Major Histocompatibility Complex, MHC
Wei Haiming [email protected]
1 Blood group antigen and blood transfusion reaction
University of Vienna Professor A. Weichselbaum: Discovered the bacterial cause of meningitis, and with Fraenckel had discovered the pneumococcus
Karl Landsteiner： The immunology of syphilis and the Wassermann reaction The cause of poliomyelitis
In 1875 Landois had reported the blood transfusion reaction In 1901-1903 Landsteiner pointed out the blood transfusion reaction again In 1909, he classified the bloods into the A, B, AB, and O groups
From 1919-1922, 12 papers on new haptens that he had discovered(Hague )
The discovery of the Rh-factor in blood(Rockefeller Institute for Medical Research in New York )
2 The Nobel Prize in Physiology or Medicine 1930
Karl Landsteiner Austria Rockefeller Institute for Medical Research New York, NY, USA b. 1868 d. 1943
It is characteristic of him that he died pipette in hand. On June 24, 1943, he had a heart attack in his laboratory and died two days later in the hospital of the Institute in which he had done such distinguished work.
3 1939年Gorer在鉴定近交系小鼠血型抗原时发现四组血细胞抗原，后证实第Ⅱ 组抗原与肿瘤及移植物的排斥密切相关，命名为H-2
Peter Gorer (left) and Phillip Levine.
4 两个经典免疫学实验两个经典免疫学实验
1. Assays for Skin Transplantation 2. Assays for T Cell Activation
5 Skin Transplantation
6 7 The Nobel Prize in Physiology or Medicine 1980 for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions"
Baruj Benacerraf Jean Dausset George D. Snell 1/3 of the prize 1/3 of the prize 1/3 of the prize USA France USA Harvard Medical School Universit?de Paris, Jackson Laboratory Boston, MA, USA Laboratoire Bar Harbor, ME, USA b. 1920 Immuno-Hematologie b. 1903 d. 1996 (in Caracas, Venezuela) Paris, France b. 1916 d. 2009
8 Assays for T cell Activation
9 10 Zinkernagel-Doherty Phenomenon (1974)
MHC restriction The term MHC restriction refers to the phenomenon whereby T cells from one individual recognising antigen X fail to recognise cells presenting the same antigen unless the presenting cells express one or more MHC alleles identical to those on the cortical thymic epithelial cells of the individual in which those T cells matured (these alleles will be those expressed by the T cell in a normal animal). This phenomenon derives in part from the requirement to recognise self MHC and in part from the different peptide binding specificity of different MHC alleles.
Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(450):701-2.
11 The Nobel Prize in Physiology or Medicine 1996 "for their discoveries concerning the specificity of the cell mediated immune defence"
Peter C. Doherty Rolf M. Zinkernagel Australia Switzerland St. Jude Children's Research University of Zurich, Institute Hospital of Experimental Immunology Memphis, TN, USA Zurich, Switzerland b. 1940 b. 1944
