins?
Some pathogens cause damage to the host by secreting proteins called toxins.
Toxins act on specific cell types and impair the function of the cell or kill the cell.
Proteins, such as toxins, that are foreign to the host can also elicit immune responses.
Describe the immune response that results after administration of tetanus toxoid (a toxin that is modified so that it is biologically non-functional).
The antibody response to a foreign protein would develop.
Antibodies generated would bind to tetanus toxin and neutralize it, by preventing it from binding to the person’s cells.
What response does the body have to extracellular bacterial infection?
Antibody-mediated response
After a dendritic cell has engulfed a bacteria, what do they do with the information?
Dendritic cells that engulf bacteria carry information from the site of infection to the lymph node to activate T helper cells.
B cells are activated by interaction with the pathogen and activated T helper cells in what kind of response?
T cell-dependent responses.
What type of cells proliferate and differentiate into effector cells and memory cells?
Activated T cells and B cells
What type of plasma cells are generated in T cell dependent responses?
The plasma cells generated in T cell dependent responses migrate to the bone marrow and are long-lived.
These antibodies can be class switch to the IgG or IgA isotype and tend to be of high affinity.
What type of plasma cells are generated in T cell-independent responses?
B cells can be activated by interaction with the pathogen in a T cell-independent manner.
The plasma cells generated in T cell-independent responses are short-lived and produce low affinity IgM antibodies.
Which secreted antibody isotype help neutralize pathogens?
IgM, IgG, IgA
Which secreted antibody isotype will opsonize a pathogen?
IgG
Which secreted antibody isotype will activate the complement cascade?
IgM, IgG
Lymphocytes are involved in specific immune reactions.
True or false?
True
B lymphocytes mature in the bone marrow.
True or false?
True
The primary lymphoid organ is where leukocytes develop; the secondary lymphoid organs are where adaptive immune responses are initiated.
True or false?
True
The peptide bound to MHC class II proteins is usually derived from exogenous proteins.
True or false?
True
MHC class II proteins present peptides to CD8 T cells.
True or false?
False.
The main difference between membrane-bound immunoglobulin (mIgs) and secreted antibodies (sIgs) is amino acid sequences at the amino-terminus of the H and L chains.
True or false?
False.
The main difference between membrane-bound immunoglobulin (mIgs) and secreted antibodies (sIgs) is amino acid sequences at the carboxyl-terminus of the H chain.
When a B cell class switches, it can change the type of heavy chain it makes, but the V regions of the heavy and light chain remain the same.
True or false?
True.
The V regions of the heavy and light chains are involved in antigen recognition.
True or false?
True
Both BCRs and TCRs have two antigen binding sites for each receptor.
True or false?
False.
There are secreted forms of both the BCR and TCR after the B cell and T cell (respectively) have been activated by antigen.
True or false?
False.
T helper cells can be activated when an antigen-presenting cell presents the specific peptide on MHC class II.
True or false?
True.
On antigenic stimulation, the plasma cells revert to B lymphocytes which secrete antibodies for humoral immunity.
True or false?
False.
Inflammation is the usual outcome of an adaptive immune response but not an innate immune response.
True or false?
False.
The innate and adaptive immune responses largely work independently of one another.
True or false?
False.
The lymphatic system is not part of the immune system.
True or false?
False.
The second signal for B cell activation is the interaction of B7 on the B cell with CD28 on the T helper cell.
True or false?
False.
The second signal is CD40 on the B cell binding to CD40L on the T helper cell
The CD40 ligand (CD40L) is expressed on B cells after the binding of antigen, and on macrophages after they have engulfed a bacterial cell.
True or false?
False
The second time your body comes across a foreign substance you will have a more intense adaptive response than the first time.
True or false.
True
The adaptive immune response, as compared to the innate response, takes longer to provide effective immunity.
True or false?
True.
In the adaptive immune response, effective immunity cannot be detected for several days after the first contact with the pathogen.
True or false?
True.
On antigenic stimulation, the plasma cells revert to B lymphocytes which produces antibodies for humoral immunity.
