Immune System

1. Immune System Macrophage (“Big Eater”) Natural Killer Cells

2. The immune system protects an organism from outside biological influences. When the immune system is functioning properly, it protects the body against - bacteria - viralinfections - foreign substances - destroys cancer cells If the immune system weakens, its ability to defend the body also weakens, allowing pathogens, including viruses that cause common colds and flu, to grow and flourish in the body. The immune system also performs surveillance of tumor cells -> immune suppression has been reported to increase the risk of certain types of cancer.

3. The immune system is often divided into two sections: • Innate immunity: Comprised of hereditary (always there) components that provide an immediate "first-line" of defense to continuously ward off pathogens. • 2. Adaptive (acquired) immunity: By manufacturing antibodies (a type of protein) and T-cells specifically designed to target particular pathogens, the body can develop a specific immunity to particular pathogens. This response takes days to develop, and so is not effective at preventing an initial invasion, but it will normally prevent any subsequent infection.

4. Innate Immune System The innate immune system, when activated, has a wide array of effector cells and mechanisms. There are several different types of phagocytic cells, which ingest and destroy invading pathogens. The most common phagocytes are neutrophils, macrophages, and dendritic cells. Another cell type, natural killer cells are especially adept at destroying cells infected with viruses. Another component of the innate immune system is known as the complement system. Complement proteins are normally inactive components of the blood. However, when activated by the recognition of a pathogen or antibody, the various proteins are activated to recruit inflammatory cells, coat pathogens to make them more easily phagocytosed, and to make destructive pores in the surfaces of pathogens.

5. The three layers of immune defenses

6. Innate Immune System First-line defense: physical and chemical barrier The first-line defense includes barriers to infection, such as skin and mucus coating of the gut and airways. Pathogens that penetrate these barriers encounter constitutively-expressed anti-microbial molecules (eg. lysozyme) that restrict the infection. The stomach secretes gastric acid which prevents bacterial colonization by most pathogens. Second-line defense: Phagocytic cells phagocytic cells (macrophages and neutrophil granulocytes) can destroy (phagocytose) foreign substances. Phagocytosis involves digestion of the bacterium by using enzymes. Anti-microbial proteins Anti-microbial proteins are activated if a pathogen passes through the barrier offered by skin. There are several classes of antimicrobial proteins, such as acute phase proteins (for example, proteins that enhance phagocytosis), lysozyme, and the complement system. The complement system is a very complex group of serum proteins, which is activated in a cascade fashion. Three different pathways are involved in complement activation: 1. classical pathway: recognizes antigen-antibody complexes 2. alternative pathway: spontaneously activates on contact with pathogenic cell surfaces 3. mannose-binding lectin pathway: recognizes mannose sugars, which tend to appear only on pathogenic cell surfaces. A cascade of protein activity follows complement activation -> destruction of the pathogen and inflammation Interferons are also anti-microbial proteins. -> secreted by virus-infected cells -> diffuse rapidly to neighboring cells -> inhibit the spread of the viral infection.

7. Innate Immune System Natural killer cells (Phagocytic cells) can distinguish between healthy cells and cancer or infected cells

8. Adaptive Immune System The adaptive immune system, also called the "acquired immune system", ensures that most mammals that survive an initial infection by a pathogen are generally immune to further illness caused by that same pathogen. The adaptive immune system is based on dedicated immune cells termed leukocytes (white blood cells) that are produced by stem cells in the bone marrow, and mature in the thymus and/or lymph nodes. It is in the lymph nodes where antigen is usually presented to the immune system.

9. Adaptive Immune System • In many species, including mammals, the adaptive immune system can be divided into two major sections: • Humoral immune system: -> acts against bacteria and viruses using immunoglobulins (also known as antibodies) -> produced by B cells. • 2. Cellular immune system: -> destroys intracellular pathogens (such as virus-infected cells and mycobacteria – causing tuberculosis) using T cells (also called "T lymphocytes"; "T" means they develop in the thymus). • There are two major types of T cells: • Cytotoxic T cells (TC cells): -> recognize infected cells by using T cell receptors to probe cell surfaces. If they recognize an infected cell, they release granzymes (proteases) to trigger that cell to become apoptotic ("commit suicide") • Helper T cells (TH cells): -> activate macrophages (cells that ingest dangerous material), and also produce cytokines (interleukins) that induce the proliferation of B and T cells.