12 免疫遗传学发展简史 年代 学者 主要贡献 1900 Landsteiner*(1930) 确定人红细胞主要的同种抗原 1900s Carrell(1912 )* 器官移植 1948 Snell和Gorer 发现小鼠H-2系统及其与组织移植的关系 1953 Snell*(1980) H-2系统由K、D两个位点组成 1954 Murray和Thomas(1990)* 肾移植和骨髓移植 1958 Dausset*(1980) 发现第一个人类白细胞抗原（Mac） 1962 Van Rood 鉴定出HLA-B座位 1967 Benacerraf*(1980)和McDevitt 发现并证明Ir基因存在于MHC中 1969 Amos 发现HLA-D座位 1970 Sandberg 鉴定出HLA-C座位 1975 Doherty *(1996) 小鼠H-2b、K抗原对Tc杀伤病毒感染 细胞的限制作用 1978 Rosenthal Ir基因产物Ia抗原参与Mφ-T相互作用 1978 Zinkernagel * (1996) MHC对T细胞发育分化的影响 1987 Tonegawa* Ig的基因结构 *诺贝尔奖获得者，括号内为获奖年代 13 抗原研究 移植研究 功能研究 11 HistocompatibilityHistocompatibility--2,2, HH--22
14 1. Histocompatibility-2, H-2
15 1.1 H-2 class I gene Classical H-2 class I gene: H-2K, H-2D, H-2L Non- Classical H-2 class I gene: H-2Q, H-2T, H-2M
1.2 H-2 class II gene Classical H-2 class II gene: I-A, I-E Non- Classical H-2 class II gene: I-M,I-O Other genes: LMP1, LMP2,TAP1,TAP2
1.3 H-2 class III gene C4A, C4B, Bf, C2, CYP21A,CY21B
16 MHC Molecules Expressed on H-2k/d Antigen Presenting Cells
Diagram illustrating various MHC molecules expressed on antigen-presenting cells of a heterozygous H-2k/d mouse. Both the maternal and paternal MHC molecules are expressed. Because the class II molecules are heterodimers, heterologous molecules containing one maternal-derived chain and one paternal-derived chain are produced. The b2-microglobulin component of class I molecules (black) is encoded by a gene on a separate chromosome and may be 17 derived from either parent. d d d d d H-2d: H-2K , H-2IA , H-2IE , H-2S , H-2D H-2b
18 22 HumanHuman leucocyteleucocyte antigenantigen
19 20 2.1 HLA class I gene Classical HLA class I gene: HLA-A, HLA-B, HLA-C Non- Classical HLA class I gene: HLA-E, HLA-F, HLA-G MHC class I chain-related, MIC
2.2 HLA class II gene HLA-DR:DRA,DRB HLA-DQ:DQA,DQB HLA-DP:DPA,DPB HLA-DM:DMA,DMB TAP: TAP1,TAP2 PSMB:PSMB9 (LMP7), PSMB8(LMP2)
2.3 HLA class III gene C4A, C4B, Bf, C2 CYP21A,CY21B HSP70 TNF, LTA, LTB
21 Nature, Vol 401, 28 OCTOBER 1999;
22 23 24 25 Nature Reviews Genetics 5, 889 - 899 (01 Dec 2004)
26 Gene map of the extended major histocompatibility complex (xMHC). Jean Dausset (1916–2009), who received the Nobel Prize of Medicine in 1980 For his discovery of the human major histocompatibility complex (human leukocyte antigen (HLA), died in Palma de Majorca, Spain, on 6 June 2009, at the age of 92.
Nature Immunology, August,2009; 10(8): 797
27 3.3. HumanHuman MHCMHC genesgenes areare highlyhighly polymorphicpolymorphic
3.1 polymorphism and allele
Nature Reviews Genetics 5, 889 - 899 (01 Dec 2004) 28 MHC class I and class II are polymorphic [variability at a gene locus (variability of alleles) at a frequency higher than predicted by chance]
