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Immunological regulation

Immunological regulation. 1. Regulation on molecular level 2. Regulation on cellular level 3. Regulation on systemic level. Regulation on molecular level. 1. Feedback regulation in the signaling transduction of activated immune cells. Protein phosphoration and dephosphoration

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Immunological regulation

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  1. Immunological regulation 1. Regulation on molecular level 2. Regulation on cellular level 3. Regulation on systemic level

  2. Regulation on molecular level 1. Feedback regulation in the signaling transduction of activated immune cells Protein phosphoration and dephosphoration Protein tyrosine kinase,(PTK)—Activate the promotion and upstream protein tyrosine phosphase(PTP)— Dephosphoration, negative regulation molecules in signaling pathway.

  3. Anti-BCR antibody Anti-BCR antibody Antigen-antibody complex Cross-linking of receptors Phosphoration Dephosphoration Recruit PTP, Syk Block/ supress Activation of B cell Function of inhibitory receptor FcgR II-B

  4. 2. Two opposite receptors 1). Activating receptor: ITAM(immunoreceptor tyrosine-based activation motif) Motifs：YxxL/V 2). Inhibitory receptor: ITIM(immunoreciptor tyrosine-based inhibitory motif) Motifs：I/Vx YxxL Activating receptors cross-linking is necessary fornegative regulation of inhibitory receptors

  5. Antigen Inhibitory receptor Activating receptor B cell Phosphoration Dephosphoration Activate B cell Inhibit B cell Immunological regulation of activating and inhibitory receptors 激活性受体和抑制性受体的免疫调节作用

  6. 3. inhibitory receptor on immune cells 1. T cell: CTLA-4 and PD-1 On activated T cells, Containing ITIM motif in the cytoplasmicdomain . Use CTLA4-Ig fusion protein and anti-CTLA-4 antibody , inhibit or Enhance the function of specific T cell. Application：anti-tumor, organ transplantation, autoimmune disease 2. B cell: FcgRII-B Containing ITIM in the cytoplasmic domain of g chain Associate with autoimmune disease

  7. Ag-Ab complex Anti-m chain IgG B cell B cell Inhibition mediated by anti-IgM IgG Inhibition mediated by anti-Immune complex IgG Inhibition of B cell function by anti-BCR or anti-immune complex antibody

  8. 3. Killing cells (NK,CTL): KIR and CD94/NKG2A Type I：Killing cell inhibitory receptor (KIR) Ligation：HLA-I，HLA-G Type II：C-type lectin receptorCD94/NKG2A： Recognize a conservative 9aa peptide presented in leader sequence of non-classical MHC class I --HLE； Containing ITIM in the cytoplasmicdomain； Application ： Physiologically， prevent the mother from rejecting the fetus ； Pathologically， Excessively activated ，fail to kill virus infected cells , escape the immune surveillance 4. Mast cells：FcgRII-B Cross-link with activating receptor FceRI on mast cells Negatively regulate the immune response

  9. Activating and inhibitory receptors 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. 2. Regulation on cellular level 1). T cell subsets and their interactions 2). Immunological regulation of idiotypic network 3). Negative immunological regulation of apoptosis

  11. 1. T cell subsets and their interactions 1）Natural regulatory T cell CD4＋CD25＋regulatory T cell Secret cytokines: TGF-、IL-10 Cell-cell contact :CTLA-4

  12. 2）CD4+ T cell and CD8+ T cell Normal ： CD4/ CD8=1.5-2:1 Upregulation: Positive regulation Downregulation： < 1，Immunodeficiency

  13. Naïve CD4+T cell Activating CD4+T cell Th0 cell Th1 cell Th2 cell Activate macrophage Enhance cytotoxicity Induce delayed Delayed type hypersensitivity Cellular immune response Activate B cell Production of neutrolizing Ab Involved in acute hypersensitivity Humoral immune response Imunological regulation of Th1/Th2

  14. Involvement of Th1 ,Th2 cell and cytokines Interconversion of Th1 and Th2 Lepra：Distinctly proliferation of Th2, Arrest the conversion of Th0 to Th1， Use IFN-g to promote Th1 ,and inhibit Th2 cells

  15. 2.Immunological regulation of idiotypic network Basel Institute for Immunology Basel, Switzerland 1984 The Nobel Prize in Physiology or Medicine Niels K. Jerne 1911-1994

  16. IdiotypeId Anti-idiotype antibodyAId 1） Anti-idiotype antibody and idiotypic network （1）Idiotype of antibod，induce Anti-idiotype antibody (anti-idiotype,Aid)，Ab2 （2）Large amount of Ab can induce the production of antibody

  17. （3）Classification of Anti-idiotype antibody: According to the distribution, Ab2a，Ab2b etc。 Ab2b (antigen internal image) Similar structure with antigen epitope , Competitively bind to Ab1 with antigen （4）Negative regulation of Anti-idiotype antibody （5） Idiotypic network：Ag—Ab---Ab2----Ab3----

  18. Immunological regulation of Idiotypic network

  19. 2）Immunointerference of Idiotypic network （1） Utilize internal image to enhance Ag-specific immune response through inducing Ab1 and Ab3 （2） Induce the production of Ab2 in vivo，decrease or eliminate Ab1, prevent autoimmune disease

  20. 3. Negative immunological regulation of apoptosis 1）activation-induced cell death and specific immune response （1）Fas 和FasL Fas： Extensively expressed on tissue cells involving lymphocytes FasL：Expressed on activated T cells（CTL,Th1），NK cell AICD (activation-induced cell death)： FasL can bind to Fas on the same cell ,and induce self-apoptosis Fas—DD—FADD—caspase 8—caspase cascade —cell death

