3WHAT IS THE FUNCTION OF THE IMMUNE SYSTEM??How does it need to function?Is there room for failure?Immunodeficiencies!!!What about speed?What about specificity?What about flexibility?What about functional overlap?Many different germs are controlled efficiently.
4Immunitas = 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 modell?)„Danger model”:(Matzinger P., The danger model: a renewed sense of self. Science Apr 12;296(5566):301-5.)harmful self / harmless selfharmful non-self / harmless non-self factors!DANGER SIGNAL / NO DANGER SIGNALobligate pathogenfacultative pathogen (Staphylococcus aureus)
5Vaccination is a powerful weapon against pathogens and prevent epidemicsSmallpox virus was declerad eradicatedIn 1979 by WHOUpper panel: smallpox vaccination was started in In 1979, after 3 years in which no case of smallpox was recorded, the World Health Organization announced that the virus had been eradicated. Since then the proportion of the human population that has been vaccinated against smallpox, or has acquired immunity from an infection, has steadily decreased. The result is that the human population has become increasingly vulnerable should the virus emerge again, either naturally or as a deliberate act of human malevolence. Lower panel: photograph of a child with smallpox and his immune mother. The distinctive rash of smallpox appears about 2 weeks after exposure to the virus. Photograph courtesy of the World Health Organization.
6THE TWO ARMS OF THE IMMUNE SYSTEM Differentiation between harmless and harmful impactsDETECTION OF STRESS AND DANGER SIGNALSINNATE IMMUNITYDifferentiation between self and non-self structuresAntigen-specific recognitionADAPTIVE IMMUNITYNeutralization and elimination of foreign and harmful structuresEXECUTIVE FUNCTIONSCOORDINATED AND REGULATED ACTIONSINNATE IMMUNITYimmediate reactionnon-transmittablenot antigen-specificno memoryADAPTIVE IMMUNITYdevelopes in several daystransmittablespecifichas memorycommunicationHumoral immunityCellular immunity
7Recognition of pathogens by the innate arm of the immune system. Almost all components of the immune system contribute to mechanisms for either recognizing pathogens or destroying pathogens, or to mechanisms for communicating between these two activities. This is illustrated here by a fundamental process used to get rid of pathogens. Serum proteins of the complement system (turquoise) are activated in the presence of a pathogen (red) to form a covalent bond between a fragment of complement protein and the pathogen. The attached piece of complement marks the pathogen as dangerous. The soluble complement fragment summons a phagocytic white blood cell to the site of complement activation. This effector cell has a surface receptor that binds to the complement fragment attached to the pathogen. The receptor and its bound ligand are taken up into the cell by phagocytosis, which delivers the pathogen to an intracellular vesicle called a phagosome, where it is destroyed. A phagocyte is a cell that eats, "phago" being derived from the Greek word for eat.
8The innate and the aquired arm of the immune system works hand-in-hand to eliminate germs IDE JON A MOZI!!!!IDE JON A MOZIAn immune response involves events that unfold both locally, at the site of an infection, and at more distant sites, such as nearby lymph nodes. We can see the integration of the different parts of the immune response if we follow the course of a typical infection. Most pathogens are kept outside of the body by epithelial barriers, such as the epidermis, and are crossed only when there is an injury or tissue damage. After an injury, bacteria cross the epidermis and establish an infection in the underlying tissue. Phagocytic cells in the tissues, such as macrophages and neutrophils, engulf the pathogen. Dendritic cells are also phagocytic, and are activated by binding pathogens to leave the site of infection and migrate to a lymph node. The migrating dendritic cells enter the lymphatic vessels and are collected in a draining lymph node. In the lymph node, T cells are activated by antigen presented by the dendritic cells, and in turn activate B cells to secrete antibody. Effector T cells and antibody molecules return to the circulation. They leave the circulation again at the site of infection, where inflammatory mediators have induced changes in the blood vessel endothelium. CD4 T cells activate macrophages to become more cytotoxic, while antibody recruits complement to lyse bacteria directly and to opsonize them, enhancing their uptake by phagocytes. In the case of a viral infection, activated CD8 T cells would kill any infected cells present.
