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APC & Antigen presentation
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antigen-presenting cell, APC
Concept A group of immune cells, whose role is to take up, process and present antigenic peptides to T cells.
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Professional APC Non-professional APC
Macrophages, dendritic cells, and B cells, which can express MHC class II molecules. Non-professional APC Other cell type capable of expressing MHC class II molecules eg. Endothelial cells, EC Fibroblasts Activated T cell
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1 Dendritic cell,DC highly branched morphology
can active naive T cells markers
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1) Markers secreting cytokines CD1a, CD11c, CD83
Pathogen receptor, FcR MHC II co-stimulating factors (CD80,CD86) Adhesion molecular CD40 CD54 (ICAM-1), etc. secreting cytokines IL1, IL-6, IL-12, TNF-a, IFN-a, chemokines
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2) Source, distribution and classification Source
DC are bone marrow-derived Myeloid DC Lymphoid DC
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Bone marrow Blood Tissue
dendritic cell Monocyte Indeterminate cell Dendritic cell Macrphage Mycloid precursor Pluripotent stem cell ?
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Distribution and classification
DCs are found in many organs throughout the body DC in lymphoid tissue Interdigitating cell, IDC Follicular DC, FDC thymic dendritic cell, TDC DC not in lymphoid tissue Langerhans cells Interstitial DC DC in body fluid Veiled cells Peripheral blood DC
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interdigitating DC, IDC
IDC express high levels of MHC molecules, and are more potent antigen-presenting cells than others.
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follicular DC, FDC FDC B cells
FDC express high levels of membrane receptors for antibody and complement. By these, FDC actives the B cells in lymph nodes.
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Langerhan’s cells, LC Langerhans cells found in the epidermis (skin) and mucous membranes (left), expressing high levels of FcR, receptor of complement, and MHC. Birbeck granule is the characteristic organelle. After capturing antigen in the tissues by phagocytosis or by endocytosis. DC migrate into the blood or lymph and circulate to lymphoid organs, become IDC(right)。
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Cell MHC-II FcR C3bR Birbeck
FDC ++/ IDC (I,II) TDC ? + LC (I,II) + + + Interstitial DC ? ? + VC ? ? -- M ++/ BL
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3) Differentiation, development, maturing and migration
Lymphoid DC DC in lymph, negative selection of T cells myeloid DC Immature mature
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Four phases Pre-DC Immature DC Migration Mature DC Monocyte, Mo
Uptake antigen Express MHC Secrete chemokines Migration Mature DC Express high levels of MHC I and II, CD80, CD86, CD40, CD54, HSP, etc.
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4) activation and tolerance Activation
First signal (MHC-peptide) Second signal (co-stimulating factors) Adhesion molecular Cytokines (IL-12) Tolerance Negative selection
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2 Mononuclear phagocyte system, MPS
Macrophages (Mf) are phagocytic cells of monocytic lineage residing within tissues and are particularly well equipped for effective antigen presentation.
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Different names in different tissues
Monocyte ( blood ) Kupffer cells ( liver ) Mesangial cells ( kidney glomerulus ) Microglia ( brain ) Alveolar macrophages ( lung ) Histiocyte ( connective tissue )
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The process of M activation
rested M responsive M stimulated M activated M suppressor M 病原体 signal LFA-1 MHC-II 细胞增生 趋化,杀菌 提呈Ag, 激活LC, 结合TC, 过度活化 适度活化 PGE 抑制免疫功能 杀瘤,杀菌 First signal: MAF/IFN-, MSF second signal: LPS/IFN-, MSF,CK, 1 2 3
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markers Functions MHC II CR1(CD35) CR3(CD11b/CD18) IgG Fc受体 Receptors
Enzymes Cytokines
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扫描电镜显示,在感染早期,M伸出长长的伪足去捕获细菌
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Biologic effects of M
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3 B cell bone marrow-dependent lymphocyte
About 5-15% of the circulating lymphoid pool are B cells difined by the presence of surface immunoglobulin.
