Defense mechanisms of the body II. Adaptive/aquired immunity. Blood group antigenes

Transcription

1 Defense mechanisms of the body II. Adaptive/aquired immunity Blood group antigenes Learning objectives Péter Sántha Bruce Beutler Jules Hoffmann Ralf Steinmann 1

2 Main characteristics of the two types of immune defense mechanims (Natural) (Aquired) Germline-specific receptors Clone-specific receptors Key cellular and humoral components of the innate and adaptive immunitiy 2

3 Recognition of the antigens adaptive immunity Adaptive (aquired) immunity highly specific receptors: lymphocite receptors and antibodies Variable regions of the T/B cell receptors and the antibodies (clone specific!) Source of the high grade diversity and antigen specificity: somatic recombination The lymphoid cells develop specific antigen-recognition receptors characteristic for a single cell or cell clone (variable region) 3

4 The concept and origin of lymphocyte clone 1. Clone selection during the maturation: elimination of forbidden, autoreactive clones 2. Clone slection following antigene exposure: proliferation of the compatible clone: clonal expansion Lymphoid tissues and organs inside the body MALT: mucosa associated lymphoid tissue SALT: Skin associated lymphoid tissue 4

5 The lymph follicles - units of the lymph organs FDC: follicular dendritic cell The lymph node connection between the lymphatic and blood circulation 5

6 Circulation of lymphocytes in the blood and lymph circulation lymphocyte surveillance Major types of the lymphocytes CD3+ CD3- CD4+ CD8+ 6

7 CD4 T-helper cells Recognition of MHC-II (APCs) + antigen (T-cell receptor) Subtype 1 enhancement of phagocytosis Subtype 2 activation of the B lymphocytes facilitation of the Ig production CD8 T-killer (cytotoxic) cells Recognition of MHC-I recptors (somatic cells) + antigen (T-cell receptor) Destruction of virus infected and tumor cells (apoptosis induction, membrane perforation) T-memory cells They might be either CD4 or CD8 positive Long-lived cells (months years) activation upon repeated antigen exposure, no need for antigen presentatio (rapid reaction) Regulatory T-cells (T-supressor) Immuntolerance suppress the activation of other T cells -Central : thymus selection of autorective clones -Peripheral: protection of immun-privileged tissues (brain, lens, testes, thyroid follicle) Activation of T-helper cells via antigen presentation by professional AP-cells (macrophages) and by B-lymphocytes 7

8 CD4 T-helper lymphocytes: participate in antigene presentation and organize the activation of the whole lymphoid system Immunological synapse CD8 T effector lymphocytes: cytotoxic reaction elimination of cells carrying the target antigen Lethal hit (or kiss?) 8

9 Activationand and final differentiationof of B lymphocytes into plasma cells Non-specific factors: cytokine background Specific factor: target antigen 9

10 The antibody classes (isotypes) classificationdepends on the type of the heavy Ig chains 10

11 Antibody chain (isotype) switch of B-lymphocytes (plasma cells) is controlled by different combinations of cytokines Armed helper T cells stimulate the proliferation and then the differentiation of antigen-binding B cells 11

12 Multiple roles of the antibodies in the elimination of antigens or antigen carrying cells Production of monoclonal antibodies hybridoma technique Diagnostic tools: RIA, ELISA, immunohistochemistry e.g.: plasma hormon cc. measurement, pregnancy tests 1975: C. Milstein és G. J. F. Köhler 12

13 Therapeutic use of specific monoclonal antibodies Administration of purified polyclonal antibodies PASSIVE IMMUNISATION e.g.: snake venom antidote, rabies prophylaxis Synthetic monoclonal antibodies: BIOLOGICAL THERAPY (-mab s) Eg.: HERCEPTIN (trastuzumab) adjuvant therapy in breast cancer The adaptive nature of the aquired immunity previous exprience modifies the behaviour in the future immun memory -- short-lived effector cells /long-lived memory cells 13

14 Difference between the primary and secondary immune reactions Faster activation (there is no need for antigen presentation) More effective Ig secretion and cytotoxic elimination Active immunisation: vaccines contain attenuated pathogens or purified antigens of the corresponding pathogenic agent 14

15 Time course and phases of the specific immune response Phasesof the adaptive immune response 1 Recognition 2 Activation/proliferation 3 Elimination 4 Decline, restitution No sharp border between the phases Paralell mechanisms Specific and aspecific mechanisms work in cooperation Time course can be variable Quantitity and quality of the antigen determines the type of responses State of the immune system: inherited characteristics (HLA phenotype) adapted caharcteristics (immune memory, age, general state, drugs, ) 15

16 Clinical signs of the proliferation phase: Leukocytosis: WBC count (is mainly not caused by new cell production, but by change in the distribution in the different compartments: bone marrow lymphoid tissue blood) rapo of young forms Enlargement of the lymphatic tissue: lymph nodes, tonsills/follicules, spleen concentration of acute phase proteins: CRP (C-reactive protein ) Increase of other biomarkers: cytokines, procalcitonin General actions of cytokines and inflammatory mediators: fever, drowsyness, feeling of weakness, lost of appetite (these symptoms could be characteristic for the later phases!) Clinical signs of the elimination process Increased antibody production: rise in gamma-globulin fraction plasma electrophoresis Increased ESR (erythrocyte sedimentation rate) Normal finding Morphologic changes tissue infiltration with leukocytes, tissue death pus formation Inflammation: local tissue and microcirculatory reaction: Increased tissue bloodflow (hyperaemia-vasodilatation) (rubor, calor) Increased vascular permeability (local swelling, oedema) (tumor) Pain, increased sensitivity (activation of nociceptive fibers)(dolor) Causes: local release of vasoactive mediators from the cells responsible for elimination (eg. mast cells, PMG) E.g.: hystamine, bradykinine, prostaglandins, leukotriens, and so on Rubor, tumor cum calore et dolore Policlonal gamma globulin production Monoclonal gamma globulin production 16

17 4. The decline/restoration phase Passive mechanisms: Immune response is provoked and maintained by an antigen. If the elimination process was successful, decreasing antigen concentration causes an immune response falloff But there are also active mechanisms (self regulation): T-suppressor cells, inhibitory proteins ( complement suppressor proteins), inhibitory cytokines, stress hormones (glucocorticoids) Does not pass away without trace: immune memory! Blood groups blood transfusion 17

18 Karl Landsteiner (Nobel prize: 1930): For description of the human blood groups" The erythrocytes lose their nuclei and HLA antigens at the end of their maturation - Less complications caused by histocompatibility There are still numerous antigens presnet on the membrane of the mature erythrocytes - BLOOD GROUP antigens The ABO and Rh (D) are the strongest and caused complications most frequently 18

19 Blood group antigen (RBC membrane) agglutinogen Blood group antibody (antibody (IgM - ABO) plasma) - agglutinin Landsteiner's rule states that if a given (erythrocyte) antigen is present in one individual its corresponding (plasma) agglutinin should be absent. Classification is based on the blood group antigen Biochemical basis of the ABO inheritance AB0 antigens are complex glycolipids DNA allels encode the seqence(s) of transferase(s) Natural antibodies they develop during the postnatal period following the colonisation of the GIT by the physiological gut bacteria (flora) 19

20 Codominant inheritance of the ABO antigens Determination of the blood groups Testing the in vitro agglutination reaction In vivo transfusion of incompatible blood results in complement activation and Immun haemolysis!! 20

21 Anti-D globulin belongs to class IgG passes the placental barrier 21

22 Anti-D prophylaxis 22

23 AHG: Anti Human Globulin 23

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