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每週必須根據文獻閱讀指南閱讀兩篇主要文獻。(PDF)
For each weekly session, students are required to read two primary literature articles using the Guidelines for Reading Papers document. (PDF)
| 1 |
介紹
Introduction |
大家先作自我介紹，然後說說對生物學內在及外在的興趣。還將討論課程計畫：課程安排、作業、要達到的目標等等。接著討論對免疫學的一般的、總的看法。最後10分鐘，我將講下防禦素和補體在先天免疫中的作用，並給大家發需要閱讀分析的論文，為下周課做準備。
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. |
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| 2 |
先天免疫
Innate Immunity |
防禦素和補體直接作用於目標，導致細胞溶菌作用或巨噬細胞噬菌作用。這兩篇文章論述了由於腫瘤細胞表達的補體抗性因數和細菌產生的抗防禦素物質而造成的潛在的免疫逃逸作用。
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. |
（〈異源CD59的表達阻止補體介導的人乳癌細胞的胞溶作用〉）Clin Exp Immunol （《臨床實驗免疫學》）115 (1999): 13-18.
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.
〈控制阻擋來自噬菌細胞的抗菌蛋白的沙門氏菌群落〉《科學》243 (1989): 1059-1062.
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 |
抗體
Antibodies |
抗體在消滅血源性病原方面起著重要的作用。抗原變異是逃避抗體結合的機制之一。我們將討論SIV變異，此變異使SIV病毒逃過已被結合失效的抗體的結合。還將看一個例子，說明抗體結合還能保護病原體避過免疫摧毀。
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. |
（〈SIV抗原變異：V4中的突變改變中立性質〉），《病毒學》 221 (1996): 14-21.
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.
（〈膜結合型IgM在克氏錐蟲逃避免疫清除中所起的作用〉）（《寄生蟲學期刊》）83 (1997): 230-233.
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 |
I類MHC抗原加工與呈遞
MHC Class I - Peptide Processing and Loading
任課教師示範演講
Instructor Demonstration of a Presentation
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胞內病原體抗原被I類MHC降解、呈遞。這周我們將瞭解抗原加工過程一系列步驟中被病毒阻斷的兩步，並討論在抗原加工途徑中，還有哪幾步可被其他病毒阻斷。最後，我將就以後你們要做的課堂演講做個示範。
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. |
（〈Epstein Barr 病毒核抗原－1的內部重複結構阻斷抗原加工過程〉）《自然》 375 (1995): 685-688.
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.
（〈一種定位於內質網的病毒糖蛋白使MHC編碼的多?轉運體失活〉）（《免疫》）6 (1997): 623-626.
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 |
I類MHC抗原重鏈的成熟
MHC Class I - Maturation of Heavy Chains |
這周將繼續講I類MHC抗原加工和呈遞途徑。重點在HCMV抑制I類MHC重鏈成熟的機制。將討論不同模式系統的利用，以及我們如何獲知病毒在細胞內的加工過程。
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. |
（〈人類巨細胞病毒US11基因產物使I類MHC抗原重鏈從內質網轉移到細胞質中〉）（《細胞》） 84 (1996): 769-779.
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.
（〈人類巨細胞病毒免疫逃逸蛋白pUS3 22kDa的功能分析〉）（《病毒學》） 315 (2003): 353-361.
Zhao, Y., and B. J. Biegalke. "Functional analysis of the human cytomegalovirus immune evasion protein pUS3 22kDa." Virology 315 (2003): 353-361. |
| 6 |
NK細胞
NK Cells |
質膜表面I類MHC抗原表達不足的細胞，易發生NK細胞介導的溶解。本周講述細胞如何通過下調I類MHC抗原的表面表達來避免CTL裂解，而不同時引起NK細胞介導的溶解。
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. |
〈人類巨細胞病毒MHCＩ類對特定薄弱區域蛋白介導的下調有抵抗力〉， （《免疫學學報》168 (2002): 3464-3469.
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.
〈m144，一種鼠類巨細胞病毒（MCMV）編碼的Ｉ類同源主要細胞適應性聯合體，使細胞介導排斥的天生消滅者可以抵禦腫瘤的發生〉 J. Exp. Med. 《實驗醫學期刊》190 (1999): 435-443.
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/II類MHC抗原
CD4/MHC Class II |
II類MHC抗原呈遞病原體的胞外形式，引起CD4＋ T細胞啟動。啟動的T細胞接著使B細胞產生抗體。本周討論HIV如何耍詭計，令T細胞不被啟動，以及皰疹病毒阻止正常II類MHC抗原呈遞的機制。
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. |
〈nef引起細胞表面CD4絲氨酸獨立磷酸化的下調〉《自然》350 (1991): 508-511.