True or false?
False.
Booster immunizations raise the level of antibodies in a recipient by stimulating the memory cells to bring about the secondary response.
True or false?
True.
What two key events must occur for a successful adaptive immune response?
- the innate immune response must sense “danger” - dendritic cells recruited to the site of infection mature and move to the lymph node.
- T helper cells must be activated - a dendritic cell must present a peptide complexed with MHC class II protein to the T helper cell.
What is the appropriate response for an extracellular bacterial infection?
Antibody response
What are the goals of an antibody response?
Depending on the class of the antibodies, they can:
- block the bacteria (or its toxins) from binding to host cell (neutralization)
- enhance phagocytosis of bacteria (opsonization)
- activate complement to MAC to kill bacteria
What are the main immune cells involved in antibody response, and what is their main purpose?
B cells to synthesize and secrete the antibody.
T helper cells to provide signals 2 & 3 to B cells to fully activate them.
Dendritic cells to activate T helper cells.
Describe how an antibody response is triggered.
- Pathogen enters body > innate responses
- Immature dendritic cell engulfs bacteria > senses danger
- Activation of T helper cell by dendritic cell
- Pathogen binding to BCR of B cell
- Interaction of B cell with T helper cell
- Proliferation and differentiation of B cells
- Secretion of antibody into body fluids
- Antibody function!
Describe the early innate response.
- Starts within a few minutes
- Mast cells release histamine > dilation of blood vessels
- Activation of complement via the alternate pathway
- Phagocytosis of bacteria by resident macrophages
- A bit later, the production of ‘alarm cytokines’ by resident macrophages to start the induced innate responses.
Describe the induced innate responses.
- Start within a few hours
- Recruitment of neutrophils, monocytes, and dendritic cells to site of infection.
- Phagocytosis of bacteria by newly arrived neutrophils
- Maturation of newly arrived monocytes into macrophages
- Phagocytosis of bacteria by macrophages and dendritic cells
Describe the inflammatory response.
Histamine released by resident mast cells results in dilation of the blood vessels.
Cytokines released by resident macrophages causes changes in the blood vessel wall that allows for neutrophils and monocytes (and dendritic cells too) to slow down, stop and be recruited to the site of infection.
Presence of bacteria and the chemokine IL-8 act as chemoattractants.
Which pathway does a dendritic cell use to display a peptide on the MHC class II protein?
Exogenous
At the lymph node, how do dendritic cells activate T helper cells?
- Signal 1: TCR complex of the mature naïve T cell binds to the MHC II - foreign peptide complex on the dendritic cell, CD4 strengthens this binds, and CD3 delivers a signal to the nucleus.
- Signal 2: involves the binding of CD28 of the T cell to the B7 of the antigen-presenting cell.
- Signal 3: T cell makes and secretes IL-2, IL-2 binds to the IL-2 receptor (IL-2R).
In the lymph node, the bacterium encounters a B cell that has a BCR that is complementary to a structure on the bacterium.
How is the B cell activated?
Signal 1 - mature naïve B cell binds the bacterium by its BCR, Igα/Igβ relays a signal to the nucleus. The BCR may be a IgM-type or IgD-type on the B cell - the different classes of mIg have the same antigen specificity. The BCR-Ag (bacterium) complex is brought into the cell as an endosome. A lysosome fuses with the endosome containing the BCR-Ag (bacterium) complex to form the endolysosome. The bacterium is digested to form peptide fragments. Peptide fragments from the bacterium are loaded onto MHC class II, and the new MHC class II peptide fragments are displayed on the surface.
Signal 2 - the binding of CD40 on the B cell to CD40L on the T cell. The TH cell “knows” that it has to help this particular B cell because of the peptide being displayed on MHC class II proteins.
Signal 3 - The T helper cell secretes cytokines (Signal 3) that help support B cell division and differentiation into effector cells called plasma (B) cells (that secrete antibodies) or memory B cells.
How does a T helper cell know that it has to help a particular B cell or not?
