Immunology

1. Immunology • Immunology, an overview • Dermatology BM2023 • Dr Tim Scott-Taylor • Health and Human Sciences

2. Topics • Innate Immunity Acquired Immunity • Phagocytosis • Antigen Presentation • Inflammatory Response • Types and functions of white blood cells • Tutorial: Innate vs Acquired Immunity

3. Learning Objectives • to know the important structures that make up innate immunity • to understand how a specific immune response is generated • to know some of the processes in a secondary immune response • to know (a little) about antibody structure and function • to list examples of white blood cells • To understand the sequence of events in an immune response

4. The Immune System • derived from immunitas: Latin for exemption • A system of cells and molecules that together formulate resistance and an immune response • Recognition of foreign antigen • Tolerance of self • Can be pathological; allergy autoimmunity

5. The Immune System Host defense against foreign bodies can be divided into Innate Immunity and Acquired Immunity. Innate immunity; • is present continuously from birth. • the initial, always on, quick-response defense system • consists of physical, chemical and cellular defenses • does not distinguish between different pathogens, non specific.

6. Acquired Immunity induced by the presence of foreign material and forms a specific response against a particular antigen. The fundamental properties are: • Specificity • Adaptiveness • Discrimination between self and non-self • Memory

7. Innate Immunity • physical barriers; obstructions • physiological barriers; conditions • biochemical barriers; anti-microbial secretions • non-specific cellular activities Consists of a series of

8. Innate Immunity

9. Physical Barriers • Skin keratinization acts as a physical barrier • Mucous membranes in the respiratory, gastrointestinal, urogenital tract trap bacteria with mucous • Trapped bacteria are removed by ciliated cells. • Saliva flush microbes from the teeth tears eyes urine urethra

10. Physiological Barriers • Fatty acids from sebaceous glands provide a detergent-like activity on skin • Bile in the small intestine inhibits bacterial growth • Acid pH on skin, in stomach, and in the urogenital tract inhibit bacterial growth • Commensal flora provide competition to inhibit gut infection and skin colonisation

11. Biochemical Barriers • Lysozyme in tears, saliva and vaginal secretions; hydrolytic action on bacterial cell walls • Complement; a series of blood proteins that activate blood cells and lyse foreign cells • C-reactive protein; produced by the liver, opsonises bacteria • Interferons; anti-viral proteins produced by infected cells

12. Lysozyme • Enzyme present in mucosal secretions eg tears and saliva cytoplasmic granules of the neutrophils egg white • functions by attacking cells walls of bacteria • hydrolyzing the bond that connects N-acetyl muramic acid N-acetylglucosamine • non-specific innate opsonin; binds to the bacterial surface reduces the negative charge facilitates phagocytosis of bacteria peptidoglycan

13. Bacterial Cell Walls Lysozyme attacks the bond between the sugar residues Peptidoglycan is an important feature of gram positive cell walls. Composed of a polymer of sugar residues, muramic acid and n- acetyl glucosamine, linked by a peptide bridge.

14. C-reactive Protein • produced by liver, collects in serum • early defense system against infection • reacts with pneumococcus C polysaccharide • opsonification, assists phagocytic binding • splits C1 (classical pathway) • baseline levels low, increases 10,000-fold • binds a wide array of; bacteria fungus parasite plant Pentraxin; flattened β-jellyroll structure within hours of inflammation chromatin histones apoptotic membranes damaged cell components ligands

15. Complement A system of ~20 serum proteins that sequentially cascade forming a lytic pore complex (ii) Classical (adaptive) andalternative (innate) pathways Initiated by (i) cross-linking of C1q by antibody (ii) LPS, teichoic acids, zymosan (i)

16. Complement • Three main actions; • opsonization marking of invading cells, bacteria, antigen for elimination by phagocytotic cells; C1q, C3b • inflammatory signals activation of basophils, mast cells, eosinophils; C4a, C3a, C5a • cytolysis formation of the membrane attack complex; C5b6789

17. Complement Punctures Cells

18. Interferon • *********8

19. Interferon Gamma IFNγ is mainly secreted by lymphocytic cells Acts on; B cells: antibody Helper T: TH2 cytokines NK cells: activation Macrophages: MHC II

20. Interferons α and β Interferon α and β protects cells from viruses Viral infection stimulates interferon production which induces resistance in surrounding cells

21. Interferon Products • "translation inhibitory protein" or "TIP“ • complexes with preexisting ribosomes. Modified ribosomes check mRNA's caps. Only correct autologous mRNA's are translated

22. Interferons • act on a wide variety of cell types to induce the synthesis of a series of proteins which interfere with viral replication both by degrading RNA and by inhibiting protein synthesis. They also potently activate NK cells.

