1. Immune system and Cancer
immune system is a "functional" system as opposed to an "organ" system
many organs are involved

2. Overview Innate (nonspecific) defense system
surface barriers
internal defenses
Adaptive (specific) defense systems
humoral immunity
cellular immunity
Cancer
innate and adaptive systems are intimately intertwined
when the immune system is functioning, we are protected from
- infectious microbes
- cancer cells
- transplanted organs (or grafts)

3. Innate (nonspecific) defense Surface Barriers
Skin
- keratin - resists weak acids and bases, bacterial enzymes and toxins
- pH 3-5: inhibits bacterial growth
- lipids in sebum are toxic to bacteria
- dermcidin in sweat - toxic to bacteria
sebaceous glands in skin secrete sebum; sebum waterproofs the skin and hair
sweat glands produce sweat - primarily for cooling; dermcidin is protein

4. Innate (nonspecific) defense Surface Barriers
Mucous membranes
- Saliva and tears: lysozyme - enzyme that destroys bacteria
- mucus in digestive and respiratory tracts capture bacteria
- stomach acidity and enzymes kill bacteria
- vaginal secretion acidity inhibits bacterial growth

5. Innate (nonspecific) defense Internal defenses
- phagocytes
- NK cells
- inflammation
- antimicrobial proteins
- fever

6. Innate (nonspecific) defense Internal defenses - phagocytes
- macrophages (WBCs)
- neutrophils (WBCs)
- microglia (brain)
macrophages - derived from monocytes - leave blood stream and enter the tissue
free macrophages - patrol tissue (ex: lungs)
fixed macrophages - Kupffer cells (liver)
neutrophils - become phagocytic on encounter with infectious material
- must recognize the bacterium as foreign; antibodies help with that...more later

7. Innate (nonspecific) defense Internal defenses - NK cells
Natural Killer Cells
- in blood and lymph
- lyse cancer cells and virus infected cells
- secrete perforins and granzymes
NK cells recognize cells by 1) lack of "self" molecules 2) antibodies
perforins poke holes in cell body
granzymes enter hole and digest the cell from inside out

8. Innate (nonspecific) defense Internal defenses - inflammation
- triggered by disruption of body tissue
- prevents spread of damage
- disposes of cell debris and pathogens
- preps for repair
physical trauma, intense heat, chemicals, infection by virus, fungi, bacteria

9. Innate (nonspecific) defense Internal defenses - inflammation
The cardinal signs
Calor (heat)
Rubor (redness)
Tumor (swelling)
Dolor (pain)

10. Innate (nonspecific) defense Internal defenses - inflammation
1) chemicals released by injured tissue (histamines, complement, kinins, prostaglandins, leukotrienes
2) chemicals cause arterioles to dilate and capillaries to become leaky - brings blood and heat to the area and causes swelling. Nerves are pressed on. (rubor, calor, tumor, dolor)
- histamine - causes blood flow and leakiness
- prostaglandins and kinins increase sensitivity in the area and contribute to pain
- aspirin inhibits prostaglandin synthesis
3) edema - sweeps away foreign debris to lymph system, delivers healing proteins (and clotting factor)
4) clots wall off the infected area

11. Innate (nonspecific) defense Internal defenses - infection
pus = dead WBCs (neutrophils) + dead tissue cells + pathogens (live and dead)
abcess = walled off infection (by collagen fibers)

12. Innate (nonspecific) defense Internal defenses - antimicrobial proteins
1) Interferons
2) complement
interferons - block protein synthesis and degrade viral RNA

13. Innate (nonspecific) defense Internal defenses - antimicrobial proteins - interferon
Interferons - secreted by a cell infected by a virus; stimulate healthy cells to be prepared to inhibit viral attack

14. Innate (nonspecific) defense Internal defenses - antimicrobial proteins - complement
- 20+ different complement proteins
- 2 pathways (classic and alternative)
- cascade of events leads to amplification of inflammation, promotes phagocytosis, and causes cell lysis
2 pathways
1) classic - antibodies bind to invader
2) alternative - triggered by structure of microorganism surface
inflammation: complement promotes release of histamine, attraction to phagocytes
phagocytosis - coats surface with chemicals to increase phagocytosis
cell lysis - inserts pores in host cell membrane