The number of known alleles at various MHC loci increases over time
1996 (122) (111) (239) (207) 1999 (323) (395)
Data in 2001 (59) our book (95) is from 2004 2004 (195) (37) (62) (50) (80) (25) (93) (89) (8) (35) (16) (12) (45) (20) (19) (20) (2) 120 23 68 32 503 728 210 414
29 Janeway’s Immunobiology,7/e,2008 3.2 co-dominance and individuality
1 3 8 1
30 31 4 Structure of MHC Class I Molecule
Bjorkman and Stern
Bjorkman(1987): HLA-A2; Stern(1994): HLA-DR1
32 4 Structure of MHC Class I Molecule
4.1 α chain and β2-microglobulin 4.2 α1,α2 domains and peptide binding cleft 4.3 α3 and β2-MG
33 34 35 Heavy chain: green Peptide: orange β-2M: yellow Proximal CD8ααsubunit: red Distal CD8ααsubunit: blue
CD8αα/HLA-A2/peptide
36 Annu. Rev. Immunol. 2006. 24:419–466
MHC: dark blue
Peptide : red
TCR: green
CD8 : yellow CD3: pink, blue, gold orange
37 38 39 40 55 StructureStructure ofof MHCMHC ClassClass IIII MoleculeMolecule
5.1 α chain and βchain 5.2 α1, β1 domains and peptide binding cleft
41 42 43 44 45 46 47 Thierry Boon
J Immunol. 2007 Mar 1;178(5):2617-21 48 Science. 1991 Dec 13;254(5038):1643-7. 二十一项值得获诺贝尔生理或医学奖的工作及科学家
1. Mario Capecchi(美国尤他大学U. Utah)，发明基因剔除技术，可能和其他1,2个做基因剔除(Oliver Smithies)或转 基因动物的人合得，也有可能和第一个做出鼠胚胎干细胞的Gail Martin(美国旧金山加州大学UCSF)合得。 (2007 年
生理或医学奖)
2. Bob Horvitz (美国麻省理工学院MIT)，细胞凋亡的遗传机理，可能合得者是：AH Wylie或JFR Kerr其中之一(细 胞凋亡的概念和电子显微镜下形态变化特征)，Susanne Cory或Stanley Korsmeyer之一(Bcl-2在细胞凋亡中的作用)。
得州大学西南医学中心的王晓东也有可能(细胞凋亡的生物化学机理)。（2002年获医学或生理学奖）
4. Elizabeth Blackburn (美国旧金山加州大学UCSF)和Carol Greider (美国霍普金斯大学Johns Hopkins)，端粒子和
端粒酶，Blackburn主要发现在UC Berkeley做，Greider那时是她的学生。（2009年获医学或生理学奖）
5. Roderick MacKinnon (美国洛克菲勒大学Rockefeller)，钾离子通道的结构，可以单独，也可以合得 (不确定合得
者，如果就钾通道而言，旧金山加州大学UCSF的Lily Jan叶公杼和YN Jan詹裕农有可能；如果广义地给离子通道，
美国西雅图华盛顿大学University of Washington的Bertil Hille有可能)。（2003年的化学奖）
8. Roger Y. Tsien 钱永健(美国圣跌哥加州大学UCSD)和 Douglas C. Prasher(美国农业部麻州Otis植物保护中心)，发
明测定活细胞内分子的新方法。Tsien发明钙染料，Prasher发现绿色荧光旦白GFP。（2008年化学奖）
11. Pamela Bjorkman (美国加州理工学院Caltech) 和 Jack Strominger (美国哈佛大学Harvard)发现MHC(主要组 织相容性抗原复合体)结构， Bjorkman是和Don Wiley做研究生时的工作，Wiley如果不去世，应该得。 Emil
Unanue (美国圣路易斯华盛顿大学Washington University)，发现抗原呈现细胞。 15. Sydney Brenner 和 Seymour Benzer (美国加州理工学院Caltech)，用遗传学方法研究发育，神经和行为。Brenner
提出用c elegans研究发育和神经，Benzer提出用果蝇做神经和行为。（2002年获医学或生理学奖） 16. Marc Raichle (美国圣路易斯华盛顿大学Washington University),用正电子扫描(PET scan)做活体人影像检测，可
能和发明改进fMRI(“功能性核磁共振”，或称“功能性磁共振影像”)的人合得。 他们的工作是生物医学影像的重要发
展。 (2003年医学或生理学奖)
17. Luc Montagnier(法国)Robert C. Gallo(美国)，发现爱滋病毒。(2008年医学或生理学奖) 49 21. RNA干扰，不一定会在近年发奖，可能等机理进一步搞清，但是发奖时会包括发现RNA干扰现象的人，有三 个重要的候选人，如果不包括机理，就是他们，如果包括机理，那么只能在这三个里面选一俩个加上以后发现RNAi
Obituary: Professor Don C. Wiley, 1944-2001 December 21, 2001 Don C. Wiley, one of the most distinguished structural biologists of his generation, has died. He was 57.