The peptide being displayed on MHC class II proteins.
Which plasma cells become long lived?
Plasma cells that migrate back to the bone marrow become long-lived plasma cells. (eg - memory B cells)
When do memory B cells class switch?
Memory B cells may have class-switch before developing into memory cells, or they may class-switch at the time of re-activation - these cells are expected to secrete IgG or IgA antibody (depends on T helper cell instructions).
What accounts for the lag time associated with the primary antibody response?
The primary antibody response takes about 7 – 10 days to fully develop, most of the lag is accounted for by the changes in gene expression (differentiation) and proliferation of the naïve T helper cells and naïve B cells.
Because of the proliferation of the T helper cells and B cells, there may be a swelling in the lymph nodes.
What is the main antibody produced early during the response (especially by the short-lived plasma cells?
IgM
What is the main antibody produced late in the response (by the long-lived plasma cells)?
IgG
Which cells die and which cells remain, after a pathogen has been eliminated?
The effector T helper cells die (and the short-lived plasma cells).
The memory T helper cells and memory B cells remain.
How long does antibody remain in circulation for?
About 6 months.
The antibody response subsides and the lymph nodes return to normal size.
What type of pathogen is able to shut down the innate immune response?
Some bacteria are intracellular pathogens (e.g., Mycobacterium tuberculosis, Listeria monocytogenes) that invade and live inside host cells such as macrophages.
These types of pathogens are able to shut down the innate immune responses and reproduce inside the macrophage.
Eventually the macrophage dies and the bacteria released from the dead macrophage can invade other macrophages and spread the infection.
How long does the secondary response take to develop and why?
The secondary response takes only about 2 – 3 days to develop - memory cells are much easier to activate than naïve cells.
Why are antibodies ineffective against bacteria that replicate inside macrophages?
The infection is inside a cell and antibodies cannot reach it.
Cell-mediated immune responses are needed to combat this type of infection.
What does a cell-mediated response use? What is the goal of the cell-mediated response?
T cells and macrophages to kill the pathogen, rather than soluble proteins in the blood such as antibodies.
In this type of situation, the goal of the immune system is to super-activate the macrophages so that they can kill the bacteria that are inside them.
The innate response differs depending on the type of pathogen invasion.
True or false?
False.
The innate response is always the same.
How can intracellular bacteria circumvent innate immunity?
Several ways:
- some bacteria thrive in acidic environments (Mycobacterium tuberculosis),
- while others can escape the phagosome (Listeria).
- Still others, such as Salmonella, modify the phagosome vesicle membrane so that they don’t fuse as efficiently with lysosomes. In these cases, the phagosome has been transformed into a specialized organelle in which the bacteria can resist acidification and replicate.
A macrophage infected with intracellular bacteria is doomed. What is the immune response in this scenario?
A small number of phagosomes do successfully fuse with lysosomes before the bacteria can modify them, which results in some of the bacteria being killed and the degradation of their proteins by lysosomal proteases. Antigenic peptides derived from the killed bacteria are then displayed on MHC class II proteins. The macrophage also expresses the protein CD40 on their cell surface.
The bacteria replicating inside it will soon kill the cell. However, if the macrophage receives special instructions from a T helper cell, it would know what additional genes it needed to transcribe to produce extremely toxic compounds to kill the bacteria. Macrophages are not mobile and cannot migrate to the lymph node to meet with T helper cells.
In this case, the T helper cell will have to go to the macrophage in the tissues.
How is help recruited when a resident macrophage is infected with intracellular bacteria?
Immature dendritic cells at the site of infection also phagocytose bacteria. Unlike the resident macrophages, the dendritic cells can migrate to the nearest lymph node, process the pathogen and present peptides from the pathogen on MHC class II proteins.
Once the dendritic cell reaches the lymph node, it activates T helper cell and instructs it to leave the lymph node and migrate to the site of to the infected macrophage.
At the site of infection the T helper cell secretes a cytokine called interferon-gamma (IFN-γ).
How can macrophages be super-activated?
Two signals.
