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THE CELLS AND MOLECULES OF THE IMMUNE SYSTEM

WHAT 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.

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 modell?) „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)

Vaccination is a powerful weapon against pathogens and prevent epidemics Smallpox virus was declerad eradicated In 1979 by WHO Upper panel: smallpox vaccination was started in 1796. 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.

THE TWO ARMS OF THE IMMUNE SYSTEM Differentiation between harmless and harmful impacts DETECTION OF STRESS AND DANGER SIGNALS INNATE IMMUNITY Differentiation between self and non-self structures Antigen-specific recognition ADAPTIVE IMMUNITY Neutralization and elimination of foreign and harmful structures EXECUTIVE FUNCTIONS COORDINATED AND REGULATED ACTIONS INNATE IMMUNITY immediate reaction non-transmittable not antigen-specific no memory ADAPTIVE IMMUNITY developes in several days transmittable specific has memory communication Humoral immunity Cellular immunity

Recognition 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.

The innate and the aquired arm of the immune system works hand-in-hand to eliminate germs IDE JON A MOZI!!!! IDE JON A MOZI An 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.

Pathogens win the battle in the absence of either the innate or the adaptive arm of immunity

Innate 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?

Recognition 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.

CONSTANT REGENERATION THE SITES OF IMMUNE CELL PRODUCTION DURING DEVELOPMENT embryo: yolk sac, liver, spleen after birth: - epiphysis - flat bones – red bone marrow (sternum, ribs, vertebras, hip bone) CONSTANT REGENERATION FAST REGENERATION INTENSE ADAPTATION

Immunocompetent cells derive from a common hematopoietic stem cell

FUNCTIONALLY DIFFERENT CELLS OF THE IMMUNE SYSTEM Resting lymphocyte NK cell Plasma cell Mast cell Monocyte Macrophage Lymph node dendritic cell Tissue dendritic cell

MONOCYTES MACROPHAGES origin: pluripotent cells of the bone marrow myeloid progenitors size: 10-15um - nucleus: bean-shaped localization: circulation out of circulation: macrophage TISSUE - VENTRICLE MACROPHAGES phagocytic cells antigen 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

BASOPHIL GRANULOCYTES NEUTROPHIL GRANULOCYTES EOSINOPHIL GRANULOCYTES 1% of circulating leukocytes large granules in the cytoplasm nucleus with 2 lobes mast cells, histamin, allergic reactions high affinity IgE receptors against parasites NEUTROPHIL GRANULOCYTES highest number in blood (68% of circulationg leukocytes, 99% of circulating granulocytes) phagocyting cells - does not present in healthy tissues tissue damage, migration, elimination of pathogens (enzymes, reactive oxygen intermediers) main participants in inflammatory processes EOSINOPHIL GRANULOCYTES agains parasites 2-3% of leukocytes allergic reactions

MAST CELLS origin: pluripotent cells of the bone marrow myeloid progenitors localization: absent from circulation differentiate in tissues especially around small vessels function: - upon activation they regulate the permeability of the vessels with their secreted molecules - native and adaptive immunity - allergic reactions (cell surface FceRI receptors) - main types: a) mucosal b) connective tissue

DENDRITIC 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 nodes antigen 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

COMMON LYMPHOID PROGENITOR CELLS B lymphocyte T lymphocyte (Bursa fabricii) (thymus) maturation: begins in bone marrow continues in bone marrow continues in thymus differentiation: peripheral tissues upon activation plasma cells effector T cells cytotoxic T cell helper T cell antigen recognition only via cell surface MHC molecules

B LYMPHOCYTES PLASMA CELLS origin: pluripotent cells of the bone marrow lymphoid progenitors maturation: 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 circulation antigen presenting cells (APC) activation: with antigens, via interaction with macrophages or T lymphocytes, lymphokines, cytokines upon activation they differentiate to plasma cells or memory B cells PLASMA CELLS function: - antibody production - humoral immun response

T LYMPHOCYTES - origin: pluripotent cells of the bone marrow lymphoid progenitors - maturation: thymus localization: in the thymus the thymocytes mature into immunocompetent T cells and they enter to the peripheral (secunder) lymphoid organs as TCR expressing T lymphocytes antigen recognition only in MHC molecules on the surface of APCs types: - T helper (CD4+) - T cytotoxic (CD8+) - T regulator (suppressor)

NK CELLS (natural killer) - origin: pluripotent cells of the bone marrow lymphoid progenitors - bigger than lymphocytes several granules in their cytoplasm has no antigen binding receptors („null cells”) participants of native immunity

Professional phagocytic cells Professional antigen presenting cells macrophages neutrophyl granulocytes dendrtitic cells the phagocytosed cells or molecules may modify the functions of the cell phagocytosis followed by enzymatic degradation Professional antigen presenting cells macrophages B lymphocytes dendrtitic cells they express MHC molecules the protein degradation products (peptides) can be presented to T lymphocytes by MHC molecules

WHITE BLOOD CELLS IN THE SMEAR OF HUMAN PERIPHERAL BLOOD eosinophil granulocyte neutrophil granulocyte MONOCYTE neutrophil granulocyte LYMPHOCYTE LYMPHOCYTE basophil granulocyte

DISTRIBUTION OF BLOOD CELLS AND LYMPHOCYTE SUBTYPES Percentage Cell number/mm3 WHITE BLOOD CELLS leukocytes 4.8 – 10.8 x 109 neutrophil granulocytes 40 – 74 1.9 – 8 x 109 eosinophil 0.1 – 5 0.01 – 0.6 x 109 basophil 0.l – 1.5 0.01 – 0.2 x 109 lymphocytes 19 – 41 0.9 – 4.4 x 109 monocytes 3.4 – 9 0.16 – 0.9 x 109 RED BLOOD CELLS erithrocytes 4.2 – 6.1 x 1012 PLATELETS thrombocytes 150-400 x 109

LYMPHOID ORGANS Primer lymphoid organs: Secunder lymphoid organs: - bone marrow - thymus Secunder lymphoid organs: - lymph node - spleen - tonsillas - MALT (Mucosal Associated Lymphoid Tissue) -GALT (Gut Associated - BALT (Bronchus Associated Lymphoid Tissue

MOLECULES OF THE IMMUNE SYSTEM Cell surface molecules: markers (CD) receptors (BCR, TCR, MHCI, MHCII, PRR, etc.) costimulatory molecules adhesion molecules (integrins, selectins, mucins, etc.) Soluble molecules: cytokines antibodies complements metabolites

The main types of cell surface molecules participating in antigen recognition and the interaction between dendritic cells and T cells

In plasma and other fluids SOLUBLE MOLECULES In plasma and other fluids plasma: 90% H2O 10% dry material: 90% organic material 10% inorganic material organic material : carbohydrate (glucose) lipid (ckolesterol, triglicerid, phospholipid, lecitin, fat) protein (globulin, albumin, fibrinoggn) glycoprotein hormon (gonadotropin, erytropoetin, trombopoietin) amino acids vitamins Minerals: in ionic, water-soluble forms BIOACTIVE MOLECULES, THEY INFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM

ROUGH CATEGORIES OF HORMONES hormons cytokines interleukines chemokines monokines lymphokines interferons