* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download antigen, acute phase response 2014
Duffy antigen system wikipedia , lookup
Lymphopoiesis wikipedia , lookup
DNA vaccination wikipedia , lookup
Immune system wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Complement system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Innate immune system wikipedia , lookup
THE TWO ARMS OF THE IMMUNE SYSTEM Monocytes/Macrophages, Dendritic cells, Granulocytes NK cells (complement system) B and T lymphocytes INNATE IMMUNITY ADAPTIVE IMMUNITY - immediate reaction communication - developes in several days - not antigen-specific - specific - no memory - has memory Humoral immunity Cellular immunity !! Innate immunity as a first line of defence !! Innate immune cells recognize frequently found structures of pathogens by PRRs , these are not found in human cells! PRRs (pattern recognition receptors) are responsible for recognize conserved structures of the microbes Examples of recognited structures: duple strain RNA bacterial cell wall components bacterial flagellin…. Recognition is inevitable ACUTE INFLAMMATION AND ACUTE-PHASE RESPONSE ACUTE INFLAMMATION A rapid response to an injurious agent that serves to deliver leukocytes and plasma proteins to the site of injury THE INFLAMMATORY RESPONSE TRIGGERS OF ACUTE INFLAMMATION: Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue Necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions MAJOR COMPONENTS OF INFLAMMATION: 1. Vascular response: Increased vascular diameter Increased flood flow. Endothelial cell activation increased permeability that permits plasma proteins and leukocytes to leave the circulation and enter the tissue edema increased expression of cell adhesion molecules e.g. E-selectin, ICAM 2. Cellular response: Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions Immunitas = exemption, protection Protection from / against what? Self or non-self substances? (What about the useful bacteria living together with us and what about tumors in this model?) - „Danger model”: (Matzinger P., The danger model: a renewed sense of self. Science. 2002 Apr 12;296(5566):301-5.) - harmful self / harmless self - harmful non-self / harmless non-self factors! DANGER SIGNAL / NO DANGER SIGNAL - obligate pathogen facultative pathogen (Staphylococcus aureus) CLASSICAL SYMPTOMES OF ACUTE INFLAMMATION: • • • • • Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of function (functio laesa) NEUTROPHIL GRANULOCYTES • 68% of circulating leukocytes, 99% of circulating granulocytes • Phagocytic cells • Are not present in healthy tissues • Migration elimination of pathogens (enzymes, reactive oxygen intermediates) • Main participants of acute inflammatory processes MIGRATION OF NEUTROPHILS PUS Pus is a whitish-yellow, yellow, or yellow-brown exudate produced by vertebrates during inflammatory pyogenic bacterial infections. Pus consists of a thin, protein-rich fluid, known as liquor puris, and dead cells. CONSEQUENCES OF MACROPHAGE ACTIVATION SYNTHESIS OF CYTOKINES ACUTE-PHASE REACTION proinflammatory cytokines hypothalamic control of body temperature increased ‚set-point’ value fever ACUTE PHASE REACTION IL-6 Complement C-reactive protein (CRP) Liver Fibrinogen Serum amyloid protein (SAP) Mannose binding lectin/protein MBL/MBP UNDER THE INFLUENCE OF IL-6 THE LIVER PRODUCES A BUNCH OF ACUTE-PHASE PROTEINS OPSONIZATION Opsonization facilitate and accelerate the recognition of the pathogen by phaogocytes, opsonins form a bridge between pathogen and a phagocyte connecting them. Main opsonins: antibodies Complement fragments Acute-phase proteins !! ACUTE-PHASE RESPONSE Pentraxin family: CRP – opsonization, complement activation SAP – opsonization, complement activation, binding of mannose/galactose Collectin family: MBL – part of the complement system (SP-A/D – collectins of lungs) Complement proteins (C1-C9) Fibrinogen blood clotting Plasma cascade systems The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC. The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects. The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury. The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators. CHEMICAL MEDIATORS Vasodilation – Prostaglandins (PG), nitric oxide (NO) Increased vascular permeability – vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation – C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever • IL-1, IL-6, TNFα, PGE2 Pain • Prostaglandins, bradykinin Tissue damage • Neutrophil and Macrophage products – lysosomal enzymes – Reactive oxygen species (ROS) – NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2 preventing the synthesis of prostaglandins Prosztaglandin-E2 CHEMICAL MEDIATORS Vasodilation – Prostaglandins (PG), nitric oxide (NO) Increased vascular permeability – vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation – C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever • IL-1, IL-6, TNFα, PGE2 Pain • Prostaglandins, bradykinin Tissue damage • Neutrophil and Macrophage products – lysosomal enzymes – Reactive oxygen species (ROS) – NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2 preventing the synthesis of prostaglandins Tissue factor : Subendothel sejtek (simaizom, kötőszövet) +endotél, makrofág TNF, edotoxin hatására Kinin rendszer a vérből kilépve aktiválódik +faktor XII prekallikrein-kalikrein—bradikinin PAF, állandóan termelődik. Pl. platlets, endotél, neutrofil, monocita De + makrofág, endotél stimulusra. No Makrofág (fagociták), endotél TNF-re fokoz Leukotrién: Hízósejt, leukociták aktiváció hatására Prostaglandinok: COX1 konstitutív COX 2 leukocita, makrofág stimulusra, hipotalamusz CHEMICAL MEDIATORS Vasodilation – Prostaglandins (PG), nitric oxide (NO) Increased vascular permeability – vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activation – C3a, C5a, LTB4, chemokines (e.g. IL-8) Fever • IL-1, IL-6, TNFα, PGE2 Pain • Prostaglandins, bradykinin Tissue damage • Neutrophil and Macrophage products – lysosomal enzymes – Reactive oxygen species (ROS) – NO NSAIDs and Paracetamol: inhibiting COX-1 and COX-2 preventing the synthesis of prostaglandins RESOLUTION OF ACUTE INFLAMMATION SEPTIC SHOCK Triggering factors : • systemic infection (bacteraemia) • microbial cell wall products and/or toxins released from the pathogens Result: Systemic activation of neutrophils and macrophages High level of cytokine (TNF-alpha) production: „cytokine storm” Excessive inflammatory response SEPTIC SHOCK The key molecule of the process: TNF-alpha TNF-alpha and other inflammatory cytokines capillar permeability blood pressure high fever multiorgan failure DIC disseminated intravascular coagulation Therapy: anti-TNF-alpha antibody DIC Disseminated Intravascular Coagulation • pathologic activation of thrombotic process • distress of thrombotic process, bleeding • other causes: snake bite, septic abortion, acute obstetric complications, malignant tumors, leukemias DIC: Disseminated Intravascular Coagulation 2nd seminar: THE ANTIGEN Definition and properties Antigenic determinant (epitope) Hapten, carrier Antigen recognition by B and T cells Superantigens ACUTE INFLAMMATION DEFINITIONS • ANTIGEN (Ag) - any substance, which is recognized by the mature immune system of a given organism Any chemical structure Soluble or corpuscle Simple or complex Originated from the body or comes from outside Genetically self or non-self Natural or artificial DEFINITIONS • ANTIGENICITY– capability of an antigen to bind specifically with certain product of the adaptive immunity: TCR or BCR/antibody, – immunogenicity - capability of an antigen to induce an (adaptive) immune response, – tolerogenicity - capability to induce immunological tolerance, specific immune non-responsiveness FACTORS INFLUENCING IMMUNOGENICITY I. From the aspect of our body: • Genetics (self/non-self) – – species (evolutionarily nonconserved molecules) individual differences (e.g. MHC polymorphism – see later) • Age – newborn – less reactive immune system – elderly – no new lymphocytes • Physiological condition (pl. immunodeficiencies, starvation) FACTORS INFLUENCING IMMUNOGENICITY II. From the aspect of the antigen: • Physical-chemical properties of the Ag – – – – size/complexity (bigger more epitopes, role of carrier) corpuscular (cell, colloid) or soluble denatured or native (different epitopes!) degradability (by APCs) • Availability (crystalline proteins of the eye are not presented to lymphocytes) FACTORS INFLUENCING IMMUNOGENICITY III. From the aspect of vaccination: • Dose • Route – intradermal/subcutan > intravenous > oral > intranasal (oral vaccine against polio virus!) • Adjuvant – enhance the response given to the antigen e.g.: alum, Freund-adjuvant, TLR ligands Complex effects: • depot effect long-lasting presence of antigen • activation of innate immunity • activation of bystander cells 077-298-32------------------218-329-10 HLA-C HLA-B HLA-A maternal HLA-A HLA-B HLA-C paternal ANTIGEN RECOGNITION BY LYMPHOCYTES antibodies (serum Ig) APC Antigen MHC BCR TCR (membrane Ig) T B B cells recognise native antigens T cells recognise processed antigens Clonal proliferation !! LYMPHOID ORGANS Primary lymphoid organs: - Bone marrow - Thymus the cells of the immune system originate in and mature here Secondary lymphoid organs: - Spleen - Lymphatic vessels - Lymph nodes - Adenoids and tonsils - MALT (Mucosal Associated Lymphoid Tissue) GALT (Gut Associated Lymphoid Tissue) BALT (Bronchus Associated Lymphoid Tissue) SALT (Skin Associated Lymphoid Tissue) NALT (Nasal Associated Lymphoid Tissue) not for cell development. (final differentiation, activation may be performed) The cells of the adaptive immune system recognize here the pathogens DEFINITIONS • ANTIGEN (Ag) - any substance, which is recognized by the mature immune system of a given organism Any chemical structure Soluble or corpuscle Simple or complex Originated from the body or comes from outside Genetically self or non-self Natural or artificial ANTIGENIC