The T helper cells mediate the first signal by secretion of IFN-γ and other cytokines.
The second signal is the binding of CD40L on the T helper cell to CD40 on the macrophage.
What do super-activated macrophages do?
After receiving signals from the T helper cell, the macrophages become much more effective at fusing the lysosomes with the phagosomes.
The macrophages increase their production of antimicrobial products such as the reactive nitrogen metabolite nitric oxide (NO), oxygen radicals and proteases.
These compounds are potent enough to kill intracellular and extracellular pathogens.
Unfortunately, sometimes these reactive compounds leak outside the macrophage and damage the healthy cells and tissues of the host, causing inflammation.
How can activated T helper cells assist further, beyond stimulating super-activated macrophages?
(during intracellular bacterial infection response)
Activated T helper cells also secrete substances that cause an inflammatory response.
Cytokines made by the T helper cells increase blood flow to the area.
They also attract neutrophils and macrophages that release bactericidal substances and phagocytose bacteria that have escaped from lysed cells.
What type of response does the body have against intracellular bacterial infections?
Cell-mediated response
Even if a naive T cell does not the co-stimulatory signal from a professional antigen presenting cell, it will still be activated.
True or false.
False
Dendritic cells are the most potent activator of naïve T cells.
True or false?
True
Activation of naïve T cells requires at least two signals; binding of the TCR to MHC-peptide on the antigen presenting cell and cytokines provided by the antigen presenting cell.
True or false?
False
(3 signals required)
Interleukin-2 (IL-2) is a cytokine that promotes the proliferation of T cells.
True or false?
True
CD4 cells are generally T helper cells and are activated when a dendritic cell presents peptide on a MHC class I molecule.
True or false?
False
Inflammation is the usual outcome of an adaptive immune response but not an innate immune response.
True or false?
False.
Delayed type hypersensitivity reactions involve memory T helper cells that recognize a peptide derived from the pathogen.
True or false?
True.
Super-activation of T helper cells is needed to kill bacteria that have infected T cells.
True or false?
False.
Activated cytotoxic cells are needed to stimulate macrophages to express genes that produce products to kill intracellular bacteria.
True or false?
False.
Super-activation of macrophages results in the killing of the intracellular bacteria without damage to healthy tissues in the host.
True or false?
False.
To get help from a T helper cell, a macrophage must present a peptide derived the intracellular bacteria on MHC class I molecules.
True or false?
False.
CD40/CD40L signalling is needed to generate the second signal to super-activate a macrophage.
True or false?
True.
Macrophages express the CD40L and B7 proteins after they have recognized the pathogen with a Toll-like receptor.
True or false?
False.
Before a T helper cell can super-activate a macrophage, it first needs to be activated by a dendritic cell.
True or false?
True.
How do viruses replicate?
Viruses must infect cells in order to replicate.
The virus must first bind to a structure (e.g., a cell surface protein) on the surface of cell.
After the virus’ genome enters the cell, the virus takes over the host cell’s metabolic resources and uses the cell’s machinery in order to replicate the genomes and assembly new virus particles.
The new viruses are released from the first infected cell and then bind to and infect a neighbouring cell, and the cycle is repeated.
What type of immune response develops following a viral infection?
Both an antibody response and a cell-mediated response involving cytotoxic T cells (CTLs).
Antibodies can neutralize viruses and prevent them from infecting cells.
CTLs are important for killing infected cells and helping to eliminate the virus infection by disrupting its replication cycle.
Describe the innate response to virus infection.
The presence of a virus pathogen would involve the Toll-like receptors (TLRs) and other PRRs that are located on the membranes of the cells endosomes.
These TLRs would recognize virus-specific molecules such as double-stranded RNA, DNA (not usually found in the cytoplasm) and uncapped single-stranded RNA.
Upon recognition, these PRRs initiate a signal transduction cascade that ultimately results in the expression of the Type I Interferon (IFN α/β) genes and the secretion of IFN α/β.
