Intro to Immuno (1/2) Flashcards
What is the complement system
Proteins made by liver & present in blood, lymph, and extracellular fluids. Coat surf of bacteria & extracellular virus particles to make them easily phagocytosed. Includes proteases. Infection triggers complement activation.
What are the 3 pathways that can initiate complement activation?
Classical, Lectin, and Alternative. They all lead to the formation of a C3 convertase (C3a is a chemoattractant & neutrophil activator) –> C5 convertase (C5 is endothelial attractant) C3 deficiency is the worst (severe susceptibility to infection) bc C3 is the most important protein of the complement system.
What is the classical activation of the complement system?
Part of both innate & adaptive immunity. Requires binding of an antibody or C reactive protein (CRP, part of innate system). Note that CRP is often a clinical indicator of systemic inflammation. It binds to phosphorylcholine of cell wall of bacteria. C1q binds an antibody or CRP, causes a conformational change. Leads to activation of C1r and C1s, then cleavage of C4 & C2 which ultimate leads to creation of a C3 convertase
What is the lectin pathway of the complement system?
MBL binds mannose on bacterial cell wall (similar to C1q of the classical pathway). Then MBL binds serine proteases MASP 1&2 . These are homologous to C1r&s because they also cleave/activate C4 & C2. & initiates creation of C3 convertase called C4b2a, which can cleave up to 1000 molecules of C3 to C3b
What is the alternative pathway of the complement system?
It’s the primary mechanism of complement activation. C3 undergoes spontaneous hydrolysis to C3(H2O) then binds to factor B, which is now cleaved by factor D into Ba (which is releasded) and Bb (which binds to C3(H2O). Ultimately forms C3bBb complex, which is a C3 convertase and can cleave many C3 molecules into C3a and C3b. C3b binds factor B & facilitates its cleavage by factor D. Ultimately leads to creation of more C3 convertase & lots more C3bBb).
All roads lead to rome- what happens once you get a C3 convertase?
C3b binds both C4b2a and C3bBb, forming the active C5 convertases C5 binds to the C3b component of the C5 convertase system C5 is cleaved by C2a or Bb to form C5b and C5a C3a, C5a, C4a all increase vascular permeability & cell adhesion molecules –> fluid leakage from BV’s & Ig’s/complement molecueles outside the vascular system –> migration of macrophages, PMNs, lymphocytes.
Complement Summary
Ultimately leads to inflammatory response
Cells of innate system
Myeloid lineage: macrophages/monocytes, granulocytes (neutrophils, eosinophils, basophils), classical dendridic cells, plasmacytoid dendridic cells Lymphoid lineage: natural killer cells
Cytokines
Secretory proteins that direct cell development, maturation, level of activation, and life span Includes interleukins, a subset that communicates between leukocytes Other examples include pro-inflammatory alarm cytokines i.e. IL-1, TNF-alpha, IL-18 Also includes anti-viral cytokines- IFN-alpha and beta, which are produced in response to viral infection & resist viral replication, activate local NK cells, etc.
How does the immune system sense pathogens?
PAMPS: pathogen-associated molecular patterns i.e. bacterial: LPS, peptidoglycan…viral: dsRNA, viral peptides…etc DAMPS: damage-associated molecular patterns i.e. K+ efflux from cell, chromatin associated proteins & cellular DNA outside nucleus, extracellular ATP
What are the 3 types of pathogen receptors?
Toll-like, nod-like, and rig-like There is redundancy in terms of what they recognize
Toll-like receptors
Triggered by bacteria, virus, fungi, protozoa. Located on endosomes & cell membranes Structure includes cytoplasmic & extracellular domains (which includes leucine-righ repeat (LRR- sensing region) and TIR) 3 principal signaling systems: NFKB, MAPK, IRF’s Pathway has lots of intermediates including MyD88, an adaptor protein that is activated by NFKB and Subcellular organization is important in TLR functions Pathway is different depending on which cell type you’re in
NOD-like receptors
cytoplasmic sensing system –> inflammasome pathway Like in TLR’s, LRR domain is used to sense. also has a nucleotide-binding oligomerization (NOD) region Inflammasome: NLR recognizes PAMP/DAMP –> assembly of protein complex (NOD/PYD/CARD domains) –> caspase 1 activation, which cleaves protease IL-1beta PYD domain defines NLRP family/mediates homotypic aggregation CARD domain = caspase recruitment domain NOD1/2 are cytoplasimc/inactive–> activated by bacterial ligands –> active NOD1/2 activate NF-kB Note that gout is because of NLRP3, which binds crystal monosodium urate & leads to inflammation
RIG-like receptors
Cytoplasmic sensors of viral infection 2 domains: helicase-like domain binds viral RNA &CARD domain interacts with adapters Signalling –> activation of NF-kB and IRF-3 2 families: RIG1 recognizes ucapped RNA & MDA recognizes long dsRNA Dock on mitochondrial membrane