  21. death effector domain Death domain Apoptosis Death effector domain Apoptosis signaling pathway mediated by Fas-FasL

  22. （2）Caspase and cell apoptosis Cysteine (c) Aspartic acid (asp) Caspase( exist in the form of zymogen) Activated Lysis Induce cascade

  23. Lack of cytokines radiation Mitochondria Cyclin C Caspase cascade Cell apoptosis Two apoptotic pathways of caspase

  24. （3）Significance of AICD Mutations of Fas and FasL Autoimmune lymphoproliferative syndrome(ALPS)

  25. T cell proliferation Ag repeat stimulation Lack of Ag and other necessory factors Mitochondria Autocrine Cyclin C T cell Activation-induced cell death (AICD) Passive cell death (PCD) Negative immunological regulation by cell apoptosis

  26. 4.Immunological regulation on Systemic and group level • Regulation of nerve-endocrine-immunological network • 1）Nerve-endocrine factors • Corticosterone , androgen --- Downregulate immune response • Estrogen , rowth hormone, thyroxine, Insulin --- Upregulate immune response • 2）Antibody and cytokines act on nerve-endocrine system ----competitive combination

  27. Central nerve system Hypothalamus Adenohypophysis Cardiac sympathetic nerve Cardiac sympathetic nerve Endocrine hormone Cytokines Immune system Thyroid gland Thyroxine Endocrine system Thymic hormone Thymus Cytokine Pancreas Insulin Gonad sex hormone Adrenal gland Corticosterone Regulation of nerve-endocrine-immunological network 神经-内分泌-免疫网络调节

  28. 2、Immunological regulation on group level 1）MHC polymorphism and group level of immunoregulation 2）Enhance the group flexibility

  29. Immunological Tolerance • Formation and characteristics • Mechnism • Immunological Tolerance and diseases

  30. Basic Concepts Immunological tolerance is a state of unresponsiveness that is specific for a particular antigen ;it is induced by prior exposure to that antigen. Differ from the universal immune suppression caused by immunodeficiency or drugs.

  31. 1. Formation and characteristics • Tolerance induced in fetal and neonatal stage ---- • Natural immunogical tolerance • Immature T, B cell contact self and foreign Ag • Last for lifetime • 2. Tolerance induced in postnatal stage ---- • Acquired immunogical tolerance • T、B cells Tolerance to Ag which they respond in normal condition • Not lifetime

  32. 1. Tolerance induced in fetal and neonatal stage Natural immunogical tolerance 1）Owen's discovery 1945, Fraternal twin cattle：chimeras， readily accept skin grafts from each other. Reject skin grafts from other cattles

  33. Hematopoietic chimeras of Fraternal twin cattle Natural immunogical tolerance

  34. 2）Medawar---Experimental immunological tolerance 1953，Medawar：Acquired immunological tolerance

  35. Week 0 Week 6 Week 7 Transfuse cells from strain B neonatal mice to strain A mice Skin implant from strain B and C mice to strain A Skin implant from B survived , that from C rejected B cell Medawar’s experimental immunological tolerance

  36. 2. Tolerance induced in postnatal stage 1）Antigen factors 2）Antigenic variation

  37. 1）Antigen Tolerogen — Antigen inducing immune tolerance 1. Dose of Antigen： High and low dose of TD Ag： High zone tolerance（T,B cell tolerance） Low zone tolerance（T cell tolerance）

  38. 2. Type of antigen： Simple structure , small molecular ,soluble ---readily induce tolerance Physical chemistry characters： BSA monomer Polymers easier to be phagocytosed and to be presented )

  39. 3. Ways of Antigen injection： Induction of tolerance Oral , i.v. > i.p > s.c Split tolerance： Taking Ag orally induce local mucosal immune response , but systemic tolerance

  40. 4. Features of Ag epitopes Hen egg white lysozyme ( HEL) induce tolerance Ts epitopes and Th epitopes exist in N and C terminus, respectivly HEL with 3 aa Deletion of N terminus will induce immune response.

  41. 2）Antigen variation and immunological variation

  42. 2. Mechanism 1. Central tolerance 2. Peripheral tolerance

  43. 1. Central tolerance Tolerance to self-antigen 1）T cell clonal deletion theory (negative selection) 2）B cell clone depletion：

  44. Positive selection Low expression of TCR ab Clonal deletion( negative selection) Mature T cell High expression of TCR ab Not bind to self peptide-MHC I complex, Survive and mature Bind to self peptide-MHC I complex, apoptosis Bind to self peptide-MHC I complex apoptosis Not bind to self peptide-MHC II complex, Survive and mature Clonal deletion theory

  45. 2. Peripheral tolerance 1）Clonal deletion and immunological ignorance T cell anergy a. Lack the second signal ---CD28-B7 b. Dysfunction of activating and proliferating signal transduction c. Ag dose : too low to induce immune response

  46. APC APC MHC- II MHC- II TCR TCR Co-stimulating molecules T cell T cell T细胞活化 T cell anergy T cell activation T cell anergy Mechanism of clonal anergy

  47. Clonal ignorance Co-existence of self-reactive T cell clones and associated tissue specific Ag , physiologically ,will not induce autoimmune disease.

  48. 2）Clonal anergy no co-stimulatory molecules on immnature DC 3）Immunosupressive cells Ts produce TGF- to inhibit Th and CTL function 4）Cytokine 5）Dysfunction of cellular signal transduction

  49. 6）Ag in immuno isolation region -----no immune response brain, anterior chamber of eye, placent (1) Physiological barrier (2) Inhibitory cytokines: TGF-b , IL-4/IL-10 inhibit Th1 Produced by placental cytotrophoblast cells and endometrium epithelial cells

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