complement, coagulation Flashcards
role in inflammation
What does CXCL10 chemokine do ?
CXCL10 (C-X-C chemokine 10, IP-10 interferon gamma-induced protein 10) is produced by several cell types in response to interferon gamma (INFG). Binds to receptor CXCR3 on Th1 cells, and NK cells resulting in chemotaxis.
What is the difference between apoptosis, necroptosis, pyroptosis, and netosis?
Apoptosis results from nuclear disruption due to TNF and caspase 8.
necroptosis relies on RIPK1 and RIPK3, as well as TLR3, TLR4 and the T cell antigen receptor. In the absence of active caspase 8. RIP1 phosphorylates RIP3 which activates MLKL which leads to cell membrane rupture.
Pyroptosis is a form of apoptosis due to PAMPs acting on NOD-like receptors within the cytoplasm rather than TLR on the cell membrane.
Netosis comes from granulocyte disintegration wherein nuclear debris traps and kills bacteria.
RIPK1 (Receptor Interacting Protein Kinase 1)
MLKL (protein mixed lineage kinase domain-like)
PAMPs (pathogen-associated molecular patterns)
What are the main pathways generating C3b via different forms of C3 convertase?
The classical pathway starting with activated C1 then C-4 and C2 results in formation of C3 convertase C4bC2a.
The lectin pathway uses MBP complexes with serum MASP to activate C4 and produce C4bC2b.
The alternative pathway continuously generates C3b (tickover) in which C3bBb constitutes C3 convertase.
MASP: mannan associated serine protease
MBP: mamman-binding protein
What results from excessive C3b accumulation?
Opsonizaton is due to C3b/C4b on the surface.
What results from C3a/c5a surface accumulation?
Inflammation due to C3a/C5a develops as does cell membrane attack due to C5b to C9.
What does C3a do ?
Inflammation due to C3a/C5a develops as does cell membrane attack due to C5b to C9.
C3a degranulates mast cells and increases chemotaxis. Carboxypeptidase B generates C3adesArg (acylation-stimulating-protein, ASP) which affects triacylglycerol synthesis and adipocytes and fibroblasts through the G protein receptor.
What does C5a do ?
C5a releases histamine and TNF alpha from mast cells, recruits phagocytes to sites of inflammation, and antigen-presenting cells to lymph nodes. It upregulates integrin activity, activates lipoxygenase, and arachidonic acid metabolism. It increases activating versus inhibitory IgG Fc receptors on leukocytes.
What does C4b do ?
C4b binds to complement receptor 1 (CR1), a single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, podocytes, hyalocytes, and splenic follicular dendritic cells. C3a and C4a have a direct antimicrobial properties.
What immunoglobulins are responsible for fixing complement?
IgM fixes complement. IgG subclass 1 and 3 fix complement well, IgG4 does not, and IgG2 is intermediate.
How does the lectin pathway work to fix complement?
The lectin pathway utilizes mannose-binding protein (MBP), this binds to sugars on pathogens, utilize associated serine proteases that function similar to C1 activating C2 and C4.
Arginine can generate citrulline via deimination, which might generate auto antigens for what diseases?
Citrulline modified auto antigens include filaggrin, fibrin, vimentin, collagen, and alpha enolase. Filaggrin is a protein in the stratum granulosum of the skin, vimentin is in intermediate filaments, and alpha enolase is a glycolytic enzyme (2Phospho Glycerate->PEPyruvate). Thought to be an auto antigen in Hashimoto’s encephalopathy, severe asthma, and Behcet’s disease.
How does homocysteine cause vascular injury?
Homocysteine induces vascular injury by promoting : Blood activate factor 7A and five, inhibit protein C and heparin sulfate, increase blood viscosity, leukocyte recruitment via chemoattractant protein-1 and interleukin 8 expression and secretion. Increase oxidative stress. Platelet aggregation directly or via the impaired endothelium-mediated platelet inhibition. Vessels: A thiolactone metabolite produces intimal foam cells. Increases smooth muscle cell proliferation and collagen production. Attenuates endothelial tissue plasminogen activator binding sites, change thrombomodulin function. Decreased nitric oxide synthase activity.
How do platelets behave immediately after endothelial injury?
After endothelial injury, platelets bind to collagen via multiple surface receptors glycoprotein 1a/2a. Von Willebrand factor (vWF) assists in binding glycoprotein 1b/9/5 which promotes collagen interaction with platelet glycoprotein 6. This activats of platelet integrins causing tight binding. Platelet granules are released-ADP, serotonin, platelet-activating factor, vWF, platelet factor 4, and thromboxane A2 (TXA2). Platelet intracellular calcium increases via Gq-linked protein receptor cascade that activates protein kinase C, then phospholipase A2 which modifies glycoprotein 2b/3a which strengthens fibrinogen binding, and platelet aggregation.
How does the extrinsic coagulation system work?
Stromal fibroblasts and leukocytes express tissue factor (TF) that combines with FVII forming TF-FVIIa which activates FIX and FX. This extrinsic route to FXa is immediately inhibited by tissue factor pathway inhibitor (TFPI). FXa and its cofactor FVa form prothrombinase which splits prothrombin into thrombin. Thrombin activates most other factors and releases FVIII binding to vWF. FVIIIa and FIXa form tenase which activates FX.
How does the intrinsic coagulation system work?
Intrinsic system relies on collagen activation of high-molecular-weight kininogen (HMWK,644aa, inhibitor thiol protease), prekallikrein (serine protease), and FXII (serine protease) to eventually form the tenase complex. Deficiencies in this pathway affect inflammation but not coagulation.
