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BMS 860 (17)
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Lecture 19

BMS 860 Lecture 19: Cancer Notes 19
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Department
Biomedical Sciences
Course
BMS 860
Professor
Radulovich
Semester
Winter

Description
Lecture 19- Immune response in cancer Immune system • Immune system distinguishes self from non-self • Eliminates harmful non-self molecules and cells from the body • Antigen is any molecule recognized by the immune system • The skin, cornea and mucosa of the respiratory, GI, and GU tracts form a physical barrier that is the body’s first line of defense. • Breaching of anatomic barriers can trigger: o Innate immunity = does not require prior exposure to an antigen to be effective ▪ Responds immediately to an invader, non-specific ▪ Components include phagocytic cells, natural killer cells and polymorphonuclear leukocytes o Adaptive immunity= requires prior exposure to an antigen to be effective ▪ Takes time to develop ▪ Cell-mediated response (T cells) ▪ Humoral immunity (B cells) • hematapoietic stem cells come from bone marrow, and can become myeloid or lymphoid progenitor cell o Myeloid progenitor cell will produce cells in the innate system o Lymphoid progenitor cells produce cells for the adaptive system ▪ cellular- t lymphocyte creates helper t cells, regulatory, and cytotoxic cells ▪ Humoral- b lymphocyte matures into plasma cells and makes antibodies Humoral immunity- mediated by b cells • 2 major domains- constant (Fc) on the bottom, and variable domains (Fab) that bind to antigens on top • Variable domains generated through combinations of genes, protein binding domains will be variable and bind many antigens • Elimination of antibody coated cells occur in 3 steps: o neutralization- antibody prevents bacterial adherence o opsonization- antibody promotes phagocytosis o complement activation- antibody activates complement, which enhances opsonization and lyses some bacteria Antigen processing • Dendritic cells phagocytose antigenic particles • Particles are fragmented into oligopeptides by proteolysis within the endosomes formed by phagocytosis • endosome- membrane bound compartment inside eukaryotic cells • MHC class II molecules migrate from ER to the endosomes • MHC class II molecules bind oligopeptides and migrate to the surface • Antigen presenting cells are professionals/unprofessional o Professional cells are in the innate system- dendritic cells Activation of B cells and antibody production • Dendritic cells presenting antigens proceed to the lymph nodes • Present antigens to helper T(H ) cells with compatible t cell receptors that recognize oligopeptide antigen • THis activated and looks for a compatible B cell • B cell is activated, differentiates into plasma cell and begins to release antibody molecules that are capable of recognizing the oligopeptide antigen. Neutralization • antibodies can directly bind infectious particles, preventing viral absorption and bacterial adherence Opsonization: macrophages • Bacteria coated by antibody, macrophages will bind the antibodies at the constant region (Fc) and through phagocytosis it will destroy bacteria and antibodies in lysosomes Opsonization: NK cells • Antibody coated mammalian cell recognized, natural killer cells will bind to the constant region (Fc) of the antibody, release cytotoxic granules, causes lysis of targeted cell Complement activation • Complement proteins in plasma bind antibody-antigen complex, create membrane channels, makes holes in the plasma membrane, cause lysis and apoptosis Cellular immune response • Mediated by cytotoxic T cells (Tc or CTL) • instead of using antibodies, uses t cell receptors (TCRs) • CTLs recognize and kill other cells displaying certain antigens on their surface • CD8 positive markers • Begins with antigen presentation through MHCI, leads to activation of naïve CD8 t cells, proliferation, differentiation, recognizes infected cells, destruction o Naïve- have not seen antigen, need to be activated Antigen presentation: MHC I • All cell types can present synthesized proteins on their surface- ex. MHC I • Synthesized proteins are processed into oligopeptide fragments • Oligopeptides enter ER and bind to MHC class I molecules • MHC class I complexes are dispatched to the cell surface Activation of CTLs by dendritic cells • Dendritic cells andHT cells can activate CTL cells • dendritic cells can present MHC class I and II • Activated CTL cell recognize and bind antigens displayed by MHC class I molecules on the surfaces of many cell types throughout the body (infected or abnormal cells) Mechanisms of killing by CTLs • CTLs contain lytic granules in its cytoplasm (pink arrows) • When contact is made with targetted cell, granules release perforin • Perforin forms cylindrial channels in the PM of the target • Apoptotic cascade o CTLs express Fas ligand o FasL binds Fas receptor displayed by the targeted cell and triggers receptor trimerization o Activation of extrinsic apoptotic cascade by caspases Innate immune response: NK cells • Cells of innate immune response can recognize and attack foreign particles without prior exposure to these agents • Cells of innate immune response recognize characteristic molecular patterns that are present on the surfaces of infectious agents (or cancer cells) but are not displayed by normal cells • Natural killer (NK) cells are thought to be the first cells that attack cancer cells • NK cell releases IFN-g and recruits other immune cells to the site of the attack o spreads cytoplasm to initiate killing, causes fragmentation in cancer cells Immune tolerance • Immune system must distinguish self antigens vs. foreign presented antigens • During development of imm
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