Wiley, whose teaching and research career spanned three decades at Harvard University, conducted key research on the structure of viruses and of proteins in the human immune system. His work focused on the molecular mechanisms that enable viruses to infect cells, and on how cells respond to external challenges by presenting antigens and mobilizing defensive cells. A senior investigator of the Howard Hughes Medical Institute, Wiley studied the structure of such viruses as the AIDS virus, Ebola, herpes simplex, and influenza. He examined the ways in which viruses bind to cell surfaces, enabling their entry into the cell, and the ways in which viruses evolve to infect different organisms and to escape the immune response of their hosts. By understanding these processes, Wiley sought to find new ways to combat these viruses. Professor Don C. Wiley 50 …… Nature. 2001 Nov 29;414(6863):475.
51 The Death Of Dr. Wiley - 'Murder, They Wrote' By Wayne Madsen CounterPunch.org 6-4-2
The reported "suicide" and then "accidental death" of noted Harvard biophysics scientist and anthrax, Ebola, AIDS, herpes, and influenza expert, Dr. Don C. Wiley, on the Interstate 55 Hernando De Soto Bridge that links Memphis to West Memphis, Arkansas, was probably a well-planned murder, according to local law enforcement officials in Tennessee and Arkansas.
After Wiley's friends and family discounted claims of suicide, the Memphis coroner concluded on January 14, 2002 that Wiley had "accidentially" fallen over the side of the bridge after a minor car accident.
However, according to U.S. intelligence sources, Wiley may have been the victim of an intelligence agency hit. That jibes with local police comments that the FBI and "other" U.S. agencies stepped in to prevent the local Memphis police from taking a closer look into the case. Employees of St. Jude's Childrens' Hospital in Memphis, on whose board Wiley served, were suddenly deluged with unsubstantiated rumors that Wiley was a heavy drinker and despondent.
It is a classic intelligence agency ploy to spread disinformation about "suicide" victims after their murders. The favorite rumors spread include those about purported alcoholism, depression, homosexuality, auto-erotic asphyxia, drug addiction, and an52 obsession with pornography, especially child pornography. Statement from Professor Jack Strominger Higgins Professor of Biochemistry, Harvard University November 27, 2001
…… His scientific work is mainly in two fields: the structure and function of histocompatibility proteins to which I have already referred, and the functions of proteins on the surface of viruses. ……. Don never worked with live viruses and I doubt he even knows how to produce them. More explicitly, our Department doesn't have facilities in which dangerous viruses could be produced. For a virus like Ebola, the causative agent of hemorrhagic fever in Africa, only two facilities, called level 4 facilities, in the United States could work with these dangerous viruses in any way. I cannot think of any possible link between Don's work or expertise and bioterrorism.
