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Immune regulation

Immune regulation. at molecular level of immune regulation at cellular level of immune regulation at whole and colony level of immune regulation. At molecular level of immune regulation. 1 、 Feedback regulation in transduction of immune cell active signaling.

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Immune regulation

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  1. Immune regulation • at molecular level of immune regulation • at cellular level of immune regulation • at whole and colony level of immune regulation

  2. At molecular level of immune regulation 1、Feedback regulation in transduction of immune cell active signaling Phosphorylation and dephosphorylation of protein Protein tyrosine kinase(PTK)—starup and upstream of transduction of immune cell active signaling Protein tyrosine phosphorylase (PTP)—dephosphorylation，negative regulation

  3. Anti-BCR antibody and Ag-Ab complex Receptor cross-linking Phosphorylation Dephosphorylation Recruiting PTP and SyK Inhibition or blocking B cell activation The function of FcRⅡ-B

  4. 2、Inhibitory receptor contain two kinds different receptor 1. Activating receptor ITAM (immunoreceptor tyrosine-based activation motif) basic structure：YxxL/V 2． Inhibitory receptor ITIM (immunoreciptor tyrosine-based inhibitory motif) basic structure：I/Vx YxxL The function of inhibitory receptor is depend on interaction between inhibitory receptor and activating receptor.

  5. Antigen Inhibitory receptor Activating receptor cell phosphorylation dephosphorylation Active B cell Inhibit B cell Immune regulation of inhibitory receptor and activating receptor

  6. 3、Various inhibitory receptor and clinic application 1．T cell : CTLA-4 and PD-1 Expressed on activated T cell，contains ITIM motif in cytoplasmic domain. CTLA4-Ig fusion protein and anti-CTLA4 antibody can inhibit or enhance antigen specific T cell activation. Application: Tumor treated, organ transplantation, autoimmune disease. 2. B cell： FcgRII-B Related to development of autoimmune disease.

  7. Ag-Ab complex Anti-µ IgG B cell B cell Anti-µ IgG inhibits immune response Ag-Ab complex inhibits immune response Anti-BCR antibody and Ag-Ab complex inhibits B cell mediated immune response

  8. 3. Killer cell(NK,CTL): KIR和CD94/NKG2A I type：Killer cell inhibitory receptor KIR，Ligands：HLA-I，HLA-G II type：C-type lectin receptorsCD94/NKG2A：recongnize conservative sequences containing nine peptides binding to HLA-E；contains ITIM motif in cytoplasmic domain of receptor； Application：protecting foetus from rejection by mother’s body，however, virus also escape immune surveilliance through its over expression. 4. Mast cell：FcgRII-B Cross linking withFceRI and negative regulate immune reaction.

  9. Activating receptor and inhibitory receptor expressed on immune cells Immune cell Activating receptorInhibitory receptor B cell   BCR FcgRII-B T cell TCR,CD28 CTLA-4, PD-1 NK cell CD16 KIR, CD94/NKG2A Mast cell FceRI FcgRII-B, gp49B1

  10. Immune regulation on cellular level 1、T cell subsets and interaction 2、Idiotypic network and immune regulation 3、Negative regulation of immune response by apoptosis.

  11. 1、T cell subsets and Interaction 1）Nature regulatory T cell CD4＋CD25＋Tr cell Secreting cytokine such as TGF-、IL-10 Cell to cell contact : CTLA-4

  12. 2）CD4+ T cell and CD8+ T cell Normal：CD4/ CD8=1.5-2:1 increase：positive regulatory of immune response decrease：less than 1，lower immune function

  13. Activated T cell Naïve T cell Th0 cell Th2 cell Th1 cell Active macrophage Enhance cytotoxicity Induce DTH Mediate cellular immune response Active B cell Promote production of neutralizing antibody Induce ATH Mediate humoral immune response Immune regulatory of Th1/Th2 cell

  14. Th1 and Th2 cells , cytokines Conversion of Th1 and Th2 , clinic significance Leprosy：abundant proliferation of Th2 Therapy:Inducing Th1 polarization by using IFN-g

  15. 2、Idiotypic networks and immune regulatory Basel Institute for Immunology Basel, Switzerland 1984 The Nobel Prize in Physiology or Medicine Niels K. Jerne 1911-1994

  16. Idiotype Id Anti-idiotype AId 1） Anti-idiotype and Idiotypic network （1） Immunogenic epitopes in or around the binding site are termed idiopopes. （2）When an antibody response is induced by antigen, this antibody will in turn evoke an anti-idiotypic response to itself.

  17. Idiotypic network and immune regulatory AId downregulates the function of antibody

  18. 2）Application (1) Through Ab1 or Ab3, enhance the immune response. (2) Inducing the production of Ab2 to eliminate autoimmune disease.