15. Innate (nonspecific) defense Internal defenses - fever
- systemic response
- Hypothalamus in the brain regulates body temperature
- Pyrogens resets the temperature higher
- secreted by macrophages and leukocytes exposed to foreign matter
- heat slows growth of bacteria (denatures enzymes)
- causes spleen to sequester Zn and Fe - required by bacteria to grow
- increases metabolic rate of tissue - speeds repair
- causes patient to rest!

16. Adaptive (specific) defense
characteristics
- specific
- systemic
- memory
2 categories (both triggered by antigens)
- humoral (antibody mediated) immunity
- cellular (cell mediated) immunity
recognizes particular pathogens - via antigens
not restricted to initial infection site
recognizes previously encountered pathogens

17. Adaptive (specific) defense - antigens
- large complex molecules not normally in the body - "non-self"
- self-antigens - protein molecules on your cells that mark them as "yours"; these are antigens to other people
- MHC (major histocompatibility proteins)
Many kinds of MHCs
unlikely 2 people share identical MHCs (except identical twins)

18. Adaptive (specific) defense - types of cells
- B lymphocytes (cells): humoral immunity; mature in bone marrow
- T lymphocytes (cells): cell mediated immunity; mature in thymus
(both lymphocytes are immunocompetent and self tolerant)
All created in the red bone marrow
must be "educated
immunocompetent - can recognize one specific antigen
self tolerant - unresponsive to self antigen

19. Adaptive (specific) defense - types of cells
Let’s focus lymphocytes (B cells and T cells)
These contain membrane proteins embedded in their cell membranes.

20. Adaptive (specific) defense - types of cells
- APCs (antigen-presenting cells) examples include:
dendritic cells (connective tissue and epidermis)
macrophages
B lymphocytes
engulf antigens and present them on their own surface to be recognized by T cells
APCs activate T cells
T cells release chemicals that activate macrophages to become "eating machines"...and secrete bacteriocidal chemicals
dendritic cells - very efficient at capturing antigens; they patrol tissues; after phagocytizing antigens they present them on their surface and migrate to the lymph organs where T cells will encounter them
spleen: lymphocytes and APCs protect against blood borne pathogens
tonsils: lymphocytes and APCs protect oral and nasal cavities

21. Adaptive (specific) defense - humoral immunity
antigen challenge = the 1st encounter between a naive lymphocyte and an antigen
- usually occurs in the spleen or a lymph node
- if the lymphocyte is a B cell - humoral immune response is triggered
clonal selection follows (next slide same as this with more notes!)

22. Adaptive (specific) defense - humoral immunity
clonal selection
- antigen binds to B cell and is absorbed by endocytosis
- B cell divides repeatedly to form an army of clones
- most clones become plasma cells; some remain as "memory cells"
- plasma cells secrete antibodies (roughly 2000 molecules/sec!) [they only last 4-5 days]
- memory cells can mount an immediate response if subjected to same antigen again

23. Adaptive (specific) defense - humoral immunity
Antibodies (aka: immunoglobins) are Y shaped proteins
Each has a constant region (the same in all of the same class of antibodies)
Each has a variable region – these are specific for each antigen (There are 5 classes of immunoglobulin)
stem region determines the class (what cells and chemicals in body it can bind to; and how it functions to eliminate pathogens)

24. There are 5 classes of antibodies (MADGE)

25. mechanisms of antibody action
neutralization - antibody blocks sites on antigen to prevent binding to cells
agglutination/precipitation - (IgM) - binds with many antigens causing a clump (agglutination) if the antigen is cell-bound or a precipitate if the antigen is a soluble chemical
opsonization - antibodies bound to antigen makes the complex more likely to be engulfed by a macrophage
(next slide continues)