IFN α/β bind to a common receptor found on neighbouring uninfected cells and triggers a signalling cascade that induces the “anti-viral response.” This response may initially limit virus replication, but adaptive responses are needed to eliminate the infection.
What is the anti-viral response?
The uninfected cell shuts off its ability to synthesize protein.
Thus, if a virus does infect the cell, it would not be able to replicate, as protein synthesis is essential in the virus’ replication cycle.
This response may initially limit virus replication, but adaptive responses are needed to eliminate the infection.
How may the production of antibodies against viruses be induced?
Either a natural infection with the virus or by the use of a vaccine.
The antibodies secreted by B cells bind to and neutralize the viruses and prevent them from infecting host cells.
The process of producing antibodies to a virus pathogen is the same as the process of producing antibodies to an extracellular bacterial pathogen.
How are viral proteins made after virus infection?
After a virus has infected a host cell, viral proteins are made in the cytoplasm of the host cell as part of the virus replication cycle.
Some of these proteins are digested by the proteasome into peptides, and MHC class I proteins present the peptides.
Meanwhile, dendritic cells have phagocytosed some virus particles.
Some of the virus proteins are digested in phagolysosomes into peptides, and MHC class II proteins present the peptides.
Recall T cell activation (quick & brief).
T cell receptor must recognize the MHC-peptide complex, the co-stimulation signal results from CD28-B7 interactions and that cytokines are needed as the third signal.
How can effective T cell responses to viruses that do not infect dendritic cells be generated?
Viruses may infect dendritic cells but not be destroyed by the dendritic cell, resulting in viral peptides being displayed on the MHC class I proteins (just like any other infected cell).
However, viruses do not always infect dendritic cells - the dendritic cell might not have the correct cell surface structure for the virus to bind to.
Dendritic cells are also capable of cross-presentation, where viruses that are ingested by phagocytosis will also result in the presentation of viral peptides on both MHC class I proteins and MHC class II proteins.
Because cross-presentation allows the dendritic cell to present exogenous peptides on both MHC class I proteins and MHC class II class proteins, the dendritic cell can activate both CD4 T cells (T helper cells) and CD8 T cells (cytotoxic T cells, CTLs).
What does the dendritic cell provide the T helper cell during their activation?
During the activation of T helper cells, the dendritic cell provides the T helper cell with IL-12, a cytokine that instructs the T helper cell to produce the cytokines IL-2 and IFN-γ.
Why are cytokines from T helper cells essential for naïve CTLs?
They are not able to produce enough IL-2 of their own to proliferate and differentiate into effector cells and memory cells.
What do effector CTLs require to kill a target cell?
Effector CTLs are primed to kill their targets and require only the recognition of the viral peptide presented by MHC class I on an infected cell.
The effector CTLs leave the lymph node and patrol the body, looking for infected cells.
The TCR of the CTL binds to the peptide/MHC class I complex on the surface of the infected cell, causing a signal cascade in the CTL.
How does a CTL kill?
Killing requires cell-to-cell contact and the signaling instructs the CTL to make secreted and cell-surface proteins (i.e., granzymes, perforin) needed to kill the target cell.
Perforin forms pores in the membrane of the target cell.
Granzymes are a set of enzymes that initiate apoptosis (programmed cell death) in the target cell.
Once a cell has been killed, the CTL detaches and seeks out another target cell displaying the same viral peptide-MHC class I complex.
Non-infected cells are not killed because they do not have this viral peptide bound to MHC class I protein on their surface.
In other words, the killing is antigen specific.
What happens to the CTL when all target cells have been eliminated?
It will undergo apoptosis (the recognition of infected target cells seems to provide a survival signal).
The body mounts both an antibody and a cell-mediated response against viral infections. How does the antibody response help?
An antibody response aids in preventing the virus from binding and entering new cells.
When does cross-presentation occur?
When dendritic cells phagocytose a foreign antigen and presents peptides derived from it on MHC class I proteins as well as MHC class II proteins.
What is the benefit of cross-presentation?
Now the dendritic cell can activate both T helper cells and naïve CTLs to fight the viral infection, stimulating both the antibody and cell-mediated responses at once.
