Innate Immunity PRRs

brad2x's version from 2017-02-21 23:08

Section PRR:PAMP:Localization:Adaptor:Effect

Question Answer
TLR 1/2Triacylated Lipoproteins; Surface; MyD88/Mal; inflammatory cytokines
TLR 2/6Diacylated Lipoproteins; Surface; MyD88/Mal; inflammatory cytokines
TLR 3dsRNA; Endosomal; TRIF; Type-1 IFN
TLR 4LPS; Surface - MyD88/Mal - Inflammatory Cytokines; Endosomal - TRIF/TRAM - T1-IFN
TLR 5Flagellin; Surface; MyD88; Inflammatory cytokines
TLR 7ssRNA; Endosomal; MyD88; Inflammatory Cytokines and T1-IFN
TLR 8 ssRNA; Endosomal; MyD88; inflammatory cytokines and T1-IFN
TLR 9 CpG DNA (ODNs); Endosomal; MyD88; inflammatory cytokines and T1-IFN
TLR 10Profilin-like proteins; Endosomal; MyD88; inflammatory cytokines
NOD1iE-DAP; Cytoplasm; CARD > RIP2 > NFkB; Inflammatory Cytokines
NOD2MDP; Cytoplasm; CARD > RIP2 > NFkB; inflammatory cytokines
NLRP(x)Infection or cellular damage; Cytoplasm; Pyrin > ASC > Caspase - 1; Inflammasome
NLRP3 / NALP3Decrease in intracellular K, ROS, Lysosomal disruption, Alum; Cytoplasm; Pyrin > ASC > Caspase - 1; Inflammasome
RIG-1 / MDA-5ssRNA (uncapped) & dsRNA; Cytoplasm; Helicase > CARD > MAVS > TRAF > IRF3; T1-IFNs
STINGcyclic dinucleotides (CDNs); Cytoplasm; TBK1 > IRF3; T1-IFNs
Complement ReceptorsC3b; Surface; GPCR; Phagocytosis
Mannose-Binding Lectin (MBL)Mannose, Fucose, GlcNAc; Extracellular Fluid; MASP1/2/3 > C2, C4; Complement: Lectin Pathway
FicolinsOligosaccharides w/ Ac-sugars; Extracellular Fluid; MASP1/2/3 > C2, C4; Complement: Lectin Pathway
C-type lectin-like family (Dectin-1)Beta-1,3-linked glycans; Surface; Phagocytosis
Mannose ReceptorMannosylated ligands; Surface; Phagocytosis
Scavenger Receptors (SR-A/1/11/MARCO)Anionic Polymers; Surface; Phagocytosis

Section PRR Categories

Question Answer
PAMP = some form of DNATLR9 (CpG DNA), STING (cyclic dinucleotides CDNs)
Endosomal PRRsTLR3, TLR4, TLR7, TLR8, TLR9, TLR10
Surface PRRsTLR1/2, TLR2/6, TLR4, Complement Receptors, Fc Receptors, C-type lectin-like family, Mannose receptor, Scavenger receptors
Cytoplasmic PRRsNOD1, NOD2, NLRP(x), NLRP3/NALP3, RIG-I/MDA-5, STING
Extracellular PRRsMannose-Binding Lectin (MBL), Ficolins, (Defensins - not PRR, but worth remembering)
MyD88 SignallingTLR1/2, TLR2/6, TLR4, TLR5, TLR7, TLR8, TLR9, TLR10 --> Inflammatory cytokines + T1-IFN if endosomal
TRIF SignallingTLR3, TLR4 --> T1-IFN
IRF3 SignalingRIG-I / MDA-5, STING --> T1-IFN
Induces PhagocytosisComplement Receptors, C-type lectin-like family, Mannose Receptor, Scavenger Receptors, (Fc Receptors)
Induces Lectin Complement PathwayMannose-Binding Lectin (MBL), Ficolins

