Lecture 28

Question 1

1. What cells are present in the adaptive immune system?
   
   1. What kind of cells are these?
   2. How are they different?
   3. How are they same?
2. How do these cells recognize specific molecules?
   
   1. How are they activated?
3. What is Antigen Presentation?
4. What is MHC I (class I)?
5. What is MHC II (class II)?

Answer 1

1. There are T cells and B cells.
   
   1. Both are a type of leukocyte called lymphocyte.
   2. T cells = cell-mediated immunity. B cells = antibody-mediated immunity. B cells mature in the bone marrow, antigen presenting cells and precursors of plasma cells (plasma cells produce antibodies). T cells mature in the thymus, interact with antigens.
   3. B and T cells circulate in blood and lymph and are concentrated in lymph nodes and spleen for interaction with antigens.
2. Both have receptors on their surface that recognize (bind to) specific molecules.
   
   1. Activation of these cells involves recognition of peptide antigens presented by other cells.
3. By phagocytes or infected cells via MHC proteins (major histocompatibility complex) on the cell surface. A system for recognizing “self” and “non-self”
4. On surface of all nucleated cells.
5. Only on surface of macrophages, dendritic cells, and B cells.

Question 2

1. What is the MHC?
2. What two protein complexes process and display peptides?
3. What does MHC I mediate?
4. What does MHC II mediate?
5. Where is the peptide held?

Answer 2

1. Cell surface molecules. Mediate interactions of leukocytes with other leukocytes or with body cells. Display an antigen (peptide). The antigen can either be “self” or “non-self”.
2. MHC I & MHC II
3. Mediates the destruction of host cells displaying non-self antigen. Nucleated cells normally display self peptides, which arise during protein turnover during viral or bacterial infection. The pathogens proteins are broken down in the proteasome of the infected cell, loaded onto MHC-I molecules, and displayed on the cell surface.
4. Mediates specific immunity to an antigen. Phagocytes (i.e. macrophages and dendritic cells) take up pathogens by phagocytosis into phagosomes. The phagosomes fuse with lysosomes, which have enzymes that digest the pathogen’s proteins into peptides. One of the kinds of peptides generated by that digestion is loaded onto the MHC-II molecule and displayed on the cell surface.
5. The peptide is held by the peptide-binding groove (binding site). The sequence of amino acids of the binding site determines which particular antigen.

Question 3

1. What do MHC proteins normally function to do?
2. Where are they located?
3. How are they anchored?
4. What parts bind foreign antigens?
5. What do they do with the antigen?

Answer 3

1. Function mainly as antigen-presenting molecules.
2. Embedded in the cytoplasmic membrane and project outward.
3. Constant part(s) anchor MHC in membrane.
4. Variable parts bind foreign (pathogen-derived) antigens. Also bind self peptides = antigens
5. Display antigens for interaction with T cell receptors (TCR).

Question 4

1. How do T cells interact with antigens?
2. What is TCR made up of?
   
   1. What do these chains contain?
3. What is the antigen binding site made up of?
4. What are the two kinds of T cells?

Answer 4

1. Interact with antigens by means of receptors (T cell receptors, TCRs) on their surface.
2. Made up of an alpha chain and a beta chain.
3. Each chain has a variable region and a constant region.
4. Made up of V_α​ and V_β domains.
5. Cytotoxic T cells (T_c cells) and helper T cells (T_H cells).

Question 5

1. How does the adaptive immune response begin?

Answer 5

1. First, a phagocytic cell (e.g., macrophage, which is an antigen-presenting cell, APC) engulfs and digest a pathogen, processes its antigens, and presents the pathogen antigens on its surface.
2. The antigens are presented on MHC proteins. All host cells display MHC I proteins, and macrophages, dendritic cells, and B cells also display an additional antigen-presenting protein, MHC II.

Question 6

MHC-I system

1. What are the proteins in the cytoplasm degrade by?
2. Where does the product released by the degradation go?
3. Where does the MHC-I/peptide complex go?
4. What does the fusion do?

Answer 6

1. Proteins in the cytoplasm are degraded by the proteasome, releasing peptides (about 10 amino acids long).
2. These peptides enter the ER via TAP proteins (transporters associated with antigen processing); there they join with newly synthesized MHC-I.
3. The MHC-I/peptide complex enters the Golgi apparatus, which places it in a secretory vesicle that moves to and fuses with the cytoplasmic membrane.
4. This fusion externalizes the MHC-I/peptide complex on the outside of the cytoplasmic membrane, where it can interact with T-lymphocytes (T cells).

Question 7

1. What do infected non-phagocytic cells present pathogen peptide antigens to?
2. What is the peptide held by?
3. What is the funtion of the T_c cells in this case?
   
