Innate Immunity Lecture Notes PDF

INNATE IMMUNITY TOLL LIKE RECEPTORS he discovery of the Toll like receptors (TLR) Immune response has to start with sensing ‘danger’ Medzhitov and Janeway (1997) Several approaches failed to find receptors that bound pathogens. 1985: Christiane Nusslein-Volhard identified Toll genes (To...

INNATE IMMUNITY TOLL LIKE RECEPTORS he discovery of the Toll like receptors (TLR) Immune response has to start with sensing ‘danger’ Medzhitov and Janeway (1997) Several approaches failed to find receptors that bound pathogens. 1985: Christiane Nusslein-Volhard identified Toll genes (Toll = cool, weird) Drosophila melangaster important gene in embryogenesis in establishing the dorsal-ventral axis 1996: Jules Hoffman finds that Toll has a role in the fly’s immunity to fungal infection- 1997: year later they reasoned that Ibiology video medzitov genes related to Toll exist in Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene. Alexander Poltorak et al Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, = resistant to endotoxin.. Mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS. Mutations of Tlr4 predispose to Gram-negative sepsis Pathogen recognition receptors (PRR) Pathogen associated molecular patterns (PAMPs) Example: TLR4 (PRR): LPS from bacteria (PAMP) Recognition of PAMP initiates various innate responses: – Chemokines/cytokines to recruit cells – Phagocytosis of pathogens – Lysis of pathogens by antimicrobial peptides TLRs trigger an intracellular signalling cascade TLR signaling MyD88 – Myeloid differentiation primary response gene (88) a universal TIR adaptor (except TLR3) MyD88 interacts via a TIR domain MyD88 promotes association of IRAK1 & 4 kinases (interleukin-1 receptor-associated kinase) IRAK4 phosphorylates IRAK1 creating a docking site for TRAF6 (TNF-receptor-associated factor 6) TRAF-6-IRAK1 dimer complex dissociates Complexes with TAK1 (+other proteins) (TGF-beta activated kinase 1) causing kinase activation TAK1 is pivotal as it activates both NFkappaB and Map kinase pathways Increased transcription of target genes TAK1 activates IKK which phosphorylates IkappaB causing activation of NFkappaB TLR activation in macrophages results in oxidative burst (phagocytosis) and inflammatory cytokine/chemokine release TLR activation in dendritic cells results in maturation, antigen presentation, and cytokine production- bridge to adaptive immunity Various TLRs (NFkB) Various cytokine receptors ( JAK/STAT) TLRs on the cell surface and endosomes for defence against a wide range of pathogens CYTOKINES AND INTERFERONS Cells of the Immune system NK cell: immune surveillance of cancer and viral infected cells Dendritic cell: antigen presentation Neutrophil: phagocytosis and and cytokine production enzyme production Macrophage: phagocytosis and cytokine production Jaks and Stats Jak – Janus kinase – Janus Roman God of doorways having two faces. Jaks have two functional sites, a binding site to associate with the cytokine R and a catalytic site, when activated, has tyrosine kinase activity – (also termed Just another kinase). Jaks bind receptor and tyrosine phosphorylation creates a binding site for the SH2 domain of Stats, firstly on the receptor and then on the Stat itself– this leads to dissociation & dimerisation Stat – Signal transducer and activator or transcription- is a transcription factor (TF) that binds DNA sequence-specifically and promotes transcription from GAS element in response to cytokine stimulation. Stats may operate with other TFs Animation of JAK-STAT signalling Cytokines induce local and systemic effects which immune cells are needed to attack viruses? Cytokines combinations can determine the type of immune response generated