1. Characteristic and mechanism of specific immune response
Chapter 13
Characteristic and mechanism of specific immune response

2. 教学大纲
掌握免疫耐受的概念、特性
熟悉免疫应答的特异性、记忆性的特点
熟悉免疫耐受形成的机制
了解BCR、TCR多样性及其分子基础、基因重排和多样性的机制
了解免疫耐受的形成、维持和终止的生物学意义。

3. Characteristics of specific immune response
specificity
memory
tolerance
acquired、reject
diversity、transferable

4. Major contents
* Specificity of Ir
* Memory of Ir
* Tolerance of Ir

5. Specificity of immune response
Have antigen specificity
Certain antigen specific antibody
sensitive lymphocyte
Specific binding

6. Molecule basis of specificity
Diversity of TCR/BCR

7. Memory of immune response
concept：when antigen first enter the body ,the activated signals and effect signals can keep in immune system. Therefore ,when the same antigen reenter the body , the immune response against the antigen will be prompt , stronger and efficacy。

8. Physical basement：
Tm，Bm ,
high affinity of specific TCR and BCR, stronger antigen presenting ability, etc. Secondary immune response only mediated by memory lymphocyte.

9. T cell mediated immune memory
Tm is easier to be activated than naive T cell ;require lower level antigen
Weak dependence on co-stimulator for activation(CD28/B7)
Tm secrete more CKs than naive T cell , higher sensitivity to CKs

10. B cell mediated immune memory
Bm Produce higher affinity antibodies;
Can develop Ab class switch;
Express more mIgG , higher level IgA、IgE and MHC-II molecule，
facilitate to taking in and presenting of antigen, low concentration of Ag can activate Th and B cell

11. has important significance for host against reintroduce of pathogen
Biological significance of Tm and Bm：
has important significance for host against reintroduce of pathogen
provide the theoretical basis for vaccination

12. Tolerance of immune response
* Concept and characteristic of immune tolerance
* Induce of immune tolerance
* Forming mechanism of immune tolerance
* Significance of studying immune tolerance

13. Tolerance of immune response
An unique form for specific immune response
*innate tolerance
*acquired tolerance

14. Owen于1945年发现异卵双胎小牛胎盘血管互相融合，出生后体内均存在两种不同血型的红细胞，即形成红细胞嵌合体（chimeras），并互不排斥。

15. Non-identical twins

16. Medawar胚胎诱导耐受实验(1953年)

18. Dresser demonstrate :Adult mice may be induced immune response (1962年)
天然BSA
tolerance
Embryo mice
soluble BSA
tolerance
Adult mice

19. 免 疫 耐 受
(Immune tolerance)
immune tolerance is a state of unresponsiveness or low responsiveness that is specific for a particular antigen after host contacted the antigen.

20. Forming of immune tolerance
embryo
Self or foreign antigen stimulate
Immature T cells and B cells
form immune tolerance
after birth
Not produce immune response for
the same antigen

21. tolerogen：a class of antigen that induce immune tolerance
can be innate tolerance，also can be acquired tolerance
antigenic specificity

22. no antigenic specificity ，
◆ similar with immune response：
Require antigen stimulation，have lag period、antigenic specificity、memory.
◆ Immunosuppression ：
no antigenic specificity ，
unresponsiveness or low responsiveness for all kinds of antigen

24. +++  Have lag period 免疫反应 免疫正应答 免疫负应答 7-14天 4-6周 4-6周 7-14天 免疫原 免疫原
耐受原
免疫原
免疫负应答
4-6周
7-14天 
Have lag period

25. intensity strong no or weak effect reject foreign protect self
Similarities and differences between immune positive response and immune tolerance
Ir tolerance
Antigen stimulation need need
lag period have have
specificity
memory
intensity strong no or weak
effect reject foreign protect self

26. common characteristics
of immune tolerance
is antigenic specificity
is induced easily by immature lymphocytes
maintenance of immune tolerance requires
persistent existing of tolerogen
in some cases ,can be induced by
mature lymphocytes

27. Tolerance of immune response
* Concept and characteristic of immune tolerance
* Induction of tolerance
* Mechanisms of immune tolerance
* Significance of studying immune tolerance

28. Induction of tolerance
antigen factors
host

29. antigen factors 1. Properties of antigen Type of antigen：monomer
Has similar background of heredity for host
Small molecule
Soluble antigen
结构简单、分子小、亲缘关系近  易诱
发免疫耐受，如血清蛋白、多糖和脂多糖。

30. (high- zone tolerance)
2. antigen dosage
T I -Ag：high doses B cell tolerance
TD-Ag：high doses T、B cell tolerance
low doses T cell tolerance
(high- zone tolerance)
（low-zone tolerance）