23. Innate Cellular Activities • Bacteria and fungi recognised by broadly specific receptors (to sugar residues) eg manose receptor • Non-specific killing by NK cells • Phagocytes include monocytes, neutrophils, macrophages, and dendritic cells. • Have complement and antibody receptors (CD3; CD35, CD21, CD16) ; uptake greatly enhanced by opsonification • Ingestion of foreign material leads to digestion, antigen presentation to lymphocytes; acquired immunity

24. Cells of the Immune System

25. Immune Cells • Blood is mostly made up of RBCs and platlets • Leukocytes can be distinguished by nucleus shape and granules • Most immune cells remain in the blood • During inflammation cells are attracted into the skin and organs

26. Non-Specific Immune Cells

27. NK Cells • Natural Killer cells • Large granular lymphocytes; abundant ER and granules • lack TCR, CD3 or Ig; null cells • do express CD16 (FcγRIII) and CD56 (NCAM) • CD94 • Ly49 • KIR • Detect ‘altered self’ • Cell lysis; porphorins, granzymes apoptosis receptors for MHC I

28. Phagocytosis Encapsulation of a pneumococcus chemotaxis, pseudopodia, phagocytosis

29. Phagocytosis Modes of ingestion are: Pinocytosis: ingestion of fluid surrounding cells Receptor-mediated: internalization of molecules bound endocytosis to membrane receptors Phagocytosis:internalization of intact particles eg bacteria

30. Phagocytosis • the phagosomefuses with lysosomes • killing occurs by a) hydrolytic enzymes b) reactive oxygen species eg. superoxide anion eg. hydrogen peroxide c) reactive nitrogen species eg. nitrous acid • Digested material is exocytosed out of the cell. • peptides bind to antigensreceptors are presented on the surface of the cell to lymphocytes

31. Positions of Phagocytes Various mononuclear phagocytes form the Reticulo-Endothelial System tissue phagocytes prominent in brain; microglia lungs; alveolar mǿ dermis; histiocytes liver; kupffer cells Derived from myeloid cells

32. Visualisation of the RES Injection of carbon particles leads to uptake by phagocytes in many prominent areas of the circulation. The RES screens lymph and blood for microorganisms and antigen

33. Inflammation • important response especially of skin to cellular injury or infection • has both a rapid innate component and prolonged acquired immunity phase. • injury or infection releases proteins causing; swelling redness • pain heat • increases blood flow and attracts cells to local area to restrict the spread of infection

34. Causes A variety of infectious and mechanical causes initiate inflammation The extent and duration of inflammation depend on the type and amount of tissue damage • mechanical trauma • chemical injury • ionising radiation • ultra-violet light • thermal injury • ischaemia • infarction • infection

35. Inflammatory Mediators Released by variety of leukocytes endothelium liver plasma Trigger and enhance particular inflammatory aspects vasodilation vascular permeabiliity pain fever chemotaxis Redness rubor calor tumour dolor HEAT swelling PAIN

36. Inflammation Histamines fibrin kinins cytokines increase vascular permeabiity induce adhesion molecules stimulate nerves, leading to pain attract leukocytes phagocytosis T and B cell activation increase immunoglobulin synthesis If inflammation persists for more than a few hours then macrophages and lymphocytes are recruited to the site. Macrophages also present foreign peptides, promoting antibodies production and acquired immunity to infection

37. Inflammation • Vasodilation • Increase capillary diameter • Tissue redness and temperature rise • Increased vascular permeability • Plasma exudate • Swelling and pain • Influx of leukocytes • Margination, diapedisis, chemotaxis • Cytotoxic and phagocytic activity • Pus and tissue repair

38. Innate Leads to Adaptive Immunity Phagocytosis Complement activation Inflammation ultimately lead to induction of adaptive immunity

39. Adaptive Immunity Adaptive immunity increases in strength and effectiveness with each encounter. Antigen specific; foreign antigen is recognised in a specific manner and memory is acquired to it by lymphocytes Naïve lymphocyte; ~ 0.001% of circulating population antigen presentation  activation  induction of cytokines receptors proliferation Memory cells; 0.1 to 0.5% of circulating population

40. Secondary Response The first encounter with an antigen is known as the primary response. Re-encounter with the same antigen causes a secondary response that is more rapid and powerful.

41. Speed Of Immune Response • The rapidity of response is often the difference between an infection and a symptomatic disease • Secondary immune response much quicker than primary response • Rapid accumulation of immune responses and activated immune cells intervenes before microbial multiplication reaches critical levels • Persistence of antigen specific, memory B and T lymphocytes gives head start on microbes on reinfection

42. Adaptive Immune System • Antibody; specific recognition of antigen • B cells; clonal induction of specific cells • T cells; activated by presentation of specific antigen by dendritic cells and mǿ

43. Antigen • A foreign substance visible to the immune system • anything that can be bound by an antibody • small antigens may not be immunogenic and need to be coupled to a carrier, a hapten, to elicit an immune response. • antibodies interact specifically with relatively small parts of molecules; antigenic determinants or epitopes • epitopes are 3-dimensional structures, referred to as conformational

44. Antibodies Antibodies are y-shaped molecules composed of heavy chains and light chains, connected by S-S bonds. The ends of the Y arms are the binding sites for antigen

45. Action of Antibodies Antibodies work in three ways. • Neutralisation; blocking the biological activity of their target molecule eg toxin binding to receptors • Opsonisation; interacting with special receptors on immune cells, including macrophages, neutrophils, basophils and mast cells allowing them to "recognise" and respond to the antigen • Complement Activation; causing direct lysis by triggereing complement cascade. Complement recruitment also enhances phagocytosis

46. Antibody Actions

47. Functions of Immunoglobulins

48. Clonal Selection • Many B cells • Each with own receptor • Selection of specific B cell by antigen • Proliferation of clone • Secretion of specific anibody in quantity

49. B Cell Memory Response

50. Lymphoctes Pivotal to specific immune responses; B cells; mature in bone marrow bursa in chickens antibody production T cells; helper CD4: MHC I self-recognition help for B and cytotoxic cells cytokine production cytotoxic CD8: MHC II foreign antgen recognition lysis of infected cells cytokine production