26. mechanisms of antibody action
complement fixation and activation
- chief defense against cellular antigens (bacteria, mismatched blood)
- several antibodies close together on invader create a complement binding site
- complement binding triggers formation of a MAC (membrane attack complex)
- MAC is a pore in the cell that causes the cell to lyse
antibody action: PLAN (precipitation, lysis, agglutination, neutralization)

27. Adaptive (specific) defense - immunological memory
Primary response - first exposure
- lag period of 3-6 days (B cells have to clone themselves)
- Plasma cells can produce 2000 antibodies per second!
- Antibody response peaks at days.
Secondary response - all following exposures
- antibody production peaks at 2-7 days
- more effective than primary response; plasma cells can function much long than 4-5 days

28. Adaptive (specific) defense - cell mediated immunity
- T cells interact directly with antigen presenting cells (APCs)
- T cells DO NOT MAKE ANTIBODIES!
- T cells clear the body of cells that have been invaded by viruses (or other pathogens)
- T cells reject tumor cells, transplants
- T cells are responsible for some allergies
B cells are only effective against "obvious" pathogens - useless against viruses and bacteria that "hide" inside cells
B cells work on foreign matter that is extracellular

29. Adaptive (specific) defense - cell mediated immunity
The antigen challenge comes from an antigen presenting cell
T cells not only recognize the antigen (displayed on the surface of the APC) but also the APC itself through MHC proteins
cells with only MHC are left alone; cells with both are attacked
dendridic cell
T cell

30. Adaptive (specific) defense - cell mediated immunity
Macrophages ingest antigens and display part of them on their cell surface.
Macrophages secrete interleukin-1 (a protein)
- interleukin-1 is the protein that stimulates the hypothalamus to increase body temperature
- in this case, interleukin-1 activates T helper cells
T helper cells (when activated) secrete interleukin-2 (and interferon)
Interleukin-2 stimulates T cells to divide rapidly
- this produces more T helper cells and memory T cells
(next slide)

31. Adaptive (specific) defense - cell mediated immunity
Interferon (also produced by cells that are being attacked by a virus)
- causes neighboring (unattacked cells) to produce antiviral proteins
- AVP’s block viral replication in the cell
Helper T cells
- activate B cells by binding to them; stimulate them to divide – stimulating humoral immunity
- activate T cells through interleukin 2
- activate infected macrophages to destroy the pathogen
- with Helper T cells, there would be NO Adaptive defense!
(next slide)

32. Adaptive (specific) defense - cell mediated immunity
Macrophages that present antigens also activate cytotoxic T cells
Cytotoxic T cells act mainly on virus infected cells
- only cells that can directly attack and kill other cells
- they secrete perforin – a protein that perforates the cell membrane of the target cell
- they secrete granzymes - digestive enzymes
- this destroys the cells and the virus in it
There are other T cell types that we won't cover

33. Immune imbalances
- immunodeficiencies - when immune cells (any) behave abnormally
(AIDS - cripples helper T cells)
- autoimmune diseases - body cannot distinguish self
- hypersensitivities (allergies) - immune system is overly sensitive to perceived threats (pollen, dander)
MS - destroys myelin
Myasthenia gravis - impairs communication between nerves and skeletal muscle
graves' disease - thyroid over produces thyroxin
Type 1 diabetes - pancreatic beta cells destroyed
lupus - kidneys, heart, lungs, skin affected
glomerulonephritis - impairs renal function
rheumatoid arthritis - destroys joints

34. Cancer characterized by cells that - divide indefinitely
- lack a response to stop growing
- can recruit a blood supply
- can migrate
- lack normal interactions with other cells

35. Cancer - multiple mutations, multiple genes
- proto-oncogenes - promote normal cell division
- mutate to oncogenes
- tumor suppressor genes - control normal cell division
- mutate to become non-functioning
if time, explain genes and mutations....

36. Cancer
Once cells acquire adhesins and proteases they can move through the tissues by adhering to connective fibers and then cutting them
metastasis can occur through blood or lymph
extravasation = movement out of blood to surrounding tissue