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Markers of B cells
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Characteristics of B cells
not actively phagocytic Class II-positive BCR
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Antigen-presenting cells
APC Present to Macrophage T cell via MHC antigen Dendritic cells B cells T cell via antigen captrue by surface antibody and MHC antigen Activated T cells
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ANTIGEN PROCESSING AND PRESENTATION
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Binding and uptake of antigen
depends on the physical state of the antigen and the cell type involved. Antigen processing MHC class I processing pathway MHC class II processing pathway Antigen presentation
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1 Binding and uptake of antigen
exogenous antigens Bacteria, cells and soluble proteins processed by APC endogenous antigens Produced within the cells, Such as viral proteins or tumor proteins processed by host cell
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Uptake antigen by immature DC
Pinocytosis Liquid or small granule Receptor-mediated endocytosis effective selective saturated FCR, 甘露糖R Phagocytosis Large molecular or microbe
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Uptake antigen by MPC Phagocytosis Pinocytosis Endocytosis
Large solid or molecular complex, such as bacteria, fragment of cells, etc. Phagecyte (mf, granulocyte) Pinocytosis Receptor-mediated pinocytosis Endocytosis Low levels of particulate or soluble antigens exocytosis
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Uptake antigen by B cells
nonspecifically engulfed BCR-mediated
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2 Antigen processing Degradation of externally- or internally- derived antigen into short peptide sequences Association of the peptide with MHC molecules
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Two antigen-processing pathways
MHC class I MHC class II Major antigen sources endogenous antigen exogenous antigen Processing machinery proteasome lysosomal enzymes Cell type where active all nucleated cells professional APCs Site of antigen-MHC binding endoplasmic reticulum lysosome and endosome MHC utilized Presents to CD8+ T cell (Tc) CD4+ T cells (Th)
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MHC class I processing pathway
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MHC class I processing pathway
Antigenic protein proteosome peptide fragment released into cytosol binds to TAP protein moves to endoplasmic reticulum(ER) Newly synthesized Class I a chain and b2 microglobulin move to ER calnexin binds to a chain peptide fragment and b2m bind to a chain release of a chain from calnexin complex moves to Golgi apparatus glycosylation in Golgi apparatus secretory vesicle plasma membrane
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Structure of MHC class I
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proteasome LMP, low molecular weight polypeptide or large multifunctional protease Structure: 20S 26S Function: Degradation of protein
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26S protease cmplex 20S proteasome twin 19S cops
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TAP, transporter associated with antigen processing
structure: TAP-1 and TAP-2 function: transports small peptides (8-13 aa) to the ER
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calnexin Structure Function
88kD integral ER membrane chaperone protein Function Binds to a nascent MHC class I a chain after release from a ribosome into the ER lumen so that the a chain will not leave the ER until it binds both a short peptide sequence and b2 microgobulin
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Molecular chaperones: calnexin, calreticulin,tapasin
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MHC class II processing pathway
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MHC class II processing pathway
Antigenic protein endosome/lysosome peptide fragment Newly synthesized class II molecules move to ER and associate with invariant chain protein molecule move to Golgi apparatus move to endosomes/lysosomes release of invariant chain from class II molecule class II binds antigenic peptide fragment transport to cell surface
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Structure of MHC class II
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Endosome & lysosome acidic protease & lysosome enzymes Function
Degrade protein into peptide fragments (10-30 aa)
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invariant chain, Ii Function Promote the formation of MHC II a b dimer
Directs the movement of newly synthesized class II molecules into the Golgi and then the late endocytic compartment of the cell Prevent the binding of antigenic peptides to class II molecules, at least until the class II molecule reaches the late endocytic compartment
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CLIP, class II associated invariant chain peptides
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3 Antigen presentation Antigen presentation
The activation of T cells via T cell receptors, which specifically recognize antigenic peptide in association with either MHC class I or II molecules on the surface of APC.
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