In the cell-mediated response, how are naïve CTLs activated?
By both dendritic cells and T helper cells
How does the CTL recognize infected cells?
Through TCR and MHC class I + virus-peptide interaction
The TCR of a thymocyte must be able to interact with an MHC protein in order for the thymocyte to escape apoptosis.
True or false?
True.
The antibody binds to a specific region on the antigen called an epitope.
True or false?
True.
T cell help is needed for the B cell to generate high affinity class switched antibodies.
True or false?
True.
Cytotoxic T cells express the CD8 protein as a co-receptor.
True or false?
True.
T helper cells can be activated when an antigen-presenting cell presents the specific peptide on MHC class II.
True or false?
True.
Cross-presentation is where a peptide derived from an exogenous protein is displayed by an MHC class I molecule.
True or false?
True.
Healthy cells of the body display MHC molecules without a peptide at the cell surface.
True or false?
False
MHC class II proteins present peptides to CD8 T cells.
True or false?
False.
MHC class I can bind peptides derived from self and pathogen proteins.
True or false?
True.
The peptide bound to MHC class I protein is usually derived from exogenous proteins.
True or false?
False.
MHC class I protein present peptides to CD8 T cells.
True or false?
True.
The cell-mediated immune response leads to the destruction of cells that are infected with viruses.
True or false?
True.
Cross-presentation by dendritic cells is necessary to generate CTL responses to viruses that infect tissues but not dendritic cells.
True or false?
True.
A vaccine that contains “live” virus particles will generate a CTL response and an antibody response.
True or false?
True.
A vaccine that contains a protein isolated from a virus particle will generate a CTL response and an antibody response.
True or false?
False.
CTLs kill their targets by activating the apoptosis (programmed cell death) programs in the target cell.
True or false?
True.
What is the initial encounter with antigen known as?
The primary response.
What is the secondary response?
A subsequent encounter with the same antigen will induce a more rapid and vigorous secondary response. The large population of memory cells generated during the primary response accounts for the rapid and vigorous secondary response.
The terms primary and secondary responses apply only to adaptive immune responses.
The terms primary and secondary responses apply to both innate and adaptive immune responses.
True or false?
False.
What happens during the primary antibody response?
Mature naïve B cells with the B cell receptor (BCR) of the correct specificity bind to an antigen and become activated.
What signals the activated B cell to divide and make identical daughter cells with the same antigen specificity?
Signals from helper T cells.
Describe which antibodies are secreted during primary immune response.
Some of the proliferating B cells may differentiate into plasma cells (antibody-secreting cells) that secrete large amounts of antibody, most of which is IgM.
There may be a some B cells that class switch to IgG or IgA before differentiating into a plasma cell.
The secreted antibody has same specificity (antigen-binding site) as the antigen receptor on original cell that had first contacted the antigen and become activated.
Do memory B cells secrete antibodies?
Memory B cells do not secrete antibodies.
They have BCR on their surface that has the same antigen specificity as the BCR on the original B cell.
How do secondary responses result?
Secondary responses only result if the B cell received T cell help during the primary response.
Describe the secondary response.
During the secondary response, the memory B cells and memory CD4 T helper cells specific for a particular antigen are activated when the antigen is re-introduced.
The activated memory B cells begin to proliferate and some of the memory B cells will give rise to more memory cells while others become antibody-secreting plasma cells.
Since you are starting with many memory B cells that recognize that specific antigen, the secondary response is much quicker and more vigorous than the primary response in which you only have a few B cells in your body that recognize that antigen.
Memory cells are also easier to activate than naïve cells.
This is the basis for immunological memory and is exploited with the use of vaccines.
Describe how the primary response primes the immune system for a secondary exposure to the same antigen.
In a primary response, there is a delay of about 5–7 days after immunization with the antigen before antibody can be detected. During this time, the T helper cells and B cells are being activated, proliferating and undergoing differentiation. As plasma cells develop and start to secrete antibody, the concentration of antibody in the blood serum gradually increases. The antibody is typically of low affinity and will last for a few weeks. If re-immunized with the same antigen, the adaptive response occurs much quicker and much more vigorously – antibody can be detected within 2 days.