53 Pamela J Bjorkman. Finding the groove. Nature Immunology, August 2006, Volume 7 No 8, pp787 - 789 54 6 The two classes of MHC molecule are expressed differentially on cells
Cell Type MHC I MHC II T cells +++ Varies, inducible in some species B cells +++ ++ Macrophages +++ + Dendritic cells +++ x10 +++ x10 Granulocytes ++ - Endothelium ++ - (inducible) Hepatocytes + - Neurons - -
55 7 Regulation of the expression of HLA genes
7.1 HLA-I: enhA(κB1,κB2), ISRE(interferon-stimulated response element), site α, enhB 7.2 HLA-II: TATA box, CCAAT box, Y box(ATTGG-NF-Y), X box, w/s box CIITA: class II trans-activator
56 57 88 MHCMHC andand MedicineMedicine
8.1 MHC and graft rejection 8.2 MHC and Anti-virus immunity 8.3 MHC and Disease susceptibility 8.4 MHC and pregnancy 8.5 MHC and tumor growth
58 8.1 MHC and graft rejection
The Nobel Prize in Physiology or Medicine 1912 "in recognition of his work on vascular suture and the transplantation of blood vessels and organs"
Alexis Carrel France Rockefeller Institute for Medical Research New York, NY, USA b. 1873 d. 1944 20世纪初，器官移植实验探索 59 1945年，Medawar提出移植排斥是免疫反应
Nobel Prize in Physiology or Medicine 1960
Peter Brian Medawar (1/2) Discovery of acquired immunological tolerance The graft reaction is an immunity phenomenon 1950s, induced immunological tolerance to skin allografts in mice by neonatal injection of allogeneic cells
Great events in history of transplantation 60 MHC的发现
Nobel Prize in Physiology or Medicine 1980
George D. Snell (1/3), Jean Dausset (1/3) Discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions H-genes (histocompatibility genes), H-2 gene Human transplantation antigens (HLA) ----MHC
Great events in history of transplantation 61 1954年，成功地进行第一例肾移植
Nobel Prize in Physiology or Medicine 1990
Joseph E. Murray (1/2) Discoveries concerning organ transplantation in the treatment of human disease In 1954, the first successful human kidney transplant was performed between twins in Boston. Transplants were possible in unrelated people if drugs were taken to suppress the body's immune reaction
Great events in history of transplantation 62 免疫抑制剂的发现
Nobel Prize in Physiology or Medicine 1988
Gertrude B. Elion (1/3) , George H. Hitchings (1/3) Discoveries of important principles for drug treatment Immunosuppressant drug (The first cytotoxic drugs) ----- azathioprine
Great events in history of transplantation 63 哈佛医学院麻省总医院进行的第一次同时哈佛医学院麻省总医院进行的第一次同时 移植肾脏和骨髓的临床试验移植肾脏和骨髓的临床试验
64 The Nobel Prize in Physiology or Medicine 1990 "for their discoveries concerning organ and cell transplantation in the treatment of human disease"
Joseph E. Murray E. Donnall Thomas USA USA Brigham and Women's Fred Hutchinson Cancer Hospital Research Center Boston, MA, USA Seattle, WA, USA b. 1919 b. 1920
65 移植排斥反应的核心机制移植排斥反应的核心机制
同种异型移植排斥反应主要是由受者的T细胞介导的、
针对移植物表面同种异型抗原的细胞免疫应答。
移植物表面同种异型抗原--MHC
受者T细胞如何识别供者MHC分子？ 为什么有如此多的T细胞能识别同种异型MHC分子？ 1%-10%的受者T细胞能识别同种异型MHC分子 10-５-10-４的特异性T细胞前体识别一般抗原
66 受者受者TT细胞如何识别供者细胞如何识别供者MHCMHC分子分子??
