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!

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)

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

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