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Immunoregulation

Immunoregulation. The immune response is subject to a variety of control mechanisms which serve to restore the immune system to a resting state when the response to a given antigen is no long required. 抗体浓度对抗体产生的调节

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Immunoregulation

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  1. Immunoregulation

  2. The immune response is subject to a variety of control mechanisms which serve to restore the immune system to a resting state when the response to a given antigen is no long required.

  3. 抗体浓度对抗体产生的调节 家兔经抗原免疫后产生特异性抗体，用血清交换人为降低抗体浓度后，可引起抗体产生量的反馈性升高, 并在到达一定强度后逐渐下降。说明机体可感知自身抗体浓度的变化，并自行启动调节机制

  4. Normal anti-infection anti-tumour Abnormal Auto-immune disease Tumour Persisitent infection Allergy Immunoregulation:homostasis

  5. Immunoregulation • Regulation of innate immunity • Immunoregulation mediated by Inhibitory Receptor • Regulation by Treg • Idiotype network • Immunoregulation by other mechanism

  6. A. Regulation of innate immunity • Feedback Regulation of secretion of inflammatory factor

  7. SIGIRR ST2 TLR4 CD14 MD2 TIR TIR Rac1 TIRAP PI 3K 受体 衔接蛋白 信号分子 激酶 转录因子 抑制因子 基因转录 激活 抑制 MyD88 PIP2 PIP3 IRAK1 SOCS1 MyD88s IRAK4 IRAK-M TRAF6 MAPK PKB ASK1 NF-B 炎症细胞因子基因转录 固有免疫中针对TLR信号转导的负向调节 TIR: Toll/IL-1 receptor; ASK1: 凋亡信号调节激酶1;IRAK: IL-1受体相关激酶; MAPK: 丝裂原激活 蛋白激酶; MyD88: 髓样分化因子 88; NF-B: 核因子B; PI 3K: 磷酸肌醇 3激酶; PIP2：2磷酸磷脂 酰肌醇; PIP3: 3磷酸磷脂酰肌醇；PKB: 蛋白激酶 B; Rac: 小G蛋白; SIGIRR: 单一Ig IL-1R相关分子; TIRAP: TIR (Toll/IL-1受体) 相关蛋白; TRAF6: TNF 受体相关因子6。

  8. A. Regulation of innate immunity • Regulation by SOCS (suppressor of cytokine signaling)

  9. 细胞因子受体 B A 细胞因子 细胞因子受体 细胞 因子 Jak Jak Stat Jak 磷酸 化 Y Yp pY Stat 其它 信号途径 Stat Stat 胞核 胞核 基因转录 DNA 生物学 效应 基因X,Y,Z SOCS 基因 C SOCS1 Jak D SOCS家族部分成员 CIS N端区 SH2结构域 SOCS框 SOCS3 CIS SOCS1 SOCS2 SOCS3 Stat 胞核 蛋白质 泛素化降解 SOCS 蛋白以负向反馈环路阻抑细胞因子的信号转导

  10. 激活性 受体 抑制性 受体 Src PTK ITAM ITIM 磷酸化 PTK Zap-70, Syk SHP-1, SHP-2 PTP 激活 抑制 磷酸化 脱磷酸化 基因转录 免疫细胞激活性受体和抑制性受体及其作用特点

  11. T细胞激活及相关免疫反应中的共信号分子及其受体T细胞激活及相关免疫反应中的共信号分子及其受体 家族 配体 受体ITAM/ITIM Ig-SFB7-1 CD28 ITAM B7-2 CTLA-4 ITIM B7-H1 PD-1 ITIM B7-DC ? B7-H2 ICOS B7-H3 ? HVEM BTLA ITIM TNF CD40L CD40 OX40LOX40 4-1BBL 4-1BB APC T T APC

  12. Ag TCR B7 CD28 B7 CTLA-4 ITIM ITAM 24h T cells inhibition Activation Negative regulation of T cell activation by CTLA-4

