For each weekly session, students are required to read two primary literature articles using the Guidelines for Reading Papers document. (PDF)

1 Introduction We will begin the course by introducing ourselves and discussing our interests inside and outside of biology. We will also discuss the plan for the course: policies, assignments, goals, etc. We will then discuss an overview of immunology. I will end class with a 10 minute lecture on the role of defensins and complement in innate immunity and distribute the papers to be read and analyzed for next week's class.  
2 Innate Immunity Defensins and complement act directly on targets leading either to cell lysis or phagocytosis by macrophages. These articles look at the potentially immunoevasive function of complement resistance factors expressed by cancer cells and anti-defensin products produced by bacteria. Yu, J., T. Caragine, S. Chen, B. P. Morgan, A. B. Frey, and S. Tomlinson. "Protection of human breast cancer cells from complement-mediated lysis by expression of heterologous CD59." Clin Exp Immunol 115 (1999): 13-18. Fields, P. I., E. A. Groisman, and F. Heffron. "A Salmonella locus that controls resistance to microbicidal proteins from phagocytes." Science 243 (1989): 1059-1062.
3 Antibodies Antibodies play a key role in the elimination of blood-borne pathogens. Antigenic variation is one mechanism for escaping antibody binding. We will discuss SIV variation to escape binding of neutralizing antibodies and also examine a case in which antibody binding may protect a pathogen from immune destruction. Kinsey, N. E., M. G. Anderson, T. J. Unanagst, S. V. Joag, O. Narayan, M. C. Zink, and J. E. Clements. "Antigenic variation of SIV: Mutations in V4 alter the neutralization profile." Virology 221 (1996): 14-21.

Garcia, I. E., M. R. Lima, C. R. Marinho, T. L. Kipnis, G. C. Furtado, and J. M. Alvarez. "Role of membrane bound IgM in Trypanosoma cruzi evasion from immune clearance." J. Parasitol 83 (1997): 230-233.
4 MHC Class I - Peptide Processing and Loading
Instructor Demonstration of a Presentation
Antigen derived from intracellular pathogens is degraded and presented by MHC class I products. This week we will examine two of the many steps along the antigen processing pathway that are interrupted by viruses and discuss which other points along the pathway are targeted by other viruses. At the end of class, I will give a demonstration of the type of oral presentation you will make later in the class. Levitskaya, J., M. Coram, V. Levitsky, S. Imreh, P. M. Steigerwald-Mullen, G. Klein, M. G. Kurilla, and M. G. Masucci. "Inhibition of antigen processing by the internal repeat region of the Epstein Barr virus nuclear antigen-1." Nature 375 (1995): 685-688.

Hengel, H., J. O. Koopmann, T. Flohr, W. Muranyi, E. Goulmy, G. J. Hammerling, U. H. Koszinowski, and F. Momburg ."A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter." Immunity 6 (1997): 623-626.
5 MHC Class I - Maturation of Heavy Chains This week we will continue our discussion of the MHC class I antigen processing and presentation pathway. We will focus on the mechanism used by HCMV to inhibit the maturation of MHC class I heavy chains. We will discuss the use of different model systems and how we can learn about cellular processes by the way they are exploited by viruses. Wiertz, E. J., T. R. Jones, L. Sun, M. Bogyo, H. J. Geuze, and H. L. Ploegh. "The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol." Cell 84 (1996): 769-779.

Zhao, Y., and B. J. Biegalke. "Functional analysis of the human cytomegalovirus immune evasion protein pUS3 22kDa." Virology 315 (2003): 353-361.
6 NK Cells If cells are deficient in MHC class I surface expression, they become susceptible to NK cell-mediated lysis. This week we will discuss the ways in which a cell might downregulate class I surface expression to avoid CTL lysis without simultaneously attracting NK cell lysis. Park, B., H. Oh, S. Lee, Y. Song, J. Shin, Y. C. Sung, S. Y. Hwang, and K. Ahn. "The MHC class I homolog of human cytomegalovirus is resistant to down-regulation mediated by the unique short region protein (US)2, US3, US6, and US11 gene products." J. Immunol 168 (2002): 3464-3469.

Cretney, E., M. A. Degli-Esposti, E. H. Densley, H. E. Farrell, N. J. Davis-Poynter, and M. J. Smyth. "m144, a murine cytomegalovirus (MCMV)-encoded major histocompatibility complex class I homologue, confers tumor resistance to natural killer cell-mediated rejection." J. Exp. Med. 190 (1999): 435-443.
7 CD4/MHC Class II MHC class II presentation of the extracellular form of pathogens leads to the activation of CD4+ T cells. These T cells then help B cells produce antibody. This week we will discuss a trick performed by HIV to prevent CD4+ T cell activation and the mechanism used by herpes virus to prevent proper MHC class II antigen presentation. Garcia, J. V., and A. D. Miller. "Serine phosphorylation-independent downregulation of cell-surface CD4 by nef." Nature 350 (1991): 508-511.