Garcia, J. V., and A. D. Miller. "Serine phosphorylation-independent downregulation of cell-surface CD4 by nef." Nature 350 (1991): 508-511.
《免疫學》 107 (2002): 129-135.
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 |
內吞/降解作用
Endocytosis/Degradation |
一些病原體被抗原呈遞細胞內吞，生成內吞小體而被摧毀。本周講述兩個例子，來說明細菌發展出來的防止內吞小體酸化從而不被降解的機制。
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. |
〈耶爾森氏菌的假結核病阻止B10的內吞小體酸化。一個液泡H＋-ATP?活動抑制中的鼠巨噬細胞〉，Microb Pathog《微生物病原體》 27 (1999): 253-263.
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.
〈排除ATP?小泡質子產生的分枝桿菌內吞小體中酸化的缺乏〉《科學》263 (1994): 678-681.
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 |
T細胞的失活與耐受化
Anergizing/Tolerizing of T Cells |
大部分自身反應性T細胞在胸腺成熟過程中被清除掉。然而，還有一些未被清除而分化成熟，存在於細胞外周，在耐受化或細胞免疫反應失活的介導過程中保持失活狀態。本周講述癌細胞和胞內細菌用來調控針對特異性抗原的T細胞的功能的機制。
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. |
〈特異性抗原T細胞失活的歸納：腫瘤發展中的早期現象〉，《美國國家科學院學報》 95 (1998): 1178-1183.
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.
《歐洲免疫學學報》27 (1997): 1696-1703.
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 |
細胞凋亡
Apoptosis |
細胞凋亡是T細胞殺死受感染細胞的機制之一。本周將講兩種病毒，它們表達蛋白使受感染細胞免於凋亡，從而不能阻止病毒的擴散。我們將討論與細胞蛋白為同源蛋白的病毒蛋白的作用。
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. |
〈Epstein-Barr病毒編碼出一種新的bcl-2致癌基因的同源物，以抑制細胞凋亡並與bax和bax相聯〉，J. Virol. 《病毒學學報》73 (1999): 5181-5185.
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.
〈CrmA，一種痘病毒編碼的絲氨酸蛋白?抑制劑，抑制細胞毒素T淋巴球介導的細胞凋亡〉，《生物化學學報》 270 (1995): 22705-22708.
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 |
細胞激素
Cytokines |
細胞激素是決定免疫反應中的關鍵介質。本周討論病毒影響正常細胞激素表達的兩個例子和在病原體影響細胞激素功能途徑中的其他步驟。
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. |
〈麻疹病毒對細胞介導免疫的抑制機制〉，《科學》 273 (1996): 228-231.
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.
〈重組畸形病毒抑制溶細胞淋巴球反應和克服對鼠痘的遺傳性抵抗--鼠白介素4的表達〉《病毒學學報》 75 (2001): 1205-1210.
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 |
植物
Plants |
本周我們將視野從哺乳動物免疫系統擴展到植物上，討論兩者相似之處及各自的病原體逃逸機制，並再次討論利用模式系統來研究人類病原體。
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. |
〈在雜交白楊樹的推導種植中，苯基丙氨酸氨裂解?活動介紹基礎上真菌毒素的作用〉，《植物科學》126 (1997): 29-38.
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.
〈延長細胞內生存的植物共生體和哺乳動物病原體的相似要求〉《科學》287 (2000): 2492-2493.
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 |
學生口頭陳述報告
Student Oral Presentations |
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| 14 |
應用及專題論文
Applications and Special Papers |
我們已探討了許多病原體針對免疫反應的逃逸機制。這些知識有利有弊：如製造工程病原菌用於生物戰爭這樣的危險用途，或生產可移植的組織、器官用於治病這樣的有益用途。本周我們要詳細討論一個正面用途的例子，並思考潛在的濫用情形。本周還要閱讀、講解Paul Ehrlich的經典實驗，證實抗原變異是一種逃避抗體結合的機制。
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. |
〈ICP47的腺病毒介導基因轉移抑制體內血管細胞I類組織適應性聯合體的表達〉《血管外科學報》31 (2000): 558-566.
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.
〈承認他們在免疫上貢獻的諾貝爾講座〉
Ehrlich, P. "Nobel Lecture in recognition of their work on immunity." 1908. |
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