Innate immunity Flashcards
PRRs
Recognise and respond to conserved structures present in microbial species (PAMPs) to trigger protection, initially in the form of inflammatory response.
Expressed in antigen-presenting cells and in many non-professional immune cells.
Four different classes of PRR families -
1. Toll like receptors (TLRs)
2. Retinoic-Acid-Inducable-Gene(RIG)-I-Like-receptors (RLRs)
3. NOD-Like receptors (NLRs)
4. C-Type lectin receptors (CLRs)
Toll-like receptors
Sense invading pathogens at cell surface, intracellular endosomes and lysosomes.
10 different TLRs in man
Different TLRs recognise distinct microbial PAMPs but signal via similar mechanisms.
Characterised by N-terminal leucine-rich repeats, a transmembrane region and a cytoplasmic TOLL/IL-1R homology domain responsible for signalling.
TLRs function as homo or hetro dimers.
10 human TLRs and what they recognise
TLR1 - bacterial triacyl lipoprotein TLR2 - bacterial/viral lipoproteins TLR3 - viral dsDNA TLR4 - bacterial/virus lipopolysaccharide TLR5 - bacterial flagellum TLR6 - bacterial/viral diacyl lipoproteins TLR7 - viral ssRNA TLR8 - viral ssRNA TLR9 - bacterial/viral/protozoan CpG DNA TLR10 -unknown
Lipopolysaccharide (LPS)
A major structural component of the outer wall of gram-negative bacteria.
Lipid A component - a potent innate immune system activator.
LPS binds MD-2 to form a complex that binds and dimerises TLR4, activating it.
TLRs and dendritic cell function
TLRs are needed to mature tissue-resident immature Dendritic cells.
Dendritic cell maturation links innate and adaptive immjne responses.
Mature DCs are responsible for antigen presenting to naive T cells, releasing costimulatory molecules and inflammatory cytokines and modulation of target genes by TLR signalling.
Cytokines
Approx 50 proteins that promote the growth and/or differentiation of leukocytes (in autocrine, paracrjne or endocrine manner)
Two major structuralky defined familes -
1. Hematopoietins - mostly interleukins, colony-stimulating factors and interferons.
2. Tumor necrosis factor family - TNFa/b, trimeric proteins
IL-1, IL-6, and TNFa
Most important pro-inflammatory cytokines
Increases -
Endogenous fever,
Systemic production of acute phase proteins by the liver,
Vascular permeability,
Expression of adhesion molecules (on vascular endothelial cells and/or leukocytes),
Chemokine production
Neutrophil production, recruitment and phagocytosis.
Cytokines classified by function
Cytokines that mediate and regukate innate immunity
IFNa/b, TNFa,IL-1, IL-6, others
Cytokines that mediate and regulate adaptive immunity
IL-2,IL-4, IFNgamma, TNFb
Cytokines that stimulate haematopoiesis
C-KIT, IL-3, IL-7, IL-9, IL-11, colony stimulating factor
TNFa and TNFRs
TNFa - a trimeric ligand, induced and secreted from PAMP/cytokime activated cells. Orchestrates communication between both immune and non-immune cells and controls many of their functions.
TNFRs - TNFR1 (ubiquitously expressed), TNFR2 (expression restricted to specific neuronal subtypes, endothelial calls, CD4 and CD8 T cells).
Trimeric TNFa ligand binds to and activates trimeric receptor complexes to turn on signalling.
Excessive TNFa/TNFR1 signaling results in chronic inflammatory disease.
TNFR1 signalling
A distinct series of protein interactions activate multiple pathways.
TNFa binding triggers recruitment of TRADD.
TRADD recruits cIAP1/2-TRAF2 and RIP1 to the receptor.
cAIP1/2 ubiquitilates itself and RIP1.
Recruitment of TAK and IKK complexes to UB chains by NEMO and TAB binding to K63Ub chains.
IL-6 signalling
Activation of the JAK-STAT pathway.
Cytokine bjndjng to gp130 receptor-dimers permits Tyr phosphorylation and activated of associated JAKs.
Active JAKs phosphorylate specific Tyr residues on the receptors cytoplasmic domain.
SH2 domains on STATs bind to tyr-phosphorylated receptor and become phosphorylated by JAKs.
Tyr-phosphorylated STATs dimerise and translocate to the nucleas to initiate transcription of specific target genes.
Cytokine signalling and rheumatoid arthritis
Triggered by an autoimmune reaction, clonal expansion of CD4 cells occurs.
Recruitment of monocytes to the synovium, which then turn into macrophages.
Fibroblasts and macrophages secrete pro-inflammatory TNFa, IL-6, IL-1 and chemokines.
Secretion of proteases from activated fibroblasts,osteoclasts and inflammatory cells leads to cartilage and bone erosion.
Anti-TNFa therapy
Blocks TNFa interaction with membrane localised receptors by bindjng TNFa thus preventing agonist bindjng and activation of TNFRs. Adjinistered subcutaneously.
TNFa decoys (Etanercept) - disulphide linked dimer of genetically engineered fusion protein, has TNFR extracellular domain, binds to TNFa with high affinity.
Anti-TNFa antibodies (Adalimunab) - first fully human monoclonal IgG antibody drug.
Anti-IL-1 therapy
IL-1 receptor antagonist - naturally occurring antagonist of IL-1,binds membrane localised IL-1 receptors, preventing agonist binding. Levels ofbthis are low in patients with RA.
Recombinant IL-1 receptor antagonist - (Anakinra) administered subcutaneously, given to patients who are unresponsive to anti-TNFa therapy
Anti-IL-6 therapy
Blocks IL-6 interaction with membrane localised IL-6 receptors.
Tocilizumab - humanised monoclonal IgG drug. Administered subcutaneously.