   1. How are these cells activated?

Answer 7

1. Infected non-phagocytic cells present pathogen peptide antigens to cytotoxic T cells via the MHC-I.
2. The peptide is held by the peptide-binding groove. The sequence of amino acids of the binding site determines which particular antigen.
3. T_c cells attack cells carrying foreign antigens on their surfaces (i.e., those infected with viruses or bacteria). Each T_c recognizes a different antigen.
   
   1. T_c cells are activated when their TCR binds to the antigen, which is presented by the MHC-I receptor on the surface of an infected cell. This binding is aided by a co-receptor on the T_c cell, CD8.

Question 8

1. What do the activated T_c cells release?
2. What do perforins do?
3. What do granzymes do?
4. What do T_c​ cells do throughout the body?
5. What type of immunity is this?

Answer 8

1. T_c​ cells released granules containing perforins and granzymes. These are cytotoxins.
2. Perforins perforate the target cell.
3. Granzymes induce the target cell to undergo apoptosis (programmed cell death)
4. Activated T_c​ cells hunt through the body for cells whos MHC-I receptors carry this antigen; they bind, release cytotoxins, and kill the infected cell. This kills off infected cells, preventing the survival and replication of bacteria and viruses that have infected them.
5. Cell-mediated immunity.

Question 9

MHC-II & T_H cells

1. How does the process begin?
2. What does the binding of the TCR of the T_H cell do?

Answer 9

1. Phagocytic antigen-presenting cells (i.e., macrophages) that have ingested a pathogen, process and present peptide antigens to T helper (T_H) cells via MHC-II.
2. Binding of the TCR of the T_H cell to the antigen-MHC II complex of the presenting cell is aided by a co-receptor on the T_H cell, CH4. This binding activates the T_H cell.

Question 10

1. What are T_H1 cells?
2. What do these cells produce when activated?

Answer 10

1. One of two kinds of T helper cells. Stand for inflammatory T cells.
2. When activated by binding via the TCR and MHC-II-antigen complex, these produce cytokines, which activate macrophages to be more actively phagocytic and to release cytokines, and which stimulate the inflammation repsone.

Question 11

1. What are T_H2 cells?
2. What cells do these T_H2 cells interact with?
3. What do B cells have on their surface?
   
   1. What does this structure function as?
   2. What happens when a B cell binds a specific antigen?
   3. What does the binding eventually lead to?

Answer 11

1. T_H2 cells (T-helper 2 cell).
2. Interact with B cells, activating them for antibody production.
3. B cells have antibody on the cell surface.
   
   1. This antibody functions as an antigen receptor.
   2. In the presence of the specific antigen that a B cell’s antibody binds to, the antigen is bound and then endocytosed and processed (digested) in the B cell.
   3. The B cell then presents peptides from the processed antigen via its MHC II proteins. A T_H2 cell with the TCR for that antigen the binds. That binding activates the T_H2 cell to release interleukins (cytokines).

Question 12

1. What two interleukins activate the B cell to clonally expand?
2. What do these newly formed cells produce?
3. Overall what do B cells function to do?

Answer 12

1. IL-4 & IL-5 activate the B cells to clonally expand and differentiate into plasma cells.
2. The plasma cells, which have a short lifespan, about a week, then produce antibodies against that antigen (the primary adaptive immune response). This is antibody-mediated immunity. The antibodies bind their specific antigen, wherever in the body they find it, and that neutralizes the antigen and targets it for destruction.
3. B cells first function as antigen-presenting cells, then respond to signals sent by T_H2 cells to become antibody producers. Also, some of the activated B cells differentiate into memory cells, which have a long lifetime. When exposed a second time to an antigen

Question 13

1. What is antibody-mediated immunity effective against?
2. What are immunoglobulins?
3. What are the five major classes of antibodies?
4. What antibodies make up most of serum?
5. What are the functions of antibodies?

Answer 13

1. Effective against extracellular bacteria and soluble pathogen products, such as toxins in the blood or lymph.
2. Proteins that bind specifically to certain portions of the antigen, called antigenic epitope (or antigenic determinant).
3. IgG, IgA, IgM, IgD, IgE
4. IgG
5. Bind their specific antigen, wherever in the body they find it, and that neutralizes the antigen and targets it for destruction.

Question 14

1. What does IgG consist of?
   
   1. How many chains does it have?
   2. What regions do these chains contain?
2. Why are these chains needed?
3. Are antibodies bivalent?
4. How are antibodies different?

