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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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!

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

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)

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

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

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

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!)

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

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)

There are 5 classes of antibodies (MADGE)

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)

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)

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 10-17 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

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

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

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)

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)

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

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

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

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....

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