9/18 Flashcards
Inflammation
Accumulation of fluid, plasma proteins, and WBCs that is initiated by physical injury, infection, or a local immune response
Attempts to remove harmful substances and initiate the healing process
Primary and Secondary Lymphoid Organs
Primary: bone marrow and thymus, where immune cells develop and mature
Secondary: where lymphocytes respond to invading pathogens, spleen, lymph nodes, tonsils
Innate vs. Adaptive Immunity
- Innate: respond rapidly and are not specific for a particular insult/infection
NK cell, neutrophil, mast cell, etc.
Inflammation
- Adaptive: immune response by B and T cells that recognize specific pathogens and generates memory immune responses
Inflammation in Sterile Injuries
Danger Associated Molecular Patterns (DAMPs): intracellular molecules released by damaged cells like HSPs, HMGB1, and DNA
Necrotic cardiomyocyte releases DAMPs after ischemic injury to result in endothelial cell activation, peripheral neutrophil activation, and mast cell degranulation
Two Types of T Cells
2 types of Glycoproteins expressed on the surface
CD4 T Cells: helper T cells, protect us by helping other immune cells work better
CD8 T Cells: cytotoxic T cells, protect us primarily by killing infected and malignant cells
Function of T Cells
Make contact with other cells and inducing them to change
CD8 T cell: kill virally infected cells after contact
CD4 TH1 cell: release cytokines to activate macrophages which can in turn release cytokines
CD4 TH2 cells: release cytokines to B cells to get plasma cell that releases antibodies
Lymphocyte Circulation
B and T cells travel through body in blood and lymph, leave blood through capillaries in lymph nodes
If encounter antigen recognized by its receptor in the lymph node it will stay and become activated
If not then leave lymphoid organ via efferent lymph vessel to the thoracic duct which empties into the left subclavian vein, returning the lymphocyte into circulation
Spleen Anatomy
Red pulp: old/damaged RBCs are removed from circulation
White pulp: where innate and immune cells reside, can respond to pathogens in the blood that is being filtered
Asplenia: lack a spleen, at increased risk of infection by encapsulated bacteria
Cyclin-Dependent Kinases Operation Pathway
Cdk start with ATP and are inactive until binding of phase-specific cyclins then get partially activated, get change in shape of the T loop
Cdk becomes fully activated by phosphorylation from CAK (Cdk activating kinase)
Additional phosphorylation by Wee1 kinase inactivates it, can be counteracted by Cdc25 phosphatase to return to being active
Cycling binding is the limiting event for the activation of CDKs, cycling expression levels vary with phases and kinase activity varies cyclically in turn
Mechanism of action of Cdk inhibitors (CKI)
- Cip/Kip proteins: inhibit the kinase activity of CDK/cyclin complexes
p21, p27, p57
- INK 4 proteins: inhibit the interaction between cyclins and CDKs
p15, p16, p18, p19
- Ubiquitin Ligase: SCF helps degrade p27 CKI
- Ubiquitin Ligase: APC (anaphase promoting complex) destroys M cycling and terminates M phase
Escape from G1 Phase
Mitogen binds to mitogen receptor to activate MAP kinase pathway and induce expression of Myc
Myc increases cyclin D expression to increase G1-Cdk activation, also raises SCF ubiquitin expression to increase p27 degradation and have higher G1/S-Cdk activity
G1-Cdk and G1/S-Cdk phosphorylates retinoblastoma (Rb) to prevent it from locking up E2F (powerful transcriptional activator of genes for S phase like G1/S-cyclin), get positive feedback since increase G1/S-cyclin expression
Cell active and mitogen depravation doesn’t impair proliferation
Alteration in E2F/Rb pathway are common in cancer
Regulation of S Phase
Need to ensure only copy DNA once
Pre-replicating complex: forms during G1 and gone by G2 and M phase, composed of origin replication complex (ORC) plus Cdc6 and MCM
S-Cdk triggers S phase, destroys Cdc6 via SCF/ubiquitin and phosphorylates MCM
S-Cdk high during G2 but reduced after M phase, M-Cdk phosphorylates Cdc6 and McM to prevent additional DNA replication during M phase
During G1 Cdc6 accumulates and the pre-RC is formed but not active since low S-Cdk activity, in the next state S-Cdk is high but Cdc6 is inactivated so the pre-RC is active but not formed
DNA Regulation Checkpoint
M-cyclins stockpile during G2/M
Unfinished replication forks somehow send negative signal to M-Cdk, activates a kinase that inhibits the Cdc25 phosphatase and allows Wee1 to keep M-Cdk in inactive state
Start of M phase Regulation
Inactive M-Cdk becomes activated
M-Cdk activates Polo kinase which activates Cdc25, which activates M-Cdk and causes a positive feedback loop to further activate Polo kinase
M-Cdk also inhibits its own inhibitor (Wee1)
M-Cdk induces assembly of the mototic spindle, chromosome condensation, nuclear envelope breakdown, actin-myosin cytokinesis, and distribution of membranous organelles to daughter cells
Regulation of Sister Chromatid Separation
Anaphase-promoting complex (APC) ubiquitin Ligase activated by M-Cdk cohesin complex keeps chromatids bound at the centromere
At end of metaphase APC targets securin that inhibits securin, a protease that degrades the cohesin complex