Aims

1. Aims • Describe the innate immune system. • Compare and contrast the innate immune system with the adaptive immune system. • Readings: Abbas & Lichtman, Chapters 1 & 2

2. Innate Immune System • Physical barriers to infection • Epithelial barrier (skin) • Mucus, saliva, tears • Phagocytic cells • Macrophages • Neutrophils • Natural Killer (NK) cells • Cytotoxicity Abbas & Lichtman’s Basic Immunology 1-3

4. Innate Immune System • Complement system • Membrane attack complex • Cytokines and plasma proteins • Interferons • C-reactive protein (CRP) • Fever Abbas & Lichtman’s Basic Immunology 1-3

5. Role of Normal Flora in Innate Immunity • Occupy receptor sites • Compete for nutrients • Produce substances which are toxic for some pathogens • Stimulate cross-protective immunity • A foreign molecule found on NF may be similar to that found on a pathogen – resulting in an immune response against the pathogen

6. Properties of the Innate Immune System • Fast • Responds within minutes of infection. • Non-specific • Molecules react to shared microbial structures. • Limited diversity • Molecules are encoded in germline (no somatic recombination) • No Memory • Responds the same way to repeat encounters with a microbe. • Primitive • Seen in all members of the animal kingdom. • Reliable • Will not recognize host cells.

7. Epithelial Barriers • Skin • Continuous epithelial layer provides barrier. • Dense outer layer of dead cells (keratin). • Epithelial cells secrete peptide antibiotics. • Keratinocytes secrete cytokines and chemokines if damaged. • Lymphocyte killing of infected cells. • Langerhans cells (migrate to lymph node and present antigen to T cells) Adapted from Abbas & Lichtman’s Basic Immunology 2-2

8. Epithelial Barriers • Respiratory tract • Same as skin. • Mucociliary escalator • Surfactants contain microorganism binding collectins which target them for phagocytosis and/or complement. • Gastrointestinal tract • Same as skin. • pH (Acidic stomach kills microorganisms) Adapted from Roitt’s Immunology 1-2

9. Corneal Epithelial Barrier • Corneal resistance to infection is thought to result primarily from components of innate immunity. • Epithelial Barrier • tight junctions between corneal epithelial cells provides a formidable barrier to microorganisms. • Tear flow • tear flow flush microorganisms down lacrimal duct.

10. Phagocytic Cells • Neutrophils • Macrophages • Resident cells all across the body • Derived from monocytes Adapted from Roitt’s Immunology 1-5

11. Phagocytic Cell Receptors • Phagocytic cells recognize bacteria through receptors which bind molecules not found on mammalian cells. • Toll-like receptors • Different Toll-like receptors bind to different components of microbes. • TLR-4 binds LPS (endotoxin). • _Mannose receptor • Bacterial glycoproteins end in a terminal mannose residue. Abbas & Lichtman’s Basic Immunology 2-1

12. Natural Killer Cell • Large granular lymphocytes • Compose ~10% of lymphocytes in the blood and peripheral lymphoid organs. • Function to eliminate cellular reservoirs of viral infection. Adapted from Abbas & Lichtman’s Basic Immunology 2-9A

13. NK Cell Cytotoxicity • NK cells are activated by IL-12 secreted by Macrophages. • NK cells in turn secrete IFNg which stimulates macrophages to be better at killing phagocytosed microbes. Adapted from Abbas & Lichtman’s Basic Immunology 2-9B

14. NK Cell Cytotoxicity • NK cells recognize cells without MHC class I molecules as targets for killing. • MHC class I acts as an _inhibitor to NK cytotoxicity • MHC class I molecules are down regulated in virally infected cells and cancer cells. Abbas & Lichtman’s Basic Immunology 2-10

15. Mechanisms of Cell Cytotoxicity • Direct cell-to-cell signaling using cell surface receptors • Indirect cell-to-cell signaling using cytokines • Granules containing proteins that damage target cells by poking holes in their membrane • Cells kill by inducing _apoptosis

16. Cytokines Adapted from Abbas & Lichtman’s Basic Immunology 2-11B

17. Plasma Proteins • Plasma mannose-binding lectin • Recognizes microbial carbohydrates. • Coats microbes for phagocytosis or lysis by complement via lectin pathway. • C-reactive protein (CRP) • Binds to phorylcholine on microbes. • Coats microbe for phagocytosis by macrophages with CRP receptor.

