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2nd seminar : THE ANTIGEN

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.

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2nd seminar : THE ANTIGEN

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  1. 2nd seminar:THE ANTIGEN Definition and properties Antigenic determinant (epitope) Hapten, carrier Antigen recognition by B and T cells Superantigens ACUTE INFLAMMATION

  2. 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

  3. 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

  4. 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)

  5. 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)

  6. 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

  7. ANTIGEN RECOGNITION BY LYMPHOCYTES antibodies (serum Ig) APC Antigen MHC BCR (membrane Ig) TCR B T B cells recognise native antigens T cells recognise processed antigens

  8. ANTIGENIC DETERMINANT (=EPITOPE) Part of the antigen which directly interacts with the antigen-binding site of a defined immunoglobulin(BCR / antibody) or TCR

  9. B cell epitope T cell epitope recognized by T cells • proteins mainly (8-23 amino acids) • requires processing by APC recognized by B cells • proteins polysaccharides lipids DNA steroids etc. (many artificial molecules) • cell or matrix associated or soluble

  10. Antigensmayhaveseveraldifferentepitopes

  11. 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

  12. Antibody 1 „carrier” (2) Antibody 2 Epitope 1 Epitope 2 „carrier” (1) EPITOPE AND „CARRIER” Antigén

  13. TYPES (STRUCTURE) OF ANTIGEN DETERMINANTS linear determinant conformational determinant (TCR, BCR, Ig) (BCR, Ig) conformational determinant Ab2 Ab1 surface/accessible determinants cleveage denaturation hidden/revealed determinant new/neoantigen determinant conformational/linear determinant

  14. LPS – antigen or PAMP?! PAMP if recognized by PRR (TLR4) Antigen if recognised by TCR/BCR Fc LPS Fab side view Fab specific antibody reactive to the glucoseamin epitope of LPS top view

  15. ANTIGEN RECOGNITION ≠ CELL ACTIVATION

  16. ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES PRESENTATION VIA MHC MOLECULES Recognition/ No activation Recognition/ Activation

  17. MHCII T cell +peptide 1 B cell CD4 TCR 2 cytokines T CELL-DEPENDENT BCELL ACTIVATION Polysacharides are not presented!

  18. 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 Strong crosslinking of BCR by repetitive polysaccharide or protein epitopes B CELL ACTIVATION (extra activation signal) (extensive receptor-aggregation)

  19. B CELL ACTIVATION WITHOUT THE HELP OF T CELLS

  20. HAPTEN molecules that are too small to provoke an immune response unless they are attached to carriers - hapten (e.g. DNP: dinitrofenil) + carrier + haptens

  21. HAPTEN free haptens haptens attached to a carrier 0 receptor cross-linking  signalization

  22. Antibody response generated against a hapten-carrier conjugate carrier + hapten antibodies carrier specific hapten specific carrier +hapten specific

  23. polysaccharides of different Streptococcus pneumoniae strains 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 toxoid toxin + toxoid complex antigen of vaccine

  24. formation of pneumococcus-specific memory B cells toxoid peptide antigen derived from toxoid polysacharid MHCII TCR BCR T cell specific to toxin/toxoid epitope B cellspecific to bacterial polysaccharid cytokines, CD40-CD40L

  25. 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

  26. SUPERANTIGENS Fever 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

  27. superantigen conventional antigen polyclonal T cell response 1:4 - 1:10 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 monoclonal/oligoclonal T cell response 1:104 - 1:105 activated T cells 1010 / 1011 107 – 108 / 1011

  28. SUPERANTIGENS .

  29. ACUTE INFLAMMATION AND ACUTE-PHASE RESPONSE

  30. THE INFLAMMATORY RESPONSE

  31. ACUTE INFLAMMATION A rapid response to an injurious agent that servesto deliver leukocytes and plasma proteinsto the site of injury

  32. 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: • Vascular response: • Increased vascular diameter  Increased flood flow. • Endothelial cell activation • increased permeability that permits plasmaproteins and leukocytes to leave the circulation and enter the tissue edema • increased expression of cell adhesion molecules e.g. E-selectin, ICAM • Cellular response: • Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions

  33. CLASSICAL SYMPTOMES OF ACUTE INFLAMMATION: • Redness(rubor) • Swelling(tumor) • Heat(calor) • Pain(dolor) • Loss of function (functio laesa)

  34. NEUTROPHIL GRANULOCYTES • 68% of circulatingleukocytes, 99% ofcirculating granulocytes • Phagocytic cells • Are not present in healthy tissues • Migration elimination ofpathogens (enzymes, reactive oxygen intermediates) • Main participants ofacute inflammatory processes

  35. NEUTROPHIL CHEMOTAXIS acPGP: N-acetyl Proline-Glycine-Proline – neutrophil chemoattractant MMP: matrix metalloproteinase

  36. MIGRATION OF NEUTROPHILS

  37. Neutrophil Transendothelial Migration (Diapedesis)

  38. 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.

  39. CONSEQUENCES OF MACROPHAGE ACTIVATION SYNTHESIS OF CYTOKINES

  40. ACUTE-PHASE REACTION proinflammatory cytokines hypothalamic control of body temperature increased ‚set-point’ value fever

  41. ACUTE PHASE REACTION IL-6 Complement Liver C-reactive protein (CRP) Mannose binding lectin/protein MBL/MBP Fibrinogen Serum amyloid protein (SAP) UNDER THE INFLUENCE OF IL-6 THE LIVER PRODUCES A BUNCH OF ACUTE-PHASE PROTEINS

  42. 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

  43. CHEMICAL MEDIATORS • 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 • Vasodilation • Prostaglandins (PG), nitricoxide (NO) • Increased vascularpermeability • vasoactive amines (histamine, serotonin), C3a and C5a (complementsystem), bradykinin, leukotrienes (LT), PAF • Chemotacticleukocyteactivation • C3a, C5a, LTB4, chemokines (e.g. IL-8)

  44. RESOLUTION OF ACUTE INFLAMMATION

  45. SEPTIC SHOCK Triggering factors: • systemic infection (bacteraemia) • microbial cell wall products and/or toxins released from the pathogens Result: Systemic activation of neutrophilsandmacrophages  High level of cytokine (TNF-alpha) production: „cytokine storm”  Excessive inflammatory response

  46. SEPTIC SHOCK The key molecule of the process: TNF-alpha TNF-alpha and other inflammatory cytokines DIC capillar permeability blood pressure high fever multiorgan failure disseminated intravascular coagulation Therapy: anti-TNF-alpha antibody

  47. DICDisseminatedIntravascularCoagulation • pathologic activation of thrombotic process • distress of thrombotic process, bleeding • other causes: snake bite, septic abortion, acute obstetric complications, malignant tumors, leukemias

  48. DIC: Disseminated Intravascular Coagulation

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