  13. 抗BCR抗体 BCR (mIgM) Ag-Ab complex FcRII-B FcRII-B ITIM ITIM Interfere B cell signaling Negative regulation of Ab production by Inhibitory receptor FcRII-B

  14. Inhibitory receptor Activation receptor Ig super family C-Lectin SF Receptors of human NK cells

  15. activation receptor allo- cell normal cell NK NK + + – no kill kill inhibitory receptor virus- Infected cell tumor cell NK NK + + kill kill NK’s cytotoxic activity depends on activation of the signaling initiated by the ligation of inhibitory receptor with its ligand

  16. Cell Activating receptor Inhibitory receptor T Cell TCR-CD3 CTLA-4, PDL-1, BTLA B cell BCR-Ig/Ig FcRII-B, CD22 NK cell KIR-S + DAP12 CD94/NKG2C + DAP12 NKG2D + DAP10 NCR + /FcR1 CD16 + /FcR1 KIR-L CD94/NKG2A ILT2 Mast cell FcRI FcRII-B CD94/NKG2A  T cell V9V2 TCR Activating receptor and Inhibitory receptor of Immune cells

  17. C. Regulation T Cells(Treg) • Suppressor T cells (Ts) (1970s) • Regulatory T lymphocytes (Treg) are a subset of CD4+ T cells whose function is to suppress immune responses and maintain self-tolerance

  18. Treg：Marker

  19. Treg • Humans IPEX (immune dysregulation, polyendocrinopathy,enteropathy, X-linked syndrome) is also associated with deficiency of Treg and is now known to be caused by mutations in the FOXP3 gene.

  20. Treg：Generation and Maintenance

  21. Treg:subsets Naturally Treg and adaptive Treg

  22. IL-12 IL-12R IFN-R pMHC TCR CCR5 Stat4 Stat1 CXCR3 IFN IFN- TNF- T-bet IL4 IFNG 细胞免疫 IL-12 Th1 IL-4R pMHC CCR3,4,8 Stat6 IL-4 IL-4 IL-5 IL-13 Gata3 IL-4 IFNG 体液免疫 共刺激 IL4 Th2 初始T Th0 IL-23 IL-23R IL-23 Stat3 IL-17 IL-17 IL-17F RORt IFNG, IL4 炎症反应 IL17 Th17

  23. Counter action of Th1and Th2 subsets

  24. Macrophages TB in Lysosomes IFN- induced Th1 to activate intracellular killing

  25. D. Regulation by idiotypes and anti-idiotypic antibodies Antibodies formed against Ag-binding sites of an Ab are called anti-idiotypic antibodies, and are capable of influencing the outcome of an immune response. Id and AId interactions may enhance or suppress Ab responses.

  26. Network Theory （1974） Jerne explains how the specific immune response is regulated. The immune response is regulated by a complicated network consisting of antibodies and anti-ab. The principles of the network theory are beginning to be exploited in prevention, diagnosis and treatment of disease. Niels K. Jerne 1911-1994,UK 1984 Nobel Prize

  27. Ag epitope   Ag Ab1 (Id) Ab2 (AId) Ab3 Ab Idiotype network and antigen internal image

  28. B Ab2 Ab2 Ab1 Ab2 Ab3 / Ab1 A Ab1 Ab2 Ag Enhance Ab1 Impair Ab1 利用独特型网络进行免疫干预的两种主要途径

  29. E. Regulation by apoptosis 1. Activation-induced cell death (AICD)

  30. F. Regulation by neuroendocrine system Lymphocytes express receptors for many hormones, neurotransmitters and neuropeptides.

  31. G. Genetic control of immune response Control of immune response by MHC Immune response genes (Ir) control all immune responses Most of the polymorphic residues in MHC molecules reside in the peptide-binding groove MHC restriction APC-Th, Th-B MHC II CTL-Target MHC I 2.Non-MHC-linked genes affect immune response:TCR，BCR，C

  32. Question • The inhibitory receptors of immune system and its biological significance • Difference between nature Treg and inducible Treg

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