Immunology Past Paper PDF

!!"#$"#% 11/25/24 Lodish: Chapter 23...

!!"#$"#% 11/25/24 Lodish: Chapter 23 Alberts: Chapter 24 The three layers of vertebrate immune defenses (Fig.23.1) Immunology Left: Mechanical defenses consists of epithelia and skin. Chemical defenses include the low pH gastric environment and antibacterial enzymes in tear fluid. Pathogens must physically breach these defenses 1 to infect the host. Dendritic cells Middle: Pathogens that have breached the mechanical and chemical expressing class defenses 2 are handled by cells and molecules of the innate immune II MHC-GFP fusion protein system (blue), which includes phagocytic cells (neutrophils, dendritic cells, macrophages), natural killer (NK) cells, complement proteins, and certain interleukins (IL1, IL6). Innate defenses involve cells and molecules that are present at all times and are rapidly activated within minutes to hours of infection but their ability to distinguish between different infection is limited. Lodish Chapter 23 Opener ! 3 ⑨ The three layers of vertebrate immune defenses The three layers of vertebrate immune defenses (Fig.23.1) (1) Mechanical/chemical defenses (2) Innate immunity Pathogens (3) Adaptive immunity Right: Pathogens that are not cleared by the innate immune system are Immediate/ Epithelia and skin The products of an innate response may potentiate an ensuing dealt with by the adaptive immune system 3, in particular B and T continuous adaptive immune response. 1 Mechanical defenses lymphocytes. Chemical defenses Rapid deployment force Full activation of adaptive immunity requires days. low pH gastric environment Antibacterial enzymes in tear fluid 2 Minutes to hours 3 Days The products of an innate response may potentiate an ensuing adaptive response 4. 5 Likewise, the products of an adaptive immune response, including antibodies may facilitate functioning of the innate immune system 5. Several cell types and secreted products straddle the fence between the A-I connect innate and adaptive innate immune systems, and serve to connect these two layers of host defense. 4 The products of an adaptive immune response may enhance innate immunity. ! 4 Fig. 23.1 Lodish et al. Mol Cell Biol 8th Ed Complement system bridge innate and adaptive immune responses chemical defenses that help prevent infection daptive · innate immunity = a immunity - ! 2 inforce !!"#$"#% 11/25/24 ⑧ 1 infection Lymph Lymph The lymphatic system · spleen : T-cell : B-cell Initiation of the adaptive immune response in lymph nodes nodes vessels The lymph node’s specific function is to filter fluid as the fluid returns from the periphery of the body back to major 2. attacks dentritic cell A network of conduits that carry a clear fluid collecting ducts. There are 500–600 lymph nodes distributed throughout the body. infection Thymus Antigen-laden called lymph. ifinfectionattac attack dendritic cell 3 B cell binds soluble antigen and Soluble 4 moves to follicle Thoracic Spleen Bone marrow: B cell development, T cell antigen lymphatic duct precursors 3 B cell follicles Afferent 4. brought through 2 lymphatic vessel vessel to lymph node Phagocytosis occurs 5. Thymus: T cell maturation lympe Antigens Spleen: Lymphocyte maturation and filtering Bone marrow of lymph. On the left upper abdomen. 1 Mature T and B cells are delivered via the circulation and take up residence in lymph 5 Activation of T cell by antigen ·BoneS se Lymph vessels: Convey lymphs a.Phytotivesicles laden dendritic nodes cell; activated T 2 cells may Lymph nodes: Filtering of lymph and reenter circulation. recognise the maturation of white blood cells. There are Tcellreceptor. 3 500-600 lymph nodes in Human body. Blood vessel 6 Sinus Activated T cells · B-cell receptor is an antibody interact with B cells, Thoracic duct: Discharges lymph into blood. Efferent leading to B-cell 1. B-cell recieves an antigen lymphatic differentiation and Tela 5 vessel Fig. 23.2 Lodish et al. Mol Cell Biol 8th Ed Fig. 23.3 Lodish et al. Mol Cell Biol 8th Ed antibody production 7 · dentritic cell are one of the most important cell romB - i will be activated B-cen 5. B.cellis releaseta The path followed by lymphocytes as they continuously recirculate between the lymph and blood The circulation through a lymph node (yellow) Initiation of the adaptive immune response in lymph nodes (Fig. 23.3) is shown here. Recognition of antigen by B and T cells located in