DETERMINANT (=EPITOPE) Part of the antigen which directly interacts with the antigenbinding site of a defined immunoglobulin (BCR / antibody) or TCR B cell epitope T cell epitope recognized by B cells recognized by T cells • proteins polysaccharides lipids DNA steroids etc. (many artificial molecules) • proteins mainly (8-23 amino acids) • cell or matrix associated or soluble • requires processing by APC Antigens may have several different epitopes T CELL-DEPENDENT B CELL ACTIVATION 1 B cell MHCII +peptide T cell CD4 TCR 2 cytokines gr2 Polysacharides are not presented! Theoretical structure of complex antigens Epitopes „Carrier” no direct interaction with the antigen-binding site These terms can only be used to describe the interaction of particular antigenic determinant and single immunoglobulin or T cell receptor EPITOPE AND „CARRIER” Antibody 1 „carrier” (2) Antibody 2 Epitope 1 Antigén Epitope 2 „carrier” (1) TYPES (STRUCTURE) OF ANTIGEN DETERMINANTS linear determinant (TCR, BCR, Ig) conformational determinant (BCR, Ig) conformational determinant Ab2 Ab1 surface/accessible determinants cleveage denaturation new/neoantigen determinant conformational/linear determinant hidden/revealed determinant LPS – antigen or PAMP?! Antigen PAMP if recognised by TCR/BCR if recognized by PRR (TLR4) Fc LPS Fab side view Fab specific antibody reactive to the glucoseamin epitope of LPS top view T CELL-DEPENDENT B CELL ACTIVATION 1 B cell MHCII +peptide T cell CD4 TCR 2 cytokines Polysacharides are not presented! B CELL ACTIVATION WITHOUT THE HELP OF T CELLS T-INDEPENDENT ANTIGEN TI-1 T-INDEPENDENT ANTIGEN TI-2 B cell Simultaneous activation of BCR and other receptors on B cells (i.e. LPS binding protein /CD14) induces the B cells to proliferate and differentiate (extra activation signal) Strong crosslinking of BCR by repetitive polysaccharide or protein epitopes B CELL ACTIVATION (extensive receptor-aggregation) B CELL ACTIVATION WITHOUT THE HELP OF T CELLS Gr1-gr9 HAPTEN molecules that are too small to provoke an immune response unless they are attached to carriers hapten (e.g. DNP: dinitrofenil) carrier + haptens + HAPTEN free haptens haptens attached to a carrier 0 receptor cross-linking signalization Antibody response generated against a haptencarrier conjugate carrier + hapten antibodies carrier specific hapten specific carrier + hapten specific ANTIGEN RECOGNITION ≠ CELL ACTIVATION ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES PRESENTATION VIA MHC MOLECULES Recognition/ No activation Recognition/ Activation EXAMPLE (Prevenar - pneumococus vaccine) Purified bacterial polysacharides used for vaccination do not lead to long-lasting immunity because the activation of T cells is required for memory B cell formation Hence the polysaccharide chains are conjugated to protein carriers which can activate T cells Carrier: CRM197 modified diphteria toxin (toxoid) (a single aminoacid change (Glu Gly) in the toxin can abolish toxicity) The toxoid acts the same way the toxin does; it activates specific T cells and may lead to the production of antitoxins by plasmacells Glu Gly toxin + polysaccharides of different Streptococcus pneumoniae strains toxoid toxoid complex antigen of vaccine toxoid peptide antigen derived from toxoid polysacharid MHCII BCR B cell specific to bacterial polysaccharid TCR T cell specific to toxin/toxoid epitope cytokines, CD40-CD40L formation of pneumococcusspecific memory B cells SUPERANTIGENS Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules resulting in a polyclonal activation Fever SUPERANTIGENS Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules resulting in a polyclonal activation. Interaction is not via the peptide binding cleft of MHC molecule. Hypotension Rash Desquamation SUPERANTIGENS Microbial proteins that bind to and activate all the T cells in an individual that express a particular set or family of TCR molecules conventional antigen superantigen monoclonal/oligoclonal polyclonal T cell response T cell response 1:104 - 1:105 107 – 108 / 1011 activated T cells 1:4 - 1:10 1010 / 1011 SUPERANTIGENS Classification Sources Endogenous 1.Mouse mammary tomor virus (MMTV) 2.Epstein-Barr virus (EBV) Exogenous 1.Staphylococcal enterotoxins (SEs): A, B, C1 to C3, D, E, G to Q 2.Staphylococcal toxic shock syndrome toxin-1 (TSST-1) 3.Staphylococcal exfoliative toxins: exoliatin A, exfoliatin B 4.Staphylococcal enterotoxin-like toxins formed due to recombination within enterotoxin gene cluster: U2, V 5.Streptococcal pyrogenic exotoxins (SPEs): A1 to A4, C, G to M 6.Streptococcal mitogenic exotoxins: SMEZ 7.Streptococcal superantigen :SSA 8.Yersinia pseudotuberculosis: Yersinia pseudotuberculosis-derived mitogen (YAM) 9.Mycoplasma species: Mycoplasma arthritidis-derived mitogen (MAM) 10.Cholera toxin: subunit A of cholera toxin 11.Prevotella intermedia* 12.Mycobacterium tuberculosis* 13.Viral superantigens: (a) Mouse leukemia virus (b) IDDMK1222- Ppol-ENV-U3 (c) HIV-Nef (d) Rabies virus-nucleoside protein .