10. Adaptive Immune System Plasma cell producing antibodies

11. Interplay of innate and adaptive immune system • Bacterium invades cell -> exposed to components of complement system • Localized inflamentory response, destruction of bacteria -> release of bacterial antigens • Dentritic cells acquire antigen -> move to lymph nodes -> activate T cells • In lymph nodes antigen-stimulated T cells proliferate and get modified to interact with B cells • Stimmulated T cells help B cells to move to bonne marrow and undergo differentiation into plasma cells (B cells that secrete antigen specific antibodies • In later stages of immune response -> activated T cells assist induction of antigen exposed B cells to transform into plasma cells that secrete high level es of antibodies. • Antibodies recognize infection -> cooperate with complement system to eliminate infection

12. Antibodies Possess Distinct Antigen-Binding Variable regions IgG Constant regions

13. Classes of Antibodies

14. IgG -> highest concentration in serum IgM -> first antibodies after exposure to antigen IGA -> major class of antibodies in external secretions (tears, bronchial mucus, ....) IgD -> role not known yet IgE -> important for protection against parasites , also responsible for allergic reactions

15. Antibody – Antigen Interaction IgG: -> 12 immunoglobulin domains -> immunoglobulin fold Immunoglobulin: -> binding of antigens through hypervariable loops

16. Antibody – Antigen Interaction VL Hypervariable Loops VH

17. Binding of Small Antigen • Interaction between Antibody – Antigen: • H – bonds • Electrostatic Interactions • Van der Waals Interactions

18. Binding of Large Antigens - Lysozyme Lysozyme Antibodies recognize different epitopes on the antigen (lysozyme) -> Polyclonal Antibodies

19. Diversity Generated by Gene Rearrangements Human Genome -> 40,000 genes How can immune system make 108 different antibodies +1012 T-cell receptors ? Light Chain: On Chromosome 2 ->Variable regions, joining regions, constant region Rearranged gene Recombination by RNA splicing J region -> encode part of the hypervariable segment -> important for diversity

20. Diversity Generated by Gene Rearrangements Heavy Chain: encoded on Chromosome 14 J (Joining) region and D (Diversity) region -> encode part of the hypervariable segment -> diversity of antibodies Diversity of antibodies increased by -> Somatic mutations 1000-fold increase of binding affinity -> affinity maturation

21. Different Classes of Antibodies are Formed by Rearrangement of the Heavy (HV) Chain Genes Recombination by RNA splicing Depending on what class of antibody should be produced different C regions are expressed. -> VDJ region not affected -> antigen specificity not affected by class switching

22. Expression and Secretion of Specific Antibodies 1. Step in Immune response -> Immature B cells produce monomeric form of IgM attached to surface (all of them are identical) IgM is associated with 2 Ig-α-Ig-β protein ITAM -> Immunoreceptor Tyrosine-based activation motif Cyclosporin A -> supresses immune system (organ transplantation) -> blocks phosphatase which activates a transcription factor (-> inhibits T cell activation) -> Antigen binding triggers oligomerization (clustering) of IgM -> triggers phosphorylation of ITAM by tyrosine kinase (LYN) -> phosphorylated ITAM serves as docking site for tyrosine kinase SYK -> SYK (when activated) phosporylates other signals transduction proteins -> including inhibitor of transcription factor -> gene expression activated -> B cell differentiation

23. Cell-Mediated Immunity Against intracellular pathogens (viruses, mycobacteria) Macrophage infected with mycobacteria

24. Presentation of Peptides from Cytosolic Proteins -> General infected cells Cytosolic proteins of infection are digested -> peptides are delivered to membran proteins on the surface of the cell (Major Histocompatibility complex) -> peptides are displayed by MHC -> Cytotoxic T- cells (killer cells) scan surface of cells -> T-cell receptor of killer cells recognises peptides -> peptides derived from foreign proteins (pathogens) drigger a signal that cell is infected -> apoptopsis of infected cell induced

25. Role of Helper T-Cells -> identifies infection of macrophages, B-cells, and dentritic cells Helper T- cells stimmulate production of B-cells and T-cells -> displays foreign peptides on cell surface -> identifies infection of macrophages, B-cells, and dentritic cells (class II MHC only on the surface of these cells) by interaction with HelperT-cell receptor -> peptides come from degratation of proteins that have been transported into the cell by endocytosis (e.i. Virus particle captured by antibody) -> infected cells call for help -> macrophages destroy infected cell -> HIV infects Helper T- cells !!!

26. Recognization of Foreign Peptides on Cell Surface Difference in used coreceptor

27. HIV Attacks Helper T-Cells Glycoproteins gp41 and gp120 on the surface of HIV Gp120 binds to CD4 receptor on Helper T-cells

28. Collaboration between T and B cells for production of antibodies

29. Time course of immune response Natural killer cells (NK) Cytotoxic T cells (CTL)

30. How does the Immune System Avoid Attacks against Host Organism? Similar Mechanism for B cells !!! • Thymus produces precursors of T cells -> Thymocytes -> Selection -> Mature T cells • Selection: • Positive selection -> prevent production of T cells that will not bind to any of the MHC complexes • Negative selection -> prevent production of T cells that will strongly bind to host proteins -> leads to self tolerance !!! • If negative selection fails -> Autoimmune diseases (Diabetes, Multiple Sclerosis, Arthritis,...) Immune response damages tissues !!! • Cancer: Proteins that are produced by cancer cells -> recognized by immune system -> cell killed -> cancer prevention !!!