Section PRR Cascades

Question Answer
NFkB activatesInflammatory Cytokines (TNFa, IL-2, IL-6)
IRF3/7 activatesType 1 Interferons (IFN-a, IFN-b)
Caspase-1 activatesInflammasome and Pyrroptosis
Surface TLR CascadeTLR1/2,2/6,4,5 (LRR) > MyD88 (TIR) > IRAK 1/4 > kinase cascade > pIkB (deg) > NFkB > Inf Cyt
Endosomal TLR Cascade (MyD88)TLR 7/8/9 (LRR) > MyD88 (TIR) > IRF7 > TBK1 > pIRF7 > T1-IFN (IFN-a/b)
Endosomal TLR Cascade (TRIF)TLR 3/4 (LRR) > TRIF (TIR) > TBK1 > pIRF3 > T1-IFN (IFN-a/b)
NOD-Like Receptors CascadeNLRPx > Caspase-1 (Pyrin D) > Inflammasome > Pyrroptosis
NOD Receptor CascadeNOD1/2 (LRRs) > RIP2 (CARD D) > NFkB > Inf Cyt

Section Complement Pathways

Question Answer
Complement Pathway NamesClassical, Alternative, Lectin
Classical C3 ConvertaseC4b2a
Lectin C3 ConvertaseC4b2a
Alternative C3 ConvertaseC3bBb
Classical Pathway UpstreamC1qrs (complex) binds Fc regions of IgM staple > C4 to C4b on surface > C2 to C4b2a on surface
Lectin Pathway UpstreamFicolin & MBL bind PAMPS > C4 to C4b on surface by MASP-2 > C2 to C4b2a on surface
Alternative Pathway UpstreamC3b created by hydrolysis or other upstream > C3bBb on surface by Factor D
Complement Pathway MidstreamC3 convertase on surface > Cleave C3, release C3a, surface C3conv3b (C5 Convertase)
Complement Pathway DownstreamC5 convertase on surface > Cleave C5, release C5a and C5b > Recruit C6, C7, C8, C9 to form MAC > Lysis
Effector Functions of Complement CascadeRecruitment of phagocytes, Phagocytosis through CRs, Lysis through MAC
Factors recruiting phagocytesC3a, C5a
Factors recognized by CRsC3b on surface

Section V(D)J & CSR & SHM & Diversity Generation

Question Answer
V(D)J PlayersRSS (23+12), RAG1/2, Ku70/80, DNA-PK:Artemis, TdT (HC only), DNA Ligase
CSR PlayersSwitch Sequences, AID, UNG, APE1, DSBR
V(D)J Coding Joint MechanismRAG1/2 binds RSS-1, then RSS-2, forming a hairpin loop and catalyzes cleavage. Small hairpin loops are left on the germline strand to become the coding joint. The split ends are stabilized by Ku70/80, then opened up by DNA-PK:Artemis complex. This results in P-nt addition. Then, TdT phos. the ends and adds N-nts (HC only). DNA ligase seals the break (imprecisely).
V(D)J Signal Joint MechanismRAG1/2 binds RSS-1, then RSS-2, forming a hairpin loop and catalyzes cleavage. Ku70/80 stabilize the split ends, which are then sealed by DNA ligase.
CSR MechanismSwitch regions (poly-C) are actively transcribed, AID deaminates C residues to U in replication fork, UNG converts U to abasic, APE1 converts abasic to ss nicks. Many ss nicks result in ds breaks, which allows the DSBR machinery to ligate the two switch sequences, removing the old Constant region.
SHM MechanismActively-transcribing regions (in CDR mainly) deaminated (C -> U) by AID. UNG converts to abasic. APE1 converts to ss nicks. Repair machinery make mutations that are selected for or against in the germinal center, resulting in affinity maturation.
Sources of DiversityN-nt addition (HC only), P-nt addition (DNA-PK:Artemis), Imprecise Joining
CSR/SHM Excision-Repair MachineryAID (ssDNA C -> U), UNG (U -> Abasic), APE1 (Abasic -> ss nick)

Section Ig Isotypes: Valency, Distribution, Fxn

Question Answer
IgMPentameric (J-Chain); Serum; Complement Activation (staple conformation exposes Fc)
IgDMonomeric; Serum; N/A
IgGMonomeric; Serum; Opsonization (Fc), Complement Activation (classical), ADCC, crosses placenta (FcRn)
IgEMonomeric; very, very low in serum; parasitic infection & allergy (x-links FcR on mast cells -> degranulation)
IgADimeric (J-Chain); Secretions across epithelium (poly-Ig receptor), 1st line defense, passive immunity, opsonization, highest [Ig} produced

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