Answer 14

1. Four polypeptide chains, two light chains (identical to each other).
   
   1. Two heavy chains (identical to each other).
   2. Variable and constant regions on both chains.
2. Variable domains of the light and heavy chains interact to form the receptors that bind antigen.
3. Antibodies are bivalent, each one can bind two of the same antigen.
4. The variable regions of different antibodies have different sequences. Each sequence type forms a different antigen-binding site and so binds a different antigen. Each person produces billions of uniquely different antigen-binding sites.

Question 15

1. What are the three ways in which antibodies function in binding to a pathogen’s antigen?

Answer 15

1. Three ways
   
   1. They prevent the pathogen from entering or damaging cells and tissues - antibodies bind to pathogens sticking them together, causing them to agglutinate (clump together).
   2. They mark the pathogen for destruction by macrophages and other cells - antibodies that bind to surface antigens on, for example, a bacterium, attract the first component of the complement cascade, initiating the action of the “classical” complement system. The binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes, a process called opsonization.
   3. They stimulate other immune responses, such as the complement pathway, to destroy the pathogen - some complement system components form a membrane attack complex that assists antibodies in killing the pathogen directly.

Question 16

1. What is a requirement of the immune system’s ability to recognize and remove pathogens?
2. How are antibodies able to recognize many different antigens?
3. How many antibodies do humans make?
4. How many genes encode these antibodies?

Answer 16

1. The immune system’s ability to recognize and remove pathogens requires that antibodies be made that can bind to the different pathogens the body interacts with.
2. The amino acid sequence of the variable regions of antibodies vary, allowing them to recognize a hige diversity of different antigens.
3. Humans make about 10 billon different antibodies, each of which can bind a distinct epitope of an antigen.
4. The number of genes that encode antibodies is only a few hundred.

Question 17

Domain variation, V(D)J (Somatic) Recombination.

1. What is unique about this region?
2. What is the variable domain?
3. What other domains are there?
4. How many variable domains does the heavy chain locus contain?

Answer 17

1. The region of a chromosome that encodes an antibody is large and contains several distinct genes for each domain of the antibody.
2. Is present in each heavy and light chain of every antibody, but can differ in different antibodies genereated from distinct B cells.
3. Diversity, joining, and constant domains, each coded for by several genes.
4. The heavy chain locus contains about 65 different variable domain genes that all differ in their hypervariable regions. Combining these genes with an array of genes for other domains of the antibody generates a huge number of antibodies with high degree of variability. This is caled V(D)J recombination.

Question 18

1. What happens to the genes for the heavy chain and light chain during the development of B cells?
2. How is the final heavy gene assembled?
3. How is the final light gene assembled?

Answer 18

1. During the development of B cells in bone marrow, the genes for the heavy chain and for the light chain each undergo rearrangement. Individual gene pieces are mixed and matched into a variety of combinations. The gene encoding each part of the antibody heavy or light chain is constructed from different gene segments; each segment codes for a portion of the final gene.
2. Assembled from a variable region segment, a diversity segment, a joining segment, and a constant region gene.
3. Assembled from a variable region segment, a joining segment, and a constant region gene.
4. Randomly selected V, D, and J segments are recombined to form the functional heavy and light chain genes.

Question 19

1. What does somatic hypermutation lead to?
2. What is the result?

Answer 19

1. Leads to even further antibody diversity.
2. Billions of possible different combinations of antigen binding sites.

Question 20

1. What is complement?
2. What do complement proteins reacting with each other do?
3. What are the three steps in complement activation and pathogen destruction?

Answer 20

1. A group of sequentially interacting proteins that are important in both innate and adaptive immunity.
2. Reacting with each other and with target cell components, causes lysis of pathogen cells or mark cells for recognition by phagocytes, stimulating them to ingest and destroy the target cell.
3. 3 steps:
   
   1. Binding of antibody to antigen.
   2. Binding of C1 proteins to the antibody-antigen complex, which leads to binding of C2 and C4 proteins and binding of C3 protein.
   3. Binding of C3 catalyzes formation of a C5-7 complex, which leads to binding of C8 and C9. The C5-C9 proteins are the membrane attack complex and cause membrane damage, leakage, and pore formation in the membrane. Very affective against Gram-negative bacteria.

Question 21

1. What is opsonization?
2. What do most phagocytic cells have?
3. How much is phagocytosis enhanced?
   
   1. What does this process work well against?

Answer 21

1. An enhancement of phagocytosis by antibody binding. And a further enhancement by binding of C3.
2. Have antibody receptors (for binding the antibody constant domain of an antibody bound to a pathogen cell). And C3 receptors (for binding C3 protein bound to a pathogen cell).
3. Normal phagocytosis is enhanced 10x by antibody binding, and another 10x by complement (C3) binding.
   
   1. Works well against gram-positive bacteria.