32. Major features of low zone tolerance and high zone tolerance
low zone tolerance high zone tolerance
Involved cell T T、B
Speed for inducing rapidly slowly
Duration long short
Types of antigen TD-Ag TD、TI-Ag

34. major differences between T cell tolerance
and B cell tolerance
T cell B cell
tolerogen TD-Ag TD、TI-Ag
Doses of antigen high or low high
Lag period short (24h) long (70 days )
Duration long (months) short (weeks)
Forming of tolerance easier difficult
mechanism central clone deletion clone abortion
peripheral lack of B suppress SIgM
anergy expression

35. （一）antigen factors mainline / oral administration
3. The routes of administration
mainline / oral administration
>subcutaneous / muscle injection
4. others
adjuvant

36. （二）host factors (intrauterine) * Maturation of immune system（ages）
embryo＞ neonatal＞ adult
* State of host
use immunosuppressant to damage mature lymphocytes
(intrauterine)

37. Tolerance of immune response
* Concept and characteristic of immune tolerance
* Induction of tolerance
* Mechanisms of immune tolerance
* Significance of studying immune tolerance

38. Mechanisms of immune tolerance
* Central tolerance
is induced by immature T、 B lymphocytes of embryo immune system contact antigen in generative lymphoid organs.
* Peripheral tolerance
is induced when mature T 、B lymphocytes contact antigens in peripheral lymphoid organs.

39. Central tolerance
T cell and B cell develop in thymus and bone marrow，in which perform negative selection
Initiate cell apoptosis ,cause clonal deletion
Reduce development of AID

40. Central tolerance Mechanism of clonal deleted（negative selection)
in thymus or bone marrow ,TCR or BCR of self reactive T B cells bind to self peptide-MHC molecule expressed on the surface of microenvironment stroma cell with high affinity ，initiate cells apoptosis，elicit clonal deletion。
Flash

41. （clonal deletion theory）
Central tolerance:
（clonal deletion theory）
胚胎期免疫系统接触特定抗原后，针对该抗原的特异性细胞克隆即被清除或被“禁闭”，机体将该抗原视为自身成份，出生后将不对此抗原产生应答。

42. 动 画 演 示 T 细胞的选择过程
Positive selection
Negative selection

45. Functions of negative selection
Negative selection of T、B cells make human establish central tolerance against self antigen.
Failure of negative selection ,may be cause autoimmune disease.

46. Reasons of self reactive T、 B cells escaping central tolerance
Peripheral tolerance
Reasons of self reactive T、 B cells escaping central tolerance
Thymus or bone marrow stroma cell not express tissue specific antigen resourced from some peripheral organs or antigen expressed after maturation.
Low expression of self antigen or affinity of BCR or TCR is too low.

47. Clonal anergy and immune ignorance
Peripheral tolerance
Clonal anergy and immune ignorance
Low levels of most tissue specific antigen，can not activate T B cells.
If concentration of antigen is moderate, self reactive T cell bind with self peptide MHC-I complex of tissue cell (signal 1)，but tissue cell not express co-stimulatory molecule (no signal 2) →apoptosis → clonal anergy
Flash

48. Mechanism of peripheral tolerance
Clonal anergy and immune ignorance
Lack of activated signal
* lack active signal 1：
* lack co-stimulating signal：（clonal anergy）

50. 2）clonal apoptosis
*mature T cells contact self antigen---produce apoptosis signal ---T cell apoptosis
3） activation of Ts cells
* release inhibitory cytokines----close signal transduction pathway of associated T cells.
(IL-10,TGF-β）

51. Fas/FasL途径对中枢耐受不是必要的，但对外周耐受则是必需的；
现在人身上也发现了类似病，称为人类自身免疫性淋巴细胞增殖综合征（ALPS)，1a型是Fas基因突变，1b型是FasL基因突变, 其表现为缺乏淋巴细胞凋亡，淋巴细胞积聚以及自身体液免疫反应。

52. T cell mediated suppression

53. Biological significance of immune tolerance
immune system establish immune tolerance against self antigen , can recognize and reject non-self antigen , maintain the balance of our body.

54. Clinical significance of immune tolerance
Hypersensitivity
AID
tumor - +
Immune tolerance
infection
Graft reject reaction

55. Tolerance of immune response
* Concept and characteristic of immune tolerance
* Inducement and mechanism of immune tolerance
* Establish , maintenance and abrogation of immune tolerance
* Significance of studying immune tolerance

56. Maintenance of immune tolerance
* Persistent existing of tolerogen
* Mature degree of immune system
* Application of immunosuppressive

57. Abrogation of immune tolerance
* disappearance of tolerogen
* Structure of self antigen change
* Enshrouded or isolation antigen release
* Cross antigen invade

58. 思考题 Concept of immune tolerance. Inducement of immune tolerance
Describe the mechanisms of central tolerance and peripheral tolerance.