Chapter 15 221 Innate Immunity Immunology: Innate immunity is non-specific defense conferred by physical barriers, chemicals, cells and processes that remain unchanged upon subsequent exposure to the same pathogens.

221 First line of defense: physical barriers, chemicals Second line of defense: inflammation, fever and macrophage system Third line of defense: B and T cells Immune surveillance:

221 First Line of Defense: Role of Skin: dendritic cells salt lysozyme sebum antimicrobial peptides: defensins, dermicidins

221 lactic acid hydrochloric acid digestive juice bile salts spermine

222 Second Line of Defense: Plasma transferrin & ferritin: transport iron siderophores: produced by bacteria, steal iron from blood lactoferrin: steals back from bacteria Defensive blood cells: leukocytes

222-223 Leukocytes: Granulocytes: Agranulocytes: Neutrophils: stain lilac with mix of acidic and basic dyes Eosinophils: stain red/orange with acidic dye eosin Basophils: stain blue with basic dye methylene blue Agranulocytes: Monocytes Lymphocytes B lymphocytes (B cells): Humoral immunity T lymphocytes (T cells): Cell-mediated immunity

Leukocytes as seen in stained blood smears Figure 15.5

224 Macrophage: King of Phagocytes Histocytes: in tissue Alveolar macrophages: in the lungs Kupffer cells: in the liver Langerhans cells: in the skin Microglial cells: in the nervous system Dendritic macrophages: in the lymph nodes Macrophages in the spleen, bone marrow, kidney and bone.

225 Opsonization: coating of microorganism with antibody and/or complement to facilitate phagocytosis Eosinophilia: helminth infestation or allergy Neutrophilia: inflammation

226 Toll-Like Receptors (TLRs): membrane proteins on phagocytes; when a foreign molecule is detected, it joins with another TLR to form a dimer. The dimer sends a signal to the nucleus. The cell responses include apoptosis, secretion of inflammatory mediators, interferons or stimulants.

226 NOD (nucleotide-oligomerization domains) Proteins: These protein receptors are found in the cytosol of phagocytes. They bind to the components of bacterial cell walls and trigger inflammation, apoptosis and other immune responses.

226 Interferon: It was discovered in 1957 by Alick Isaacs and Jean Lindenmann of the National Institute for Medical Research in London. The core of interferon is made up of about 150 amino acids. The core is called minimal interferon. Sugar molecules are found at both ends of interferon. So, interferon is a glycoprotein.

226 Families of Interferon: Alpha (leukocyte) interferon: produced by leukocytes Beta (fibroepithelial) interferon: produced by fibroblasts and connective tissues Gamma (immune or T-) interferon: produced by T lymphocytes

226 Characteristics of Interferon: Stable at low pH Resistant to temperatures of 50oC or slightly higher Susceptible to proteolytic enzymes

226-227 Actions of Interferon: When a cell is attacked by a virus, the infected cell secretes interferon, as a warning chemical, before it dies. The interferon attaches to the receptor of a neighboring healthy cell. 3. The cell is stimulated to produce an enzyme called 2,5-oligoadenylate synthetase. The enzyme (2,5-oligoadenylate synthetase) activates ribonuclease L. 5. When the virus invades the cell, ribonuclease L can degrade the viral RNA. The cell is thus protected.

The antiviral activity of interferon.

227 Complement: Complement is a heat-labile protein found in the serum. Complement system is a collection of 9 major complements (C1 to C9) consisting of over 30 proteins. It is so named because its action complements that of antibodies (IgG, IgM) in lysing the foreign cells.

227 Activation of Complement System Classic pathway: 1. The patient is infected with a pathogen. 2. The immune system produces complement-fixing antibodies (IgG, IgM). 3. The antibody binds to the pathogen. 4. The Fc fragment of the antibody attracts C1q.

227 C1r is activated. It binds to C1q. C1s is activated. It binds to C1r. The complex of antibody and C1 serves as an enzyme, which cleaves C4 into C4a and C4b, and C2 into C2a and C2b. The C4b and C2a fuse, and binds to the surface of the pathogen. The C4bC2a complex serves as an enzyme, which splits C3 into C3a and C3b.

227 C3b binds to C4bC2a to form C4bC2aC3b complex. 11. The complex (C4bC2aC3b) splits C5 into C5a and C5b. 12. C5b binds to a second membrane site. 13. Through a cascade reaction, C6, C7, C8 and C9 bind to C5b to form a lytic complex (MAC: membrane attack complex). 14. About 15 units of C9 form a ring (a hole) in the cell membrane, and the cell is lysed.

Overview of the complement pathways.

227-228 Alternative Pathway of Complement Activation: This pathway protects individuals who have a deficiency in the complement system. It does not use C1, C2 and C4. It does not require the activation by antigen-antibody complex.

227 Alternative Pathway: 1. A patient is infected. The polysaccharides, lipopolysaccharides, endotoxins of the pathogen or even aggregates of antibodies activate C3 to react with a protein called factor B to form a C3B complex. The complex (C3B) acts as an enzyme, which cleaves another molecule of C3 into C3a and C3b.

227 C3b binds to the surface of the pathogen. A serum protein called factor B binds to C3b to form C3bB. Factor B of C3bB is cleaved by factor D into Ba and Bb. Ba is released and Bb is still attached to C3b to form C3bBb complex. The complex (C3bBb) is stabilized by properdin and is changed to a convertase.

228 8. The convertase cleaves C5 into C5a and C5b. C5b attaches to the membrane of the pathogen, and the complement cascade continues as in the classic pathway.

228 The Lectin Complement (Mannan-Binding Lectin, MBL) Pathway: When macrophages ingest pathogens, they release mannan-binding lectin (MBL). This protein binds to the mannose of mannan (a polysaccharide of mannose) of the bacterial membrane to form MBL-polysaccharide complex. The complex attracts C4, C2 and

228 C3 to form a larger complex. The complex activates C5 and initiates the formation of MAC that causes lysis or opsonization of the cell.

228 Inflammation: An inflammatory response is initiated by trauma caused by infection or tissue injury or by necrosis caused by physical or chemical agents. Functions: to mobilize and attract immune components to the site of injury. to set in motion mechanisms to repair tissue damage. to clear away harmful substances to destroy invading microorganisms.

229 Fever: Fever is initiated by the stimulation of monocytes, macrophages or granulocytes by bacteria, viruses or endotoxins secreted by G- bacteria. The cells secrete a low molecular weight protein called endogenous pyrogen. This protein is carried by the blood stream to the hypothalamus, which then initiates a physiological response to increase the body temperature.

229 Low grade: 37.7o to 38.3oC Moderate: 38.8o to 39.4oC High: 40o to 41.1oC People become disoriented if the temperature reaches 43.3oC and become comatose if the temperature is higher. Death occurs if the body temperature rises to 45oC or the brain temperature reaches 40.5oC.

229 Benefits of Fever: It inhibits the multiplication of pathogens. It impedes the nutrition of bacteria by reducing the availability of iron released from macrophages. It increases metabolism. It stimulates immune response.