The memory T helper cells and memory B cells are re-activated, and the B cells quickly respond by differentiating into plasma cells. Because of the proliferation of the T helper cells and B cells during the primary response, there are more cells that recognize this specific antibody. Thus, when the plasma cells develop, there is a larger pool of plasma cells to secrete antibody. The antibody is typically of higher affinity and will last for many months or years.
What is active immunity?
How can it be acquired?
Active immunity is where the individual’s immune system is producing effector cells (e.g., antibody-producing plasma cells, activated T cells) and memory cells. In case of re-infection, your body will have a secondary response.
Active immunity can be acquired naturally by exposure to a pathogen, or artificially by vaccination.
What is passive immunity?
The transfer of pre-formed antibodies from an immune donor to a non-immune recipient confers passive immunity.
It provides immediate, but temporary immunity (e.g., the transferred antibodies last only a few weeks).
No memory responses are developed in passive immunity.
Passive immunity can be acquired naturally or artificially.
Describe how passive immunity can be acquired naturally.
Naturally occurring passive immunization is important early in life before a child’s adaptive immune system is fully developed.
IgG antibodies from the mother’s blood crosses the placenta and provides immunity for the fetus.
IgA antibodies in mother’s milk provide immunity for the baby before the baby’s immune system has fully developed.
Describe how passive immunity can be acquired artificially.
Artificially acquired passive immunity can also be used in life-threatening emergencies.
For example, if a person has come into contact with a dangerous pathogen (e.g., rabies virus), the person may die before their primary immune response can make enough specific antibodies to neutralize the virus.
The injection with pre-formed antibodies specific for the virus can neutralize the danger.
How do vaccines work?
What aspect of the immune system do they utilize?
Many of the vaccines used today induce the production of antibody that recognizes the structures on the pathogen (e.g., virus, bacteria, toxin) that is involved in binding to the host cell.
The vaccine allows the person to have a primary response to the pathogen without getting sick.
If the person is subsequently exposed to the infectious form of the pathogen, the memory T helper cells and memory B cells mount the secondary responses that quickly eliminate the pathogen so that the person does not get sick.
Vaccines utilize the “memory” aspect of the adaptive immune system.
What is the primary response and how is it delayed?
The primary response is when mature, naïve B or T cells bind to an antigen and become activated.
The primary response is delayed as lymphocyte proliferation and differentiation (into effector cells and memory cells) takes time.
What is the secondary response, and why is it faster than the primary response?
The secondary response is the faster and more vigorous response the body has to a pathogen it has already encountered: due to the proliferation of memory cells and effector cells made during the primary response.
Compare passive and active immunity.
Active immunity is when the individual’s immune system is making the cells or antibodies to fight the pathogen.
Passive immunity is when pre-formed cells or antibodies are transferred from one individual to another.
The innate mechanisms of host immunity play a role in the defense of the body regardless of the specific immune response.
True or false?
True
Naturally acquired active immunity may be obtained by an infusion of antibodies across the placenta membranes from the mother’s vascular system to that of the fetus.
True or false?
False.
Naturally acquired active immunity can develop from the administration of antibodies against the rabies virus.
True or false?
False.
What two key events must occur for a successful adaptive immune response?
- The innate immune response must sense ‘danger’ - dendritic cells recruited to the site of infection mature and move to the lymph node.
- T helper cells must be activated - a dendtric cell must present a peptide complexed with MHC class II protein to the T helper cell.
What happens to cells that have an intracellular infection, but are not capable of expressing MHC class II?
These cells cannot be activated.
The bacteria will continue to grow until the cell dies and the bacteria are released into the extracellular environment.
How many the bacteria respond to a macrophage engulfing it?
- Thrive in the acidic environment
- Modify and resist acidification
- Escape!
How may a macrophage be activated?