9Pathogens win the battle in the absence of either the innate or the adaptive arm of immunity
10Innate immune mechanisms establish a state of inflammation at sites of infection. Illustrated here are the events following an abrasion of the skin. Bacteria invade the underlying connective tissue and stimulate the innate immune response.How do innate cells recognize bacteria and various other pathogens?Is the reaction specific?
11Recognition of lipopolysaccharide by Toll-like receptor 4 (TLR4)In the initial stages of an immune response, the innate immune system recognizes the presence of pathogens and provides the first line of defense. Dendritic cells, which are circulating through the tissues, have the ability to recognize the presence of pathogen associated molecular patterns or PAMPS. PAMPS are conserved features of pathogens, such as the lipopolysaccharides or LPS, which are components of the cell membranes of all gram-negative bacteria. Dendritic cells have the ability to recognize PAMPS through the expression of a family of Toll-like receptors or TLRs. In the case of LPS, it is recognized by one member of the TLR family, TLR-4, which is expressed on the surface of the dendritic cell. LPS is transported by the soluble LPS-binding protein, LBP, to the surface of the dendritic cell, and deposited on the cell surface protein CD14. The presence of LPS is detected by TLR-4 through its interaction and recognition of the LPS bound to CD14. The signal delivered by the TLR initiates maturation of the dendritic cell. The dendritic cell can now migrate to regional lymph nodes and activate the acquired immune response.
12CONSTANT REGENERATION THE SITES OF IMMUNE CELL PRODUCTION DURINGDEVELOPMENTembryo: yolk sac, liver, spleenafter birth: - epiphysis- flat bones – red bone marrow(sternum, ribs, vertebras, hip bone)CONSTANT REGENERATIONFAST REGENERATIONINTENSE ADAPTATION
13Immunocompetent cells derive from a common hematopoietic stem cell
14FUNCTIONALLY DIFFERENT CELLS OF THE IMMUNE SYSTEM Resting lymphocyteNK cellPlasma cellMast cellMonocyteMacrophageLymph node dendritic cellTissue dendritic cell
15MONOCYTES MACROPHAGES origin: pluripotent cells of the bone marrowmyeloid progenitorssize: 10-15um- nucleus: bean-shapedlocalization: circulationout of circulation: macrophageTISSUE - VENTRICLEMACROPHAGESphagocytic cellsantigen presenting cells (APC)main types (based on tissue localization):microglia (brain)Kuppfer-cells (liver)histiocytes (connective tissue)osteoclasts (bone)alveolar macrophages (lung)- function: in cellular and humoral immun response
16BASOPHIL GRANULOCYTES NEUTROPHIL GRANULOCYTES EOSINOPHIL GRANULOCYTES 1% of circulating leukocyteslarge granules in the cytoplasmnucleus with 2 lobesmast cells, histamin, allergic reactionshigh affinity IgE receptorsagainst parasitesNEUTROPHIL GRANULOCYTEShighest number in blood (68% of circulationg leukocytes,99% of circulating granulocytes)phagocyting cells- does not present in healthy tissuestissue damage, migration, elimination of pathogens(enzymes, reactive oxygen intermediers)main participants in inflammatory processesEOSINOPHIL GRANULOCYTESagains parasites2-3% of leukocytesallergic reactions
17MAST CELLS origin: pluripotent cells of the bone marrow myeloid progenitorslocalization: absent from circulationdifferentiate in tissuesespecially around small vesselsfunction: - upon activation they regulate the permeability of the vessels withtheir secreted molecules- native and adaptive immunity- allergic reactions (cell surface FceRI receptors)- main types: a) mucosalb) connective tissue