Sievers, E., J. Neumann, M. Raftery, G. Schonrich, A. M. Eis-Hubinger, and N. Koch. "Glycoprotein B from strain 17 of herpes simplex virus type I contains an invariant chain homologous sequence that binds to MHC class II molecules." Immunology 107 (2002): 129-135.
8 Endocytosis/Degradation Some pathogens are endocytosed by antigen-presenting-cells and destroyed in endocytic vesicles. This week we will discuss two examples of bacteria that have developed ways to prevent acidification of these vesicles and thereby escape the ensuing degradation. Tsukano, H., F. Kura, S. Inoue, S. Sato, H. Izumiya, T. Yasuda, and H. Watanabe. "Yersinia pseudotuberculosis blocks the phagosomal acidification of B10. A mouse macrophages through the inhibition of vacuolar H+-ATPase activity." Microb Pathog 27 (1999): 253-263.

Sturgill-Koszycki, S., P. H. Schlesinger, P. Chakraborty, P. L. Haddix, H. L. Collins, A. K. Fok, R. D. Allen, S. L. Gluck, J. Heuser, and D. G. Russell. "Lack of acidification in mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase." Science 263 (1994): 678-681.
9 Anergizing/Tolerizing of T Cells Most auto-reactive T cells are deleted during the process of maturation in the thymus. However, some auto-reactive cells mature and are inactivated in the periphery via the process of tolerization or the induction of anergy. This week we will discuss the mechanisms used by a cancer cell and an intracellular bacteria to regulate the function of T cells specific for their antigens. Staveley-O'Carroll, K., E. Sotomayor, J. Montgomery, I. Borrello, L. Hwang, S. Fein, D. Pardoll, and H. Levitsky. "Induction of antigen-specific T cell anergy: An early event in the course of tumor progression." Proc. Natl. Acad. Sci. 95 (1998): 1178-1183.

Darji, A., B. Stockinger, L. Wehland, T. Chakraborty, and S. Weiss. "Antigen-specific T cell receptor antagonism by antigen-presenting cells treated with the hemolysin of Listeria monocytogenes: a novel type of immune escape." Eur. J. Immunol 27 (1997): 1696-1703.
10 Apoptosis Apoptosis is one mechanism by which T cells kill infected cells. This week we will study two viruses and the proteins that they express to prevent cells that they have infected from undergoing apoptosis and thus limiting the spread of the virus. In the process, we will discuss the role of viral proteins that are homologs of cellular proteins. Marshall, W. L., C. Yim, E. Gustafson, T. Graf, D. R. Sage, K. Hanify, L. Williams, J. Fingeroth, and R. W. Finberg. "Epstein-Barr virus encodes a novel homolog of the bcl -2 oncogene that inhibits apoptosis and associates with bax and bak." J. Virol. 73 (1999): 5181-5185.

Tewari, M, W. G. Telford, R. A. Miller, and V. M. Dixit. "CrmA, a poxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediated apoptosis." J. Biol. Chem. 270 (1995): 22705-22708.
11 Cytokines Cytokines are key mediators in determining the course of an immune response. This week we will examine the two cases of pathogen interference with normal cytokine expression and we will discuss other steps in the pathway of cytokine function that are affected by pathogens. Karp, C. L., M. Wysocka, L. M. Wahl, J. M. Ahearn, P. J. Cuomo, B. Sherry, G. Trinchieri, and D. E. Griffin. "Mechanism of suppression of cell-mediated immunity by measles virus." Science 273 (1996): 228-231.
Jackson, R. J., A. J. Ramsay, C. D. Christensen, S. Beaton, D. F. Hall, and I. A. Ramshaw. "Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox." J. Virol. 75 (2001): 1205-1210.
12 Plants This week we will expand our study of evasion from its focus on the mammalian immune system to that of plants. We will examine the similarities of the both immune systems and the evasion mechanisms used by their respective pathogens. We will again discuss the use of model systems to study human pathogens. Vurro, M., and B. E. Ellis. "Effect of fungal toxins on induction of phenylalanine ammonia-lyase activity in elicited cultures of hybrid poplar." Plant Science 126 (1997): 29-38.

LeVier, K., R. W. Phillips, V. K. Grippe, R. M. Roop II, and G. C. Walker. "Similar requirements of a plant symbiont and a mammalian pathogen for prolonged intracellular survival." Science 287 (2000): 2492-2493.
13 Student Oral Presentations    
14 Applications and Special Papers We have studied many mechanisms used by pathogens to evade an immune response. This knowledge could be used in a dangerous manner to engineer a pathogen for use in biowarfare or in a beneficial manner to prepare tissues for transplantation. This week we will discuss one positive example in detail and consider potential misuse of information covered previously in the course. This week we will also read Paul Ehrlich's description of his classic experiments demonstrating antigenic variation as a mechanism for escaping antibody binding. Furukawa, L., L. S. Brevetti, S. E. Brady, D. Johnson, M. Ma, T. H. Welling, and L. M. Messina. "Adenoviral-mediated gene transfer of ICP47 inhibits major histocompatibility complex class I expression on vascular cells in vitro." J Vasc. Surg. 31 (2000): 558-566.
Ehrlich, P. "Nobel Lecture in recognition of their work on immunity." 1908.