Spring 2000 Immunology Exam #3 KEY - Chapters 8 - 10

There is no time limit on this test, though I have tried to design one that you should be able to complete within 3 hours, except for typing. You are not allowed to use your notes, or any books, any electronic sources, nor are you allowed to discuss the test with anyone until all exams are turned in at 9:30 am on Monday April 10, 2000. EXAMS ARE DUE AT CLASS TIME ON MONDAY APRIL 10. You may use a calculator and/or ruler. The answers to the questions must be typed on a separate sheet of paper unless the question specifically says to write the answer in the space provided. If you do not write your answers on the appropriate pages, I may not find them unless you have indicated where the answers are.

-3 pts if you do not follow this direction.
Please do not write or type your name on any page other than this cover page.
Staple all your pages (INCLUDING THE TEST PAGES) together when finished with the exam.
Name (please print here):


Write out the full pledge and sign:

Here is the honor code

"On my honor I have neither given nor received unauthorized information regarding this work, I have followed and will continue to observe all regulations regarding it, and I am unaware of any violation of the Honor Code by others."

How long did this exam take you to complete (excluding typing)?


I. Define these terms - 2 pts each. When the term is followed by an asterisk (*), provide a specific example to further demonstrate your knowledge. These terms can be define succinctly so using a lot of words is not the best way to demonstrate your fluency with these terms. However, do not leave out important information that you assume the reader knows. Be sure to avoid the word "it".

1) lectin. A sugar-binding protein and selectins are represent a family of lectins that are used for cellular adhesion via addressins.
2) B7. One type of costimulatory proteins expressed by professional antigen presenting cells such as dendritic cells that can stimulate clonal expansion of T cells. B7.1 and B7.2 are two specific examples of the generic name B7.
3) immature dendritic cell *. A Langerhan cell is an example of an immature dendritic cell. It is located under the epithelium and is able to internalize pathogens but is incapable of activating lymphocytes. After engulfing pathogens, it travels to a lymph node and differentiates into a mature dendritic cell which is an APC.
4) cyclosporin A. A drug used to immunosupress patients who have received organ transplants. It works by blocking calcineurin from activating the transcription factor NF-AT which is needed to activate T cells.
5) switch regions of Ig genes. DNA in the Ig gene that is not a part of somatic recombination used to generate diversity of idiotypes, but rather for changing the isotype of a particular idiotype (e.g. from IgM to IgA).
6) Bcl. This molecule is an important player in blocking apoptosis in lymphocytes that have received a survival signal. Normally, when apoptosis is initiated, cytochrome c is leaked from the mitochondia which in turn activats more caspases. Bcl binds to mitochondria and blocks the release of cytochrome c.
7) C3 convertase. This can be composed of three sets of proteins and both sets can convert the complement protein C3 into C3a and C3b, the latter lands on the membrane of cells and continues the complement cascade.
8) extravasation. The process which describes how a leukocyte slows down in a blood vessel, rolls along the endothelial walls, stops, and passes between two endothelial cells and then migrates towards an area of inflamation.
9) follicular dendritic cell. This cell does not originate in the bone marrow, is not a professional APC, and does not express B7. It is located in primary follicles, then germinal centers, of lymph nodes and traps antigens on its surface for B cells to bind after undergoing somatic hypermutation.
10) chemokines *. One example of a chemokine is IL-8. It is expressed in areas of inflamation and are used as a chemoattractant. Chemokines are small cytokines, fall into one of four family types based on the position of their cysteine amino acids, and produced mostly by lymphoctes.

Questions that require you to synthesize what you know:
8 pts.
1) Explain the selective advantages and selective disadvantages behind the concept of original antigenic sin.
The primary advantages are that subsequent immune responses produce higher affnity responses (for antibodies), larger numbers of effector cells, and faster responses.
The primary disadvantages are that as pathogens change their antigens, the individual can only respond to the previously seen antigens until all antigens are new. When all the antigens are new, then the individual has to start from scratch to generate a primary immune response. The body has "missed" opportunities to keep the lymphocytes as updated as the pathogen until it is too late.