18DENDRITIC CELLS origin: myeloid or lymphoid progenitors localization: the immatured dendritic cell migrates from the circulation into the tissues and upon pathogen uptake it differentiates to matures dendritic cell and migrates to the draining lymph nodesantigen presenting cells (APC)types :a) myeloid DCs: - Langerhans cells (mucosa, skin)- intersticial DCs (liver, spleen, etc.)b) lymphoid DCs: - thymic DCs- plasmacytoid DCs (pDC)Follicular DCs: stroma cells of the centrum germinativum of lymph nodes
19COMMON LYMPHOID PROGENITOR CELLS B lymphocyte T lymphocyte(Bursa fabricii) (thymus)maturation:begins in bone marrowcontinues in bone marrow continues in thymusdifferentiation:peripheral tissuesupon activationplasma cells effector T cells cytotoxic T cellhelper T cellantigen recognitiononly via cell surfaceMHC molecules
20B LYMPHOCYTES PLASMA CELLS origin: pluripotent cells of the bone marrowlymphoid progenitorsmaturation: bursa equivalent tissues(embrionic liver, later bone marrow)localization: takes 5-10% of the circulating lymphocytes; migrate from the bone marrow to the secondary lymphatic organs thorugh the circulationantigen presenting cells (APC)activation: with antigens, via interaction with macrophages orT lymphocytes, lymphokines, cytokinesupon activation they differentiate to plasma cells or memory B cellsPLASMA CELLSfunction: - antibody production- humoral immun response
21T LYMPHOCYTES - origin: pluripotent cells of the bone marrow lymphoid progenitors- maturation: thymuslocalization: in the thymus the thymocytes mature intoimmunocompetent T cells and they enter to the peripheral (secunder)lymphoid organs as TCR expressing T lymphocytesantigen recognition only in MHC molecules on the surface of APCstypes:- T helper (CD4+)- T cytotoxic (CD8+)- T regulator (suppressor)
22NK CELLS (natural killer) - origin: pluripotent cells of the bone marrowlymphoid progenitors- bigger than lymphocytesseveral granules in their cytoplasmhas no antigen binding receptors („null cells”)participants of native immunity
23Professional phagocytic cells Professional antigen presenting cells macrophagesneutrophyl granulocytesdendrtitic cellsthe phagocytosed cells or molecules may modifythe functions of the cellphagocytosis followed by enzymatic degradationProfessional antigen presenting cellsmacrophagesB lymphocytesdendrtitic cellsthey express MHC moleculesthe protein degradation products (peptides) can be presentedto T lymphocytes by MHC molecules
24WHITE BLOOD CELLS IN THE SMEAR OF HUMAN PERIPHERAL BLOOD eosinophilgranulocyteneutrophilgranulocyteMONOCYTEneutrophilgranulocyteLYMPHOCYTELYMPHOCYTEbasophilgranulocyte
25DISTRIBUTION OF BLOOD CELLS AND LYMPHOCYTE SUBTYPES PercentageCell number/mm3WHITE BLOOD CELLSleukocytes4.8 – 10.8 x 109neutrophilgranulocytes40 – 741.9 – 8 x 109eosinophil0.1 – 50.01 – 0.6 x 109basophil0.l – 1.50.01 – 0.2 x 109lymphocytes19 – 410.9 – 4.4 x 109monocytes3.4 – 90.16 – 0.9 x 109RED BLOOD CELLSerithrocytes4.2 – 6.1 x 1012PLATELETSthrombocytesx 109
27MOLECULES OF THE IMMUNE SYSTEM Cell surface molecules:markers (CD)receptors (BCR, TCR, MHCI, MHCII, PRR, etc.)costimulatory moleculesadhesion molecules (integrins, selectins, mucins, etc.)Soluble molecules:cytokinesantibodiescomplementsmetabolites
28The main types of cell surface molecules participating in antigen recognition andthe interaction between dendritic cellsand T cells
29In plasma and other fluids SOLUBLE MOLECULESIn plasma and other fluidsplasma: 90% H2O10% dry material: 90% organic material10% inorganic materialorganic material : carbohydrate (glucose)lipid (ckolesterol, triglicerid, phospholipid, lecitin, fat)protein (globulin, albumin, fibrinoggn)glycoproteinhormon (gonadotropin, erytropoetin, trombopoietin)amino acidsvitaminsMinerals: in ionic, water-soluble formsBIOACTIVE MOLECULES, THEY INFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM
30ROUGH CATEGORIES OF HORMONES hormonscytokinesinterleukineschemokinesmonokineslymphokinesinterferons