lymph nodes initiates an ! Microbial antigens are usually carried into the Afferent lymph node by activated dendritic cells (not adaptive immune response. lymphatic vessel shown), which enter the node via afferent Lymphocytes leave the circulation and take up residence in lymph nodes 1 lymphatic vessels draining an infected tissue (green). Lymph carries antigen in two forms – soluble antigen and antigen-laden dendritic Efferent ! B and T cells, by contrast, enter via the blood, cells; both are delivered to lymph nodes via afferent lymphatics 23 lymphatic vessel migrating out of the bloodstream into the Postcapillary venule lymph node through postcapillary venules. Soluble antigen is recognized by B cells 4 ! Unless they encounter their antigen, the B and Antigen-laden dendritic cells present antigens to T cells 5 Thoracic duct T cells leave the lymph node via efferent lymphatic vessels, which eventually join the Productive interactions between T and B cells 6 allow B cells to move into follicles thoracic duct. and differentiate into plasma cells, which produce large amounts of antibodies. Artery Vein ! The thoracic duct empties into a large vein Efferent lymphatic vessels return lymph from the lymph node to the circulation. carrying blood to the heart, completing the circulation cycle for T and B cells. ! A typical circulation cycle for these lymphocytes takes about 12–24 hours. 6 8 Fig. 24.18 Alberts et al. Mol Biol Cell 6th Ed · dendrite will pagocytose & 4  !!"#$"#% !!"#$"#% & A simplified drawing of a human lymph node going in (i) B cells are primarily clustered in structures Complement system Afferent lymphatic vessel called lymphoid follicles, whereas T cells are found mainly in the paracortex. ! Complement was discovered approximately 100 years ago as a heat- Lymphoid (ii) Chemokines attract both types of sensitive component of plasma that enhances the opsonization of follicle lymphocytes into the lymph node bacteria by antibodies and facilitates antibody-dependent killing of (mainly B cells) from the blood via postcapillary venules bacteria. Paracortex (mainly T cells) Postcapillary venule ! Complementary to that of humoral immunity. Marginal ! Made up of many different plasma proteins that react with one sinus another to opsonize pathogens. Germinal center Medullary sinus ! Induces a series of inflammatory responses to fight infection. Medulla going out ! Several complement proteins are proteases, present as precursor (iv) The lymphatic vessel ultimately empties into the Efferent lymphatic vessel zymogens. bloodstream, allowing the Artery (iii) B and T cells then migrate to their respective areas, ! They themselves are activated by proteolytic cleavage. lymphocytes to begin another attracted by different chemokines. If they do not cycle of circulation through a Vein encounter their specific antigen, both B cells and T cells peripheral lymphoid organ. then enter the medullary sinuses and leave the node via ! Three pathways through which complement can be activated on the efferent lymphatic vessel. 9 pathogen surfaces. "" Fig. 24.20 Alberts et al. Mol Biol Cell 6th Ed - temp. Sensitive zymogen (inactive ↓ enzyme] ⑨ Dendritic cells as functional links between the innate and adaptive immune systems · I proteins compliment the antibody) I Plasma protein! opsonize pathogens Activated cells migrate to site The complement cascade activation Zymogens ! proteases Inflammatory responses of infection via the blood occurs - zymogen cleared Activated by proteolytic cleavage Skin mannose Remnants of Classical pathway MB-Lectin Pathway Alternative pathway phagountosis MHC protein microbe in phagolysosome Activated dendritic cell Activated T cell Antigen:antibody complexes Lectin binding to pathogen surfaces Pathogen surfaces Microbes CD28 Dendritic Co-stimulatory cell protein (B7) Lymph node Complement activation Microbes enter through break Activated dendritic cell Activated dendritic cell activates in skin and are phagocytosed carries microbial specific cells to respond to microbial by dendritic cell peptides to local nymph peptides bound to MHC proteins on node dendritic cell surface INNATE IMMUNE RESPONSE. ADAPTIVE IMMUNE RESPONSE Recruitment of Opsonization of Killing of Dendritic cells pick up invading microbes or their products at the site of an infection. The microbial inflammatory cells pathogens pathogens PAMPs activate the dendritic cells to express