9 pts.
2) Design a potential vaccine to protect us from leprosy. Remember that leprosy lives inside macrophages. There will be more than one right answer to this question but you must provide an answer that is consistent with what we have learned so far. A complete answer will include what is to given to the patient and why this would work as a vaccine.
Since I want to attack a pathogen inside macrophages, I would want to include IL-12 and IFN-g in my immunization to produce TH1 CD4+ cells instead of TH2 CD4+ cells.
Next, I would want to display a peptide that would get displayed in MHC II, so I might create a hapten conjugated to a large molecule such as bovine serum albumin that would be easily detected (opsonized by antibodies) and phagocytosed.
I would also include adjuvant to make sure all the APC's were activated to express co-stimulatory molecules such as B7.
Finally, I would inject this into muscle to facilitate the uptake by Langerhans cells.

9 pts.
3) Design a potential vaccine against HIV that will work for a lifetime. Remember that HIV infects CD4+ cells and HIV envelop proteins mutate 65 times faster than the flu virus. There will be more than one right answer to this question but you must provide an answer that is consistent with what we have learned so far. A complete answer will include what is to given to the patient and why this would work as a vaccine.
I would want a two pronged vaccine.
First, I would try to produce a molecule that would bind to CCR5, an important co-receptor for HIV. This molecule (perhaps a human monoclonal antibody Fab fragment) would prevent or delay the ability of HIV to infect cells but not crosslink the co-receptor.
Second, I would produce a CD8+ response against a very stable portion of HIV, such as RT or protease. To do this, I would create a harmless DNA virus that carried RT and/or protease genes. This virus would infect some cells (not CD4+ cells) and generate an immune response that produced CD8+ memory cells. This would prime people to destroy infections that did occur if the first prong was bypassed.

8 pts.
4) Since IgE gives us mostly allergic responses, why did we evolve it in the first place? In your answer, provide at least three specific effects that contribute to IgE responses being advantageous.
We evolved the IgE responses to fight off large eukaryotic pathogens, such as worms, which are too large to phagocytose. These parasites can best be destroyed when mast cells and eosinophils bind to the worm via IgE. The binding stimulates the exocytosis of toxic substances which can kill the parasite.
The specific effects include: 1) the recruitment of other effector cells, 2) increase flow of lymph draining the area, 3) the induction of exocytosis of toxic compounds, 4) triggering muscle contractions that can lead to physical expulsion of parasites, and 5) a very fast response (seconds).

8 pts.
5) Explain how it is possible that so many APC's can wind up congregating in a single infected tissue.
APC's, like all leukocytes, are recruited to inflamed tissues via chemokines. When the innate immune system responds to an infection, it produces inflammatory molecules that cause the local blood vessels to become leaky. The leak permits more leukocytes (macrophage and B cells) to enter the tissue. Inflammation can also induce endothelial cells to express adhesive molecules which facilitate extravasation (see ID definition above).

8 pts.
6) We all know plasma cells cannot isotype switch. Think about this: armed TH cells express CD40L after encountering B cells displaying antigen, and IL-4 induces isotype switching. The book is not clear on this fact but you should be able to deduce the answer. Where is the most likely location for isotype switching to occur? To receive full credit, you must explain your answer.
The most likely area for isotype switching would be in the primary focus within the T cell zone of a lymph node. This is where a TH cell would encounter the antigen displaying B cell before the B cell differentiated into a plasma cell.