直接识别（direct recognition） ：
不需要抗原的加工过程，受者T细胞直接识别移
植物细胞表面完整的同种异型MHC分子。
67 交叉识别(Cross recognition)
正常情况： 同种异型移植：识别供者MHC分子-Ag肽复合物 识别自身MHC分子- 分子基础：两者决定簇可能很相似 68 外来Ag肽复合物 间接识别（Indirect recognition）
同种异型MHC分子作为常规的外来蛋白质，被受 者APC加工递呈，为T细胞识别
排斥反应较弱、较缓慢 急性排斥反应中晚期和慢性排斥反应中起更重要的 作用 急性排斥反应早期与直接识别机制协同发挥作用
69 直接识别和间接识别示意图
Recipient T cell
TCR Peptide Peptide from donor MHC molecule Donor MHC Recipient molecule MHC molecule
Donor MHC molecule Donor APC Recipient APC 70 直接识别和间接识别的比较
直接识别 间接识别
MHC分子形式 完整的同种异型 同种异型MHC分子 MHC分子 来源的抗原肽 APC 不需受者APC 需要受者APC 活化的T细胞 CD4+/CD8+T细胞 CD4+/CD8+T细胞 排斥反应中作用 急性排斥反应 慢性排斥反应 排斥反应强度 非常强烈 较弱
71 MechanismsMechanisms ofof graftgraft rejectionrejection
TNF, NO2 IL2, TNF, IFN Inflammation
IL2, IL4, IL5 IL2, IFN lysis
ADCC
lysis Rejection
72 同种异型移植排斥反应分类
宿主抗移植物反应 (Host-versus-graft Reaction, HVGR) 见于一般器官移植
移植物抗宿主反应 (Graft-versus-host Reaction, GVHR ) 主要发生在骨髓移植和其他免疫细胞移植
73 宿主抗移植物反应
超急性排斥反应 急性排斥反应 Acute rejection of a kidney with inflammatory cells in the interstitium and between epithelial cells of the tubules
慢性排斥反应 Chronic rejection in a kidney allograft with arteriosclerosis
Hyperacute rejection of a kidney allograft with endothelial damage, platelet and thrombin thrombi, and early neutrophil infiltration in a glomerulus 74 肾移植10年存活率 HLA-A,B,DR错配数 10年存活率 0 62％ 1 47％ 2 45％ 3 40％ 6 33％
75 移植物抗宿主反应
同种异型骨髓移植时，供者骨髓移植物中的免疫活性细胞识 别宿主移植抗原而发生的排斥反应 GVHR可以损伤宿主，引起移植物抗宿主病（graft versus host disease，GVHD） 急性GVHD 慢性GVHD
76 1、急性GVHD 2、慢性GVHD
A B
C A. Acute GVHR with vivid palmar erythema.
B. Early, chronic GVHD with widespread, almost confluent hyperpigmented lichenoid papules and toxic epidermal necrosis-like appearance on knee. C. Late, chronic GVHD with hyperpigmented sclerotic plaques on the back.
77 8.2 MHC and Anti-virus immunity
Zinkernagel-Doherty Phenomenon（1974）：
CTL from CBA(H-2k): kill target cells (H-2k) with bovine vaccine virus don’t kill target cells (H-2b) with bovine vaccine virus
78 8.3 MHC and Disease susceptibility Frequencya Disease Antigen Race Patients Controls Narcolepsy HLA-DR2 C 1.0 0.22 O1.00.34 Ankylosing spondylitis HLA-B27 C 0.89 0.09 O 0.81 0.01 N 0.58 0.04 Reiter disease HLA-B27 C 0.47 0.10 Insulin-dependent diabetes mellitus HLA-B8 C 0.40 0.21 HLA-B15 C 0.22 0.14 HLA-DR3 C 0.52 0.22 HLA-DR4 C 0.74 0.24 HLA-DR2 C 0.04 0.29 HLA-DRB1*0301 C 0.54 0.27 HLA-DRB1*0401 C 0.59 0.25 HLA-DQA1*0301 C 0.85 0.35 HLA-DQB1*0302 C 0.81 0.23 Rheumatoid arthritis HLA-DR4 C 0.68 0.25 O 0.66 0.39 N 0.44 0.10 Hodgkin disease HLA-A1 C 0.40 0.32 HLA-DRB1*1104b C 0.058 0.013 Hemochromatosis HLA-A3 C 0.76 0.28 Psoriasis HLA-Cw6 C 0.87 0.33 Celiac disease HLA-DR3 C 0.79 0.26 Multiple sclerosis HLA-DR2 C 0.59 0.26 C, Caucasian; O, Oriental; N, Black. 79 80 HLA-DR1 and HLA-DR4.1: structural characteristics associated with rheumatoid arthritis.
Jones et al. Nature Reviews Immunology 6, 271–282 (April 2006) | doi:10.1038/nri1805
81 EscapeEscape fromfrom immunosurveillanceimmunosurveillance
LackLack ofof classclass II MHCMHC
82 83 84 85 86 87 88