co-stimulatory proteins and increased amounts of MHC proteins on their surface and to migrate via lymphatic vessels to a nearby lymph node. In the lymph 3 ways in which the complement system protects against infection node, the activated dendritic cells activate T cells that express appropriate receptors for the co- stimulatory proteins (a B7 protein, either CD80 or CD86) and the microbial peptides bound to MHC Inflammatory cells: Neutrophil, macrophage, monocyte, eosinophil, and basophil proteins on the dendritic cell surface. Fig. 24.11 Alberts et al. Mol Biol Cell 6th Ed 10 Fig. 2.18 Immunobiology 6th Ed by Janeway et al. !" offers protein MHC to r-cell to take $ & !!"#$"#% 11/25/24 Classical pathway 8 The classical pathway of complement activation ! The first protein in the classical pathway of (regulatory domain) -serineease The cleavage of C4 by C1s exposes a reactive group on C4b that allows it complement activation is C1 to bind covalently to the pathogen surface. ! C1 is a complex of C1q, C1r, and C1s. C4b then binds to C2, making it susceptible to cleavage by C1s. CTS change-induce Cr clearescIs =Recoma The larger C2b is the active protease of the C3 convertase. ! C1q is composed of six identical subunits domain conformation : -globular protease with globular heads and long collagen-like C1 complex Kanbindtas It cleaves many molecules of C3 to produce C3b. ( tails. (C1q6:C1r2:C1s2) ! The tails combine to bind to two molecules each of C1r and C1s, forming C3b binds to the pathogen surface and acts as an opsonin. Opsonins act the C1 complex: C1q6:C1r2:C1s2. as tags to label things in the body that should be phagocytosed by phagocytes ! The heads can bind to the constant region of immunoglobulin molecules, or directly to pathogen surface. C3a, C4a and C5a are anaphylatoxins that mediate inflammation. ! Binding causes conformational changes in C1r, which then cleaves and activates the C1s zymogen (serine protease). Fig. 2.21 Immunobiology 6th Ed by Janeway et al. "# 15 Cra : : < 196 JISc complex : / ! (4 before Ciscleaves a CIS ⑳ The classical pathway of complement activation earestviamatulate ↓ G The classical pathway 1 Ch is cleave C1s C1s C4b.2b ce becomes crasc2 Antigen ↓ CLa floats C26 kinds 046 , (C4b 2b) (C4b 2b 3b) (forming Cs convertase) IgM Activated C1s cleaves C4 C1s cleaves C2 to C2a C4b.2b is an active C3 convertase cleaving C3 One molecule of C4b.2b can cleave up to 1000 Co contentase cleares IgG to C4a and C4b, which and C2b. binds to the microbial C4b then binds C2b, to C3a and C3b, which molecules of C3 to C3b. ↓ C1q C1 proteins recruited to antibody-bound forming the C4b.2b binds to the microbial Many C3b molecules bind C1 C1r surface. C399134 complex surface or to the to the microbial surface 33 becomes C1s cell surface antigens. as convertase C3b acts as an opsonin /become The complex of C4b 2b is a serine protease. convertase itself 336 bincs us ca convertase an opsonin C1 specifically binds to the Fc domain of antigen-bound IgG and IgM. C4b 2b is called "C3 convertase" because it catalyzes the cleavage of C3. - > Cab becomes attract C1 complex is composed of C1q, C1r, and C1s protein subunits. It deposits large numbers of C3b molecules on the pathogen surface. cell > - Cs g are phagocytotic C1r subunit has protease activity that becomes active following C1 binding. C3b acts as an opsonin and, C3a acts as an inflammatory mediator. !" inflammatory mediato Ref: Immunopaedia.org 16 Fig. 2.22 Immunobiology 6th Ed by Janeway et al. 25a 15 ↓ e5 into cleares 5 convertase antibody bind to antigen (CC) · proteins 3tom attracts other c5b a bind to antibody or surface of cell Co attract& (7 8 et attract 29 top 28 attract Clysis)  11/25/24 11/25/24 same sly same sif The classical pathway The classical pathway Antigen 2 4 C4b C3 covertase C4b C2b C1 C3 C1s C1s C4 C3b C4b C3a C4a C1 C4b.2b is an active C3 convertase cleaving C3 to C3a and C3b, which binds to the Binding of C1 to the Fc causes conformational changes in C1r, which then cleaves microbial surface or to the convertase itself. and activates the C1s zymogen (serine protease). C3b functions as an opsonin. Activated C1s cleaves C4 to C4a and C4b, which binds to the microbial surface. C3b is also required to constitute C5 convertase enzyme system. C4a is anaphylatoxin that mediates inflammation. Ref: Immunopaedia.org 17 Ref: Immunopaedia.org 19 same Sin siY The classical pathway The