The last two questions are very large ones that integrates many concepts and processes.
15 pts.
7) Using an outline format, list how your immune system is activated after you have just spent the day with a runny-nose child who has given you a virus that you now must fight off. Begin after the virus has infected your cells and don't stop until all the viruses are gone. This answer should include all the major parts of a complete immune response. You do NOT need to list steps involved in signal transduction pathways.
I. Innate Response
A. Langerhans cells pick up virus that come from infected cells.
B. NK cells identified virally infected cells and killed those with altered MHC I or not enough MHC I on their surfaces.
C. Macrophages phagocytose free viruses and secrete TNF-
a to induce inflammation and later clot local vessels to prevent spreading of virus.
II. Transition Towards Adaptive
A. Langerhans cells move to lymph node and differentiate into dendritic cells that display viral peptides in MHC I.
B. Dendritic cells express co-stimulatory molecules such as B7.
III. Activation of Adaptive
A. Naive CD8+ T cells enter lymph node via HEV.
B. CD8+ T cells that are specific for viral peptides bind to dendritic cell and become activated. The T cells divide and differentiate into effector and memory T cells.
C. Effector CD8+ cells leave the lymph node.
IV. Homing of Effector Cells
C recirculate until they home to inflamed area (due to neutrophil and macrophage phagocytosis induced production of cytokines).
V. Killing
C bind to and kill virally infected cells by secreting perforin and granzymes to induce apoptosis.
VI. Humoral Response
Meanwhile, B cells that bind to the free virus internalized viruses and presented peptides in MHC II, entered lymph nodes, and presented them to CD4+ T cells that were also activated by macrophages and dendritic cells that presented peptides in MHC II. This resulted in an antibody response that:
A. neutralized free virus
B. bound to viral envelop proteins on infected cells and targeted them for destruction by NK cells.

15 pts.
8) Use an outline format to list the major steps involved in an adaptive immune response that begins with a splinter in your thumb and winds up with an IgG antibody response to eventually eliminate the bacteria that were resting on the splinter. Make sure you include what happens after the antibodies are made that leads to death of the cells. You do NOT need to list steps involved in signal transduction pathways.
I. Innate Responses
A. Langerhans cells, neutrophils, and macrophages phagocytose bacteria.
B. Macrophages secrete TNF-
a to induce inflammation and later clot local vessels to prevent spreading of bacteria.
C. Complement (via alternative and/or MBL pathways) may start to destroy bacteria either directly or via opsonization, and also produce more inflammation.
II. Transition Towards Adaptive
A. Langerhans cells and macrophages move to lymph node and differentiate into professional APCs that display bacterial peptides in MHC II.
B. Dendritic cells and macrophages express co-stimulatory molecules such as B7.
III. T-helper Cell Activation
A. Naive CD4+ T cells enter lymph node via HEV.
B. CD4+ T cells that are specific for bacterial peptides bind to APCs and become activated. The B cells divide and differentiate into effector and memory B cells, presumably TH2 in the presence of IL-4.
C. Effector CD4+ cells stay in the lymph node and eventually, one or more naive B cell that has bound and processed a bacterial peptide in MHC II enters the lymph node via an HEV.
IV. B Cell Activation
A. B cells interact with activated CD4+ cells, become activated, proliferate to form the primary focus, differentiate, and isotype switch.
B. Some B cells go to the medulary cord to produce plasma cells and thus antibodies. Some of the antibodies bind to antigen draining from the infected tissue and then follicular dendritic cells' Fc receptors. Other antibodies leave the node, enter the blood, and start to bind to bacteria in the infected tissue.
C. Other B cells go with CD4+ T cells to form a germinal center.
D. B cells in the germinal center undergo somatic hypermutation and compete for binding to antigen and then activation by the layer of CD4+ cells.
V. Affinity Maturation
B cells with higher affinities survive and leave the lymph node. They differentiate into plasma cells and memory cells.
VI. Functional Consequences of Antibodies
Antibodies are produced to bind to the bacteria. This has thee main consequences:
A. Opsonize the bacteria for phagocytosis.
B. Neutralize bacteria from binding to receptor sites.
C. Lead to bacterial inflamation, more opsonization, and bacterial death via the classical pathway for complement.

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