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Dr. Ali Khan took these papers at University of Lucknow for Immunology course in past. It includes: Fashion, NFAT, Immunosuppressive, Determine, Embarressment, Decompressor, Recombination, Granzymes, Homozygosed, Mediated, Phenotypes
Typology: Exams
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a. Explain in a stepwise fashion how signals from the T cell receptor induce NFAT activity in the nucleus. Explain briefly how you think FK506 /Tacrolimus (an immunosuppressive drug) works.
A) Please provide a diagram of deletional VDJ signal and coding joint formation (include a diagram of the important parts of the locus before VDJ recombination, the two intermediates, and the end products. Please indicate any regions which are altered in the process).
B) You have just examined a male infant with recurrent oral candidiasis (thrush) and non-pyogenic lung infections. Another male sibling received a bone marrow transplant four years ago after presenting in a similar manner. Serum immunoglobulins are normal, but the child lacks CD4 T cells, CD8 T cells, and NK cells. The diagnosis of severe combined immunodeficiency is made. What do you think may be the molecular defect in this child?
Viruses have been shown to evade every aspect of innate and adaptive immunity. Viruses which can evade the host’s immune system to establish a chronic, persistent infection have a selective advantage over those viruses which are not able to evade the immune system..
Three examples of viral immune evasion strategies are described below. For each of the three strategies, please state whether virally-infected cells would be killed by i) CTLs and/or ii) NK cells, and explain why target cell killing would or would not occur (1 sentence)
A) HIV taken from HLA-A2 positive individuals often harbors mutations in the sole viral epitope presented by HLA-A2, resulting in loss of binding to HLA-A2.
i) HLA-A2-restricted CTLs -
ii) NK cells -
B) Human cytomegalovirus (HCMV) encodes a protein called US3 that binds to MHC Class I molecules and retains them in the ER, so that they never get presented on the cell surface.
i) CTLs -
ii) NK cells -
C) Poxviruses encode a protein called crmA, which can inhibit caspases, which are proteins in the apoptosis cascade downstream of granzymes and Fas.
i) CTLs -
ii) NK cells-
D) Other viruses have strategies to evade MHC Class II presentation, and therefore CD4 +^ T cell activation. Given that eradication of the infected cell requires MHC Class I presentation, give two reasons why would it be advantageous for these viruses to inhibit CD4 +^ T cell activation.
A) You'd previously been working on a vaccine for Hepatitis B and have immunized wild type mice in four different ways:
Will any of these immunizations generate a good humoral immune response? Explain why each immunization may or may notinduce a humoral immune response (1 sentence each).
B) Excited about innate immunity, you create TLR 1Æ10 (all inclusive) knockout mice. Will any of these immunization strategies work for your TLR 1-10 knockout mice? Briefly explain.
A) Complement subserves many functions. Please list three functions mediated by the complement cascade and its byproducts.
B) What aspect of the IgM molecule facilitates its ability to initiate the classical complement pathway?
C) Fascinated by the germinal center reaction, you find a way to eliminate the follicular dendritic cell. Describe some expected phenotypes of your mice.
D) Explain how AID is thought to mediate isotype switching,
C) Different inbred strains have different susceptibilities to some pathogens. For example, BALB/c mice are extremely susceptible to infection with the intracellular pathogen, Leishmania. C57Bl/6 mice are resistant to Leishmania infections, and are able to easily overcome the infection.
A large kindred in Utah is being studied to examine susceptibility to a multi-gene disease. In this syndrome, skin rashes are frequently observed in affected individuals, some of whom presented with inflammation of the pleura and the pericardium, while others developed kidney disease. The following results from an affected patient were made available to you. (Rheumatoid factor: Negative, Anti-double stranded DNA antibodies: Present at high titers, Circulating immune complexes: Positive)
A) What is your first diagnostic choice?
Affected individuals were found to carry deletions or loss of function mutations in a gene called Mer. This gene was expressed in macrophages and dendritic cells and its sequence predicts an N-terminal signal peptide, a putative extracellular domain, a transmembrane anchor sequence and a tyrosine kinase domain. In order to better understand how this gene contributes to disease, a Mer knockout mouse was created. Thymoctes from wild type and mutant mice were treated with dexamathasone in vitro (dexamathasone induces thymocyte apoptosis) and mixed with macrophages from a normal littermate. Please examine the accompanying figure and legend.
Figure 1. Phagocytosis of opsonized thymocytes. Apoptosis was induced in vitro using Dexamethasone. Apoptotic (AT) and untreated /normal thymocytes (UT) were opsonized with a non-activating anti- T cell antibody (an IgG antibody) that recognizes the T cell surface, or isotype-matched non-specific antibody. OAT, AT opsonized with anti-T cell antibodies; IAT, AT incubated with isotype control non-specific antibody; OUT, UT with anti-T cell antibodies; IUT, UT with isotype-matched non-specific antibody. The average and standard error from three experiments are plotted. Black bars, phagocytosis by macrophages from wild-type mice; light grey bars, phagocytosis by macrophages from mer kd mice. Asterisk, P < 0.05; double asterisk, P < 0.001.
B) What appears to be the function of Mer? Explain in no more than 3 sentences.
Macrophages with Phagocytosed AT (%)
merkd
Figure by MIT OCW.
A young girl with a skin disorder was also found to have high levels of IgM, and barely detectable IgG, IgA, or IgE. B cells were purified from her peripheral blood and stained with anti CD40. Flow cytometry revealed normal levels of CD40 on B cells. Total RNA was reverse transcribed and PCR sequencing of CD40 was performed. The CD40 sequence was found to be normal.
Proliferation Assays using 3H-thymidine. Stimulus Control B cells Patient’s B cells IL-4 33, 000 cpm 35, 000 cpm
CD40L 97, 000 cpm 870 cpm
A) Make an educated guess as to the nature of the gene defect in this girl. Explain very briefly.
B). Do you think that immunization with a pneumococcal polysaccharide vaccine will or will not result in specific antibodies being generated in this girl. Briefly explain your answer.
C) Will immunization with tetanus toxoid result in similar or different antibodies being generated in this girl and a normal unaffected cousin? Provide a brief explanation for your answer.
A young woman enters your office, obviously terrified. She describes sensations of “pins and needles” in her extremities, a broken arm from a recent stretch of “clumsiness” and difficulty with coordination. What really brought her in today was a sudden monocular loss of vision this morning that lasted for 5 minutes and then passed. She’s convinced she has a brain tumor, but you aren’t so sure. She mentions a recent upper respiratory tract infection and asks if that could be related.
A) What disease are you most concerned about?
Molecular mimicry is one theory for the initiation of autoimmune disease. Basically, the theory is that an adaptive response to a pathogen leads to a cross-reactive population of cells that then attacks self, usually in a Th1 dependent manner.
B) How could you test the molecular mimicry hypothesis?
C) If molecular mimicry is the mechanism of autoreactive cell generation, describe a cell population that could control these autoreactive cells (include potential effector mechanisms for this cell population).
D). Another way to treat disease is to alter the ability of effector cells to reach their target. List two ways of preventing these cells from reaching their target tissues.
E) It might be possible to alter the function of the effector cells. Describe a way of achieving this goal therapeutically (i.e. what would you administer)?
F) Are central and peripheral tolerance redundant? Why or why not?