classical pathway 3 Antigen 5 C4b.2b is C3 convertase C4b.2b.3b is C5 convertase C4b C5 covertase C2b C3b C3b C3 C4b IgM covertase C2b C5 IgG C1 C1 C5b C1s C5a C2b C1s C2 The C5 convertase cleaves C5 complement protein into C5a (that is released) and C5b C2a that recruits additional complement proteins involved in the formation of the membrane attack complex (MAC). C1s also cleaves C2 to C2a and C2b. C5a functions as anaphylatoxin that stimulates inflammation. It induces expression of TNF- α, IL-1, and IL-6 in monocytes and macrophages. C4b then binds C2b, forming the C4b.2b complex It also participates in endothelial activation (leading to leucocyte extravasation). Ref: Immunopaedia.org 18 Ref: Immunopaedia.org 20 9 10 !!"#$"#% 11/25/24 514 · FC binds to The classical pathway The classical pathway 6 8 Antigen NK cell · winbind to complemea opso phagocytosed Kill Fc par t of ant body receptor Kill C3b C5b C3b C3b Phagocytosis C6 Complement IgM receptor C8 IgG C7 C1 C5 covertase C9 Fc C5b recruits C6 and C7 complement proteins and the protein complex inserts into the cell receptor membrane. Phagocyte Further recruitment of C8 and C9 complement proteins then follows. Enhanced phagocytosis of target cell is mediated by surface-bound complement protein, which is detected by complement receptors in phagocytes. 23 Ref: Immunopaedia.org "! Ref: Immunopaedia.org 514 on a re sugary there MB-Lectin Pathway · The classical pathway the sur face of the 7 Pattern recognition in the innate immune system a ell (need to be in particular spacing) Kill ma Mannose-binding lectin Membrane C3b Opsonin ins imhusbian an rose , attack complex ↑ N-acetylglucosamine) - (MAC) C3b Lysis C5 covertase C1 C8 and C9 complement proteins constitute a membrane-bound pore that mediates cell lysis. The group of complement proteins C5b-C9 is known as the membrane attack complex MBL binds with high affinity to mannose and Mannose and fucose residues that have (MAC) fucose residues with correct spacing different spacing are not bound by MBL In addition, the Fc domain of bound antibody and cell surface bound C3b enhance detection by phagocytes expressing Fc and complement receptors. Binding sites recognize D-mannose, L-fucose, N-acetylglucosamine Opsonin Ref: Immunopaedia.org !! Fig. 2.11-b Immunobiology 6th Ed by Janeway et al. 24 !! 12  !!"#$"#% !!"#$"#% pathway as classical same & The Mannose-Binding Lectin (MBL) Pathway & The mannose-binding lectin pathway is homologous to the classical pathway 1 ! The MB-lectin forms a complex with serine proteases that resembles the complement C1 complex. MB Lectin (2-6) ! MBL forms clusters of 2-6 carbohydrate-binding Cliker ) heads around a central collagen-like stalk. MBL ! Associated with the complex are two serine proteases, MBL-associated MASP-1 serine proteases -1 and - 2 (MASP-1 and MASP-2). (likes ). or -carbohydrate MASP-2 Polysaccharide ! On binding of MBL to bacterial surfaces, these serine proteases become antigen activated. The lectin complement pathway is initiated by recognition of specific carbohydrate ! Activated serine proteases activate the complement system by cleaving molecules on the cell surface by MBL. and activating C4 and C2. Binding of MBL activates the enzyme activity of MBL-associated serine protease 1 or 2 (MASP-1 or MASP-2). Fig. 2.24 Immunobiology 6th Ed by Janeway et al. "# Ref: Immunopaedia.org !" sil The Mannose-Binding Lectin (MBL) Pathway MBL recognizes bacterial surfaces by their particular spacing of 2 carbohydrate residues MBL is a plasma protein that is a part of the pathogen recognition MB Lectin system of the innate immunity. Polysaccharide antigen C4b Activated MASP The presence of mannose or MASP MASP-1 C4 fucose residues is not enough to C4a or MASP-2 ensure binding. Activated MASP-1 or MASP-2 cleaves C4 into C4a (that is released) and C4b that binds to the cell surface. Only if the mannose and fucose residues have the correct spacing will C4a functions as an anaphylatoxin that stimulates inflammation. the MBL be able to bind. They induce chemotaxis, inflammation and generation of cytotoxic oxygen radicals. Fig. 2.11-a Immunobiology 6th Ed by Janeway et al. !" Ref: Immunopaedia.org !" !& !% 11/25/24 !!"#$"#% six 5/4 The Mannose-Binding Lectin (MBL) Pathway The Mannose-Binding Lectin (MBL) Pathway C3b also functions as an opsonin 3 5 Polysaccharide antigen C4b C5 covertase C3b C2b C3 C4b C3b covertase C2b Opso