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

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

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

Structure of the skin

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?)

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

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

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!

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

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)

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

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

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)

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

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

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

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

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

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