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
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.
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.
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.
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.