By two signals:
- secretion of IFN-γ by the T helper cell is one signal
- binding of CD40L on the T helper cell to CD40 on the macrophage.
What does a super-activated macrophage do?
The super-activated macrophage activates transcription of different genes, inducing the production of nitric oxide (NO), oxygen radicals and proteases.
This will kill the bacteria, but also the macrophage and the healthy tissue in the surrounding area.
What type or response is appropriate for an inert virus particle (eg - protein, nucleic acid) in an extracellular state?
An antibody response is appropriate to neutralize the virus before it binds and infects the cell
What type of response is appropriate for replicating viral nucleic acids (eg - gene expression, viral proteins) in the intracellular state?
A CTL response is appropriate to kill cell to disrupt virus replication before it is complete.
What are the main cell types involved in a CTL response to an intracellular virus ?
CTL-P which are activated to CTL
T helper cells to provide extra IL-2 needed for CTL proliferation
Dendritic cells to activate T helper cells and CTL-P
What structures are typical in virus infections that internal TLR recognize?
Uncapped RNA and double stranded RNA
What induces expression of the Type I Interferon (IFN α/β) genes?
Internal TLR recognizing viral structures in an innate response to a virus pathogen.
What does IFN α/β do?
Binds to a common receptor found on neighbouring uninfected cells and triggers a signalling response.
This results in the cell shutting down protein synthesis so that if they get infected, the virus won’t be able to replicate
Both the infected cell and the neighbouring cell might die, but damage is minimal compared to uncontrolled virus replication.
What happens to a virus engulfed by dendritic cells near the infection site?
- Initiates the exogenous peptide presentation pathway
- Peptides produced in the phagolysosome
- MHC II - expected > activates T helper cell > activates CTL-P
- MHC I - X-presented > activates CTL-P > CTL activated
- Activated CTLs find and kill virus infected cells
What happens to a virus infecting a non-dendritic cell of the body?
- Virus replication begins
- Viral genome replication, then viral proteins synthesized
- Virus proteins digested by proteasome (endogenous)
- Peptides displayed on MHC I
- Activated CTLs find and kill this infected cell
Describe what happens if a muscle cell is infected with a virus.
The muscle cells is infected with a virus and presenting a viral peptide on MHC class I, but it does not express the B7 co-stimulatory molecule.
A naïve CTL-P that interacts with it will becomes anergic - living, but nonresponsive (kind of useless), since it does not receive signal #2.
What cell surface proteins do dendritic cells constitutively express?
MHC I
MHC II
B7
What happens to a virus that gets into a lymph vessel?
- Virus gets into lymph node
- Virus binds to BCR of B cell
- Interaction of B cell with T helper cell
- Proliferation and differentiation of B cells
- Secretion of antibodies into body fluids
What happens to a virus in tissues?
- Dendritic cell engulfs pathogen
- Activation of T helper cell by dendritic cell
- Interaction of B cell with T helper cell
- Proliferation and differentiation of B cells
- Secretion of antibodies into body fluids
Primary and secondary responses only apply to what type of immunity?
Adaptive
What is the primary response?
- the initial exposure to a pathogen (that has evaded or overwhelmed the innate responses):
- involves activation of naive T cells and naive B cells
- relatively slow, takes 7 - 10 days to develop
What is the secondary response?
- those that follow exposure to the same pathogen, quicker and more vigorous than the primary response
- involves re-activation of memory T cells and memory B cells
- relatively fast, takes 2 - 3 days to develop
Concept can be exploited for vaccinations
What is active immunity?
Your immune system is doing the work of making antibodies
Your B cells and T cells are becoming activated, proliferating and differentiating, you will develop memory responses!
Natural - no intervention by medical personnel (infection)
Artificial - intervention by medical personnel (vaccine
What is passive immunity?
You are getting antibodies made by someone else.
Your immune system has done zero work
You will not develop memory responses,
Temporary treatment since the injected antibodies are degraded over time
Natural - antibodies crossing a pregnant woman’s plancenta and into her baby
Artificial - you are injected with antibodies after a snake bite to neutralize the venom
