Immunoregulation

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

severe inflammation reaction in lung SARS patient healthy subject

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

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

PAMP PAMPs (Pathogen associated molecular patterns) are conserved structures among many pathogens. PAMPs are generated by microbes and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self- and nonself. Furthermore, PAMPs are essential for microbial survival. LPS, CpG DNA，ssRNA，dsRNA, PGN, LTA, HSP, et al.

PRR Pattern Recognition Receptors (PRRs) charateristic Few diversity Non clonal ditribution Immediate immune response

PRR: classification Mambrane PRR:TLR1,2,4,6;MR；SR； Secretory PRR:MBL;CRP;LPB； Cytoplasm RR:TLR3,TLR7/8,TLR9; NLR;RIG-Ⅰ,MDA-5;

固有免疫中针对TLR信号转导的负向调节 炎症细胞因子基因转录 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 SOCS1 IRAK1 MyD88s IRAK4 TRAF6 IRAK-M MAPK PKB NF-B ASK1 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。

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

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

补体成分C3 裂介后产生 的相关分子 Complement regulatory Protein C3 C3 转化酶 C3a C3转化酶 C3b I factor C3f iC3b I factor+ H Factor C3c 补体成分C3 裂介后产生 的相关分子 C3d C3g C3dg

Inhibitory receptor mediated regulation 蛋白质 ATP -OH + ADP O ‖ -O-P-O- | O- HO-O-P-O- H2O 蛋白激酶 蛋白磷酸酶 蛋白磷酸化 蛋白脱磷酸化 PTK and PTP 蛋白磷酸化和脱磷酸化分别由蛋白激酶和蛋白磷酸酶促成

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

CTLA-4对T细胞激活的反馈调节 Ag TCR B7 CD28 B7 CTLA-4 I TAM I T I M T细胞 抑制信号 激活信号 24 h T细胞 抑制信号 激活信号 CTLA-4对T细胞激活的反馈调节

抑制性受体FcRII-B对抗体产生的反馈性调节 抗BCR抗体 BCR (mIgM) Ag-Ab复合物 FcRII-B FcRII-B ITIM ITIM 干扰 B 细胞激活的信号转导 抑制性受体FcRII-B对抗体产生的反馈性调节

抑制性受体FcRII-B对抗体产生的反馈性调节 BCR (mIgM) 抗BCR抗体 (Ab2) FcRII-B ITIM B 细胞激活信号转导受阻 抑制性受体FcRII-B对抗体产生的反馈性调节

人NK细胞主要的抑制性受体和激活性受体

Activating receptor and Inhibitory receptor of Immune cells 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  T cell V9V2 TCR CD94/NKG2A Activating receptor and Inhibitory receptor of Immune cells

C. Regulation by Treg lymphocytes Naturally Treg and adaptive Treg characteristic Nature Treg adaptive Treg Induction location Thymus (periphery), periphery Foxp3 +++ + IL-2 dependence CD25 -/+ Antigen specificity Auto-antigen Tissue-specific Ag and exogenous Ag mechanism Cell-contact, CK independence Cell-contact, CK dependence Function Inhibit ART mediated Response Inhibit pathological response Example CD4+CD25+T CD4+ Tr1,Th3

Differing immunosuppressive mechanisms used by TReg cells in lymphoid and non-lymphoid tissues. Nature Reviews Immunology 11, 119-130

Th1 初始 T Th 0 Th2 Th17 TNF- pMHC IL-4 IL-5 IL-13 共刺激 IL-17 IL-17F IFN- TNF- CCR5 CXCR3 IL-4 IL-5 IL-13 CCR3,4,8 Th1 Th2 pMHC Th 0 初始 T IL-4R Stat6 IL4 Gata3 IFNG IFN-R IL-12 IL-12R TCR Stat4 Stat1 T-bet IL-23 IL-23R Stat3 IL17 IFNG, IL4 IL-17 IL-17F Th17 IFN 细胞免疫 体液免疫 炎症反应 RORt

发挥调节作用的Th1和Th2亚群在功能上的相互拮抗 Th1和Th2亚群各自藉助分泌的细胞因子和激活的亚群专一性转录因子以调节性T细胞的形式抑制另一亚群的分化

IFN-逆转Th2极化格局通过激活Th1诱导抗胞内菌免疫

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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.

Isotype The genes for isotype variants are present in all healthy member of a species.

(2) Allotype This refers to genetic variation between individuals within a species.

(3) Idiotype Variation in the V domain ,particularly in CDR, produces idiotype.

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

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

E. Regulation by apoptosis 1. Activation-induced cell death (AICD) Fas (CD95) and FasL Fas membrane protein is expressed on lymphoid and other cells but is increased in expression with cellular activation. FasL is expressed on activated T cells. Thus, activation of T cells results in the expression of both Fas and FasL. The intracellular portion of the Fas receptor molecule contains ‘death domains’, which recruit proteins that lead to the activation of a cascade of proteases which induce apoptosis. Fas-FasL interaction is a major means of mediating AICD in CD4+ T cell.

(1) Fas/FasL and death signal transduction evoked by Fas molecules (receptor) 150 aa Fas (CD95), a type I membrane protein with 325 aa (48 kD) FasL (Fas ligand), a type II membrane protein with 235 aa sFasL DD: death domain 70 aa 80 aa

Fas-FasL pathway Caspase:胱天蛋白酶 RIP：renal ischemic preconditioning c-FLIP： FLICE inhibitory protein DISC: death inducing signaling complex Caspase:胱天蛋白酶

Major advances have recently been made in mapping the loci which govern susceptibility to the autoimmune disease. When the lymphoproliferative (lpr) gene is present in mouse strains, it causes the development of a characteristic clinical syndrome. The mice develop anti-DNA antibodies, rheumatoid factor, circulating IC and glomerulonephritis.

A lpr FasL gld B Fas AICD Phe 自身抗原 自身免疫性淋巴 无疾病 细胞增生综合征 Ile Asn 死亡结构域 lpr Fas Ile Asn FasL gld CYT TM EXT Phe WT TTT GAG GAA TCT AAG ACC TTT TTC GGC TTG TAT AAG gld TTT GAG GAA TCT AAG ACC CTT TTC GGC TTG TAT AAG Leu 自身免疫性淋巴 细胞增生综合征 自身抗原 自身抗原驱动下的淋巴细胞克隆扩增 克隆收缩 受阻 无疾病 AICD B

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

Figure 14. 3. Anti-inflammatory effects of corticosteroid therapy Figure 14.3. Anti-inflammatory effects of corticosteroid therapy. Corticosteroids regulate the expression of many genes, with a net anti-inflammatory effect. First, they reduce the production of inflammatory mediators, including cytokines, prostaglandins, and nitric oxide. Second, they inhibit inflammatory cell migration to sites of inflammation by inhibiting the expression of adhesion molecules. Third, corticosteroids promote the death by apoptosis of leukocytes and lymphocytes.

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 1)Polymorphisms in the genes encoding cytokine receptors have been shown to correlate with an increased susceptibility to infection, SCID or inflammatory conditions.

2) Genetic control of specificity of an immune response Antigen is recognized by the lymphocyte that express specific antigen receptor (TCR/BCR) for that antigen. TCR and BCR are encoded by corresponding genes, thereby specificity of an immune response is genetically controlled.

3) Other non-MHC genes also modulate immume responses Deficiency in C1q,C1r,C1s SLE and lupus nephritis Deficiency in C3 bacterial infections ‘atopy gene’ on human allergy (high IgE chromosome 11q production)

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