18. Antimicrobial Factor Secretion by Corneal Epithelial Cells • Mucins • aggregate bacteria and inhibit epithelial colonization. • -defensin • Cationic peptides which inhibit growth or viability of many bacterial pathogens. • Lysozyme • Hydrolytic enzyme against gram positive bacteria.

19. Recognition of “foreigness” via Innate Cells • Recognize broad categories or patterns of foreign molecules via receptors that are “hardwired” into the DNA - e.g. Toll-like receptors on phagocytes. Thus, non-mutable. • Recognize lack of self - e.g. Killer immunoglobulin-like receptors (KIRs) on natural killer cells – bind self molecules called MHC

20. Adaptive Immune System • Antigen Recognition molecules • B-cell • antibody or immunoglobulin (IgG) • T-cell • T-cell receptor (TCR) • All cells • Major Histocompatibility Complex (MHC)

21. Adaptive Immune System • Slow • Response develops over days following infection. • Genetic • Genetic recombination occurs to create diversity. • Specific • Each cell responds to a specific antigen. • Memory • Repeated exposure results in faster and stronger responses. • Sophisticated • First found in early vertebrates.

22. Adaptive Immunity NaturalAcquired Active:Patient acquires Patient is disease then recovers vaccinated Passive:Mother passes Patient receives immunity to child preformed immune either transplacentally components or through breast- (e.g. gamma globulin) feeding.

23. Recognition of “foreignness” via Adaptive Immune System • Recognize foreignness in highly specific manner via unique receptors that are randomly generated during ontogeny. • This random rearrangement enables the body to generate lymphocytes capable of responding to an almost limitless number of foreign invaders

24. Recognition of “foreignness” via Adaptive Immune System • T cells recognize only those foreign molecules (antigens) that have been previously “processed” by another cell • B cells can recognized unprocessed antigens • Receptors are not “hardwired” but are highly susceptible to random somatic mutations occurring during development (ontogeny) – prior to encountering a foreign molecule

25. Innate vs. Adaptive Immunity • Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) • Cells of the adaptive immune system specifically recognize and respond to particular foreign molecules through receptors

26. Innate vs. Adaptive Immunity • Cells of the innate immune system recognize broad categories or patterns of foreignness • Cells of the adaptive immune system specifically distinguish between self and non-self

27. Innate vs. Adaptive Immunity • Innate immune response is pre-existing • Adaptive immune response does not pre-exist, resulting in a “lag time” before the first response can be detected • 7-10 days to detect the 1st response • 3-4 days to detect the 2nd response

28. Innate vs. Adaptive Immunity • Innate immune responses have no “memory” • Adaptive immune response possesses an anamnestic (“memory”) response • not only is the anamnestic response quicker, but it is more vigorous than the 1st response

29. KEY CONCEPT • The innate and adaptive responses do not lead separate lives. • They constantly interact with one another. • The innate response initiating the adaptive response and the adaptive response will, in-turn, regulate the innate response.

30. Next Time • Complement Cascade • Characteristics of antigens and immunogens • Readings: Abbas & Lichtman, Chapters 3 & 8

31. Objectives • Describe the components, functions, and properties of the innate immune system. • Describe the mechanisms of cell cytotoxicity. • Cytokines, Plasma proteins, Antimicrobials • Describe the components, functions, and properties of the adaptive immune system. • Describe how innate and adaptive immune components recognize “foreigness” • Describe the differences between innate and adaptive immunity.