  19. 3、Apoptosis and Immune regulatory 1) Activation-induced cell death(AICD) and immune response （1）Fas and FasL Fas is expressed on variety cells including lymphocytes, however activated T cell and NK cell expressed FasL.

  20. DD apoptosis DED FAS-FASL mediates cell apoptosis

  21. 2）Caspase and apoptosis Cysteine, (c), Aspartic acid ,(asp) Normallycaspase exists in a proenzyme form, lyastes after activation, and induces cascad reaction.

  22. Deficency of cytokines Ray mitochondrion Cytochrome C Cascade reaction apoptosis Caspase mediates cell apoptosis

  23. (3) AICD and clinical significance For example: ALPS is also related to the mutation of Fas and FasL.

  24. 已有 细胞凋亡介导的负调节作用

  25. Immune regulatory on genetic background and race level 1、Neuro -endocrine-immune network 1）Neuro-endocrine system Corticosteroids and androgen---downregulate immune response. growth hormone, thyroxineandinsulin can enhance immune response. 2）Antibody and cytokines effect on neuro-endocrine system.

  26. Central nervous system hypothalamus adenohypophysis sympathetic nerve pituitary hormone cytokine neurotransmitte sympathetic nerve thyroid hormone thyroid thoracic gland hormone Immune system thymus cytokine endocrine system pancreas insulin Sex hormone gonad adrenocorticotropic hormone adrenal gland

  27. 2、Immune regulatory on racial level 1）Polymorphasim of MHC 2）Enhancing racial adaptive ability to the change of environment.

  28. Immune tolerance • The form of immune tolerance • Mechanism of immune tolerance. • immune tolerance and clinic medicine.

  29. Basic conception Immunological tolerance is a state of unresponsiveness or lower-responsiveness that is specific for a particular antigen. It is different from a state of general immune suppressiveness of immune deficiency and drug treated

  30. 1、The form of immune tolerance 1、Nature immune tolerance is a phenomenon immune system encounter antigen duringembryonic and neonatal period immature T and B cell encounter self or non-self antigen 2、Acquired immune tolerance is mature T and B cell irresponse to antigen for vaious factors

  31. 1、 Nature immune tolerance 1）in 1945, Owen Chimeras of blood type

  32. Phenomena of chimeras（nature immune tolerance ）

  33. 2）Medawar---experimental induction of tolerance 1953年，Medawar：Acquired tolerance

  34. 6 weeks 0 week 7 weeks Treated A strain mice with cells from B strain mice Transplant skin piece from B and C strain mice to A strain mice Rejection of skin piece from C strain mice B C B cell Experimental induction of tolerance

  35. 2、Acquired immune tolerance

  36. 1）Antigens Tolerangen 1. Dosage ： Certain ranges of low doses can induce a state of immunologic unresponsiveness, or tolerance. Conversely, an excessively high dose can also induce tolerance.

  37. 2.The nature of antigens： Molecular structure, molecular size, solubility Chemicalcompositionand heterogeneity

  38. 3.The route of administration Digestive tract,Intravenous,Intraperitoneal,Subcutaneous Split tolerance： This term describes a situation in which one type of graft(e.g, skin) is rejected, while anoher graft from the same donor (e.g, heart)is accepted.

  39. 4.Epitopes: Hen egg-white lysozyme,(HEL) Ts epitopes, Th epitopes

  40. 2）Antigen variation and immune tolerance

  41. Mechanisms of central tolerance Central tolerance Peripheral tolerance

  42. 1、central tolerance Tolerance to self antigens 1）Negative selection 2）B cell deletion

  43. Positive selection Clone deletion Mature T cell Lower expression of TCRαβ Higher expression of TCR αβ Incontact with MHC-I-peptide complex expressed on DC contact with MHC-I-peptide complex expressed on DC contact with MHC-Ⅱ-peptide complex expressed on DC Incontact with MHC-Ⅱ-peptide complex expressed on DC Clone deletion

  44. 2、peripheral tolerance • 1）Clone deletion and Immunological ignorance • T cell anergy • Deficiency of secondary signaling • Bloching of signal transduction • An insufficient dose of antigen will not stimulate an immune response because it fails to activate enough T lymphocytes

  45. APC APC MHC- II MHC- II TCR TCR Co-stimulatory signaling T cell T cell T cell anergy T cell activation Mechanism of clone anergy

  46. Immune ignorance In general, auto-reactive T cells could’t induce the development of autoimmune disease.

  47. 2）Clone anergy immature DC, co-stimulating molecules 3）Supression T cell Secreting TGF- 4）Cytokines, TGF-  5）Signal transduction and immune tolerance

  48. 6）immunologically privileged sites brain, placenta, eye anterior chamber (1) Physiological barriers (2) Supressive cytokines:TGF-b , IL-4/IL-10 Trophoblastic cells, endometrial epithelium

  49. 三、Immune tolerance and Clinical medicine 1、Establish tolerance 2、Breake down tolerance

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