Chapter 16: Nonspecific Immunity

1. Chapter 16: Nonspecific Immunity • Specific vs. Nonspecific responses • Innate nonspecific immunity • Cells and tissues involved in immune responses • Molecular immunity • Complement • Cytokines • Inflammation • Physiological changes • Fever • Metabolism

2. Nonspecific vs. Specific Immune Response • Vertebrates (humans too) have two lines of defense against invaders, nonspecific and specific immune response • The first line of defense is the nonspecific response • These are physical barriers and physiological defense mechanisms • It is called nonspecific because they are directed at any invading organism • Specific immunity takes time to develop and is only effective following the nonspecific response

3. Innate nonspecific immunity • Tissue barriers and nonspecific factors are important in nonspecific immunity • Physical barriers • Skin - Sweat • Mucous membranes - Saliva, tears, mucus • Urine flow • Nonspecific antimicrobial factors • Lysozyme - Destroys cell walls • Beta-lysin - kills G+ • Defensins - small, antimicrobial peptides • Peroxidase - found in saliva and neutrophils • Complement - Punch holes in bacteria • Interferons - interfere with viral replication • Lactoferrin - Competes with bacteria for iron

4. Structure of the skin

5. Complement cascade system • Complement is a series of proteins that are activated by infection, and form an antimicrobial complex • Complement can be activated by three different pathways, the classical pathway (antibody based), the alternative pathway (endotoxin or cell wall activated), or the lectin pathway • Both result in the formation of a membrane attack complex that punches holes in the cell membranes of bacteria and other invaders (not viruses, why?)

6. The Classical Pathway • An antibody-antigen complex interacts with C1, which produces an active enzyme that cleaves C2 and C4 • The cleaved products of C2 and C4 (C4bC2a) produce an enzyme called the C3 convertase • The C3 convertase cleaves C3, producing C3b • C3b is the C5 convertase, which cleaves C5 into C5a and C5b • C5b organizes C6, C7, C8, and C9 into the membrane attack complex (MAC), which results in lysis of the bacterial cell

7. The alternative pathway • The alternative pathway skips a few steps of the classical pathway • C3b is produced in very low levels spontaneously from C3 • C3b interacts with endotoxin and other bacterial cell wall components and Factors B, D, and P to form C3bBb, which is an alternative C3 convertase, which produces more C3b, the C5 convertase • This produces C5b, which results in formation of the MAC

8. Lectin Pathway • The lectin pathway is very similar to the classical pathway, except for activation • Activation occurs when mannose binding lectin (MBL) binds to mannose found on the surface of some bacterial cells (often part of LPS) • This then activates two proteins called MASP-1 and MASP-2, and all three stick together • This complex then cuts C4 and C2, and off we go!

9. http://www.medicine.uiowa.edu/martinlab/complement.html

11. Chemical defense mechanisms • Cytokines are molecular messages between cells that are important in the immune response as well as other communications between cells • There are many different kinds of cytokines, which act in specific ways to stimulate different aspects of the immune response • Some important cytokines • Interferons (INF) • Interleukins (IL) • Tumor necrosis factors (TNF)

12. Cytokines • Interferons (IFN’s) - Antiviral proteins. Three types are known • IFN-alpha - produced by white blood cells (leukocytes); antiviral • IFN-beta - produced by tissue cells (fibroblasts); antiviral • IFN-gamma - produced by immune cells (T-cells); antiviral, also involved in other immune responses • Interleukins (IL) - Function in many aspects of the immune response. Will be discussed in subsequent chapters • Colony-stimulating factors - Cause a proliferation of certain cell types • Tumor necrosis factors (TNF’s) - Kill some tumor cells, also involved in other immune responses

13. Inflammation • The first host response to invading organisms (injury) is inflammation • There are four cardinal signs associated with inflammation • Redness • Heat • Swelling • Pain • The same sequence of events occurs in response to any injury, whether caused by invading bacteria, burns or trauma

14. The inflammatory response • During inflammation, C3a and C5a (complement) cause the release of chemicals from tissue mast cell granules (histamine, leukotrienes, and kinins, in particular) • These chemicals increase permeability of the small capillaries, leading to increased blood flow • Circulating leukocytes (white blood cells) adhere to receptors on the inner walls of blood vessels and migrate out in response to chemical attractants (chemotaxis) • Neutrophils show up first, then moncytes (macrophages) and lymphocytes (pus)

15. http://www.biologymad.com/Immunology/inflammation.jpg

16. Phagocytosis • Phagocytosis involves the process of phagocytic cells engulfing and killing microorganisms • Step one - Find the invader • Chemical products of microorganisms, components of complement (C5a) and phospholipids released by the mammalian cell are all chemoattractants for phagocytes • Step two - Attach and engulf • C3b helps with this part (opsonization) • Step three - Kill, kill, kill • Neutrophils contain granules, monocytes have lysosomes that contain digestive enzymes that kill the invader • http://www.exploratorium.edu/imaging_station/gallery.php?Asset=Human%20macrophage%20-%20phagocytosis&Group=&Category=Blood%20Cells&Section=Introduction

17. Physiological changes affect the immune response - Fever • Fever - Normal body temperature is closely regulated, but in the case of infection, a higher setting is used to: • Elevate the temperature above that preferred for optimal growth of pathogens • Activate and speed up a number of body defenses • Fever can be activated by the cytokine IL-1, which is released by phagocytic cells that have come in contact with microorganisms. It can also be activated by TNF-alpha • By slowing the growth rate of the bacteria, and increasing enzymatic activity of the immune response, fever helps speed clearing of an infection

18. Changes in iron metabolism • The ability to limit iron availability to invading organisms is a major nonspecific defense mechanism • There are two important iron-binding proteins in blood • Transferrin • Lactoferrin • High iron levels in blood can increase the chances for infection

19. Cells involved in the immune response • All blood cells (white blood cells = leukocytes; red blood cells = erythrocytes and platelets) arise from a single precursor, the hematopoietic stem cell • Leukocytes are the cells primarily responsible for the defense of the body against microorganisms • Granulocytes - Neutrophils, Basophils and Eosinophils • Agranulocytes – • Mononuclear phagocytes - Monocytes and macrophages • Lymphocytes – B, T, and NK cells

20. Natural Killer cells • NK cells are so named because they don’t seem to require recognition of MHC (which we’ll learn about in the next chapter) and don’t have a TCR (ditto) • NK cells recognize (how, we’re not sure) our cells that are infected or have mutated, and kill them without being specific