Module 1 References Flashcards
Generation of diversity
Macfarlane and Burnet described clonal selection; Tonegawa discovered somatic recombination; TCRs discovered by Reinherz; AID KO mice- no class switching- Mumatsu et al.; heavy chain of antibody-chromsome 14; kappa-2; lambda-22; Macnamara- HLA-A02 and HLAcW08- 50% reduction in cases and x3 decrease in VL; HLA-DQ2- 90% of coeliac; Hill- HLAb27 protective for HIV whilst HLAB35 bad; martin- HLA homozygosity strongly assoc with HIV prorgession to AIDs
Complement
discovered- jules bordet- heat-labile substance in normal plasma who activity could complement bactericidal activity of immune sera; Ehrlich- copmlement and hypothesised it must be carefully controlled; factor H mutation- C3 glomerulonephropathy- Gale; no treatment tho C5a ameliorate in small trial-McCaughan defieincies in termianl pathway- neisseria- Braz described cases; Botto et al- apototic clearance; ASCOT trial natural ab; factor B 80-90% of complement activation; Bao- anti-C5ab ameliorates; 10,000 fold inc/year in Neisseria in japan with MAC defieicneis; injection of C3 and C5 anaphylaxis;
Innate receptors
MHC- chromsome 6–Gorer; Netea - trained immunity suggesting innate system has some memory as plants and invertebrates mount some response against reinfection; Beutler- 4 means of recognition; PRRs- Janeway and Medzhitov; phagocytic scavengers- Brown and Goldstein; phagocytic cells basis of immunity after visualised of ingestion of material in starfish larvae- Mtchnikoff; TLRs- Lematire; MyD88 has a deaht domain- Vogel; IRAK4 deficiency= susceptibility to encapsulated bacterai as low inflam cytokines- Burnuth; Hoshino- mutation in TLR4 are LPS-hyporesponsive- no NFkB; HMGB1 arthritis- macrophage and innate immune system- Pulleritis; TLR3 deficiency- HSV encephalitis; TLR4 on Paneth- AMPs; toll mutation- overwhelming fungal mutation and death within 3 days
Antigen presentation
mice without DCs cannot prime CD8- Santos; DCs- steinman and cohn; inflammatory Dcs induce Th17-Segura; Banchereau- DCs can be exploted for vaccine use’ Hsu et al- against B cell lymphomap first trial; Provenge- 4 months in survival-Kantoff; TAP -/- deficient in MHC-I presentation- Van KAer; cross-presentation- Bevan; Ackerman and Cresswell- viral derived TAP antagonist inhibited cross presentation’ bare lymphocyte syndrome- CIITA (MHC-II regulator) KO mice have global lack of MHC-II expression-Chang; Holland- TCR not hardwired for MHC but CD4/8; Takahama- thymoproteasome uses beta5t subunits in mice wiht B5 -/- get reduced number of functioanlly competent CD8 cells selected fro; martin- HLA homozygosity strongly assoc with HIV prorgession to AIDs; Hill- HLAb27 protective for HIV whilst HLAB35 bad; Napolitani- TLRs synergise to augment DC cytokine production- DCs with LPS and guanosine analgoue produce increased IL-12 than when incubated with one PAMP; Takemoto et al- increased matching ireduces rejection; TAP deficiency- bare lymphocyte syndrome ; cytosloic antigens through autopahgy entering endosome- Dengjel et al.
B cells
store operated C entry model- 1990s multiple groups worldwird; B cell deficient mice redcued 60-70% in CD4 response- Bouaziz; Bregs and produce IL-10- Yanaba; Syk- fostamitinib IgA nephroapthy and reduces disease in late GN-McDoo; Rag gene deletion- inability to produce TCRs and BCRs- Mombaerts; Maher- 80% of ALL patients had CR with CD19 CARs ; follicular B cell produce 95% antibody in loodstream; Francke et al- hyperIgM as a deficiency of CD40/CD40L; 100 fold inc in freq of antigen-specific B cells in second response; CD19:CD21:CD81 KO 10-100 fold decreasei n ab prodction; KO of CD81- CD19/21 unable to enhance BCR signalling or associate with lipid rafts; ICOS-/- T cell actiavted with anti-CD3 have reduced proliferation and production of IL-2
T cells
MHC restriction: zinkerngala and doherty ( CTLs induced by viral infection in mice of MHCa kill MHCa cell affected but not MHCb,c,d); Miller- thymectomised mice develop wasting syndrome and die; Claman- thymus and bone marrow transfer and ab production; Th1/2- Mossman and Coffman; differentation is very plastic- demonstrated by giving diffefrnt cytokines-Hirota; response is faster and with more cells upon reinfection-Flynn; Eventually all Tems cahnge to Tcms since host cannot have memory pool of easy to activate Tms in blood-Kaech and Werry; Pinkosi- moelcules smaller than granzyme didnt diffuse through perforin pores; Keefe- endosomolysis- calcium influx, repair mechanisms take up granules; Moryka- Granzyme gain entry via mannose-6-receptor; Lopez- inhibiting endosomal trafficking has no effect on granzynme entry into cells (no endosomolysis); Woodhouse- CTLA4 KO mice-die <4 weeks; Tregs proposed- Gerson; Treg transfor in NOD T1DM- Salamon; Bollard et al- CTL vaccines in EBV+ HL; dupulimumab- IL-4 and IL-13 block improves asthma; Gever- secukinumab reduces 63% lesion
Immunological synapse
imaged in 1990s- secretion of perforin/cytokines limited to contact site- Kupfer;
Memory
Lefrancois-Goldilocks model (strength regulates reponse outcome- optimal integration during activation results in devleopment of Tcm,Tem); Scholer- injected OVA into WT and ICAM -/- mice then injected OVA-need interaction between T and DCs via ICAM to egnerate memory; Joshi- WT mice infected with peptide loaded DC with and wtihout listeria- inflam directs memory precursor - inc inflam-more effector less memory; Araki- blocking mTOR with rapamycin increases memory formation and maintenace; paust and andrian- Nk memory cells induced in viral infections or delayed hypersensitivity; reside in liver, role unknown; IL-7Ra with mice infected with LCMV; rhesus disiease; original antigenic sin;
AI disease
Berer- if breed mice with TCR specific cells for myelin develop EAE but not in germ free, but if transfer faecal microbes from mice bred in normal enviornmen-develop EAE (need commensals for EAE); Wu- Th17 key to RA, only develop with segmented filamenotous bacteria; Cheng and richard- interactiosn between diet/gut microbiota/immune system important in controlling inflam and disease progression
EBV
achieves latency with circular episome- Thorley lawson model; henle- EBV transforms primary B cells;
Death/inflammation
inflammation now 7th hallmark of cancer-Mantovani; danger thoary of inflam-Matzinger; Botto- C1q-/- mice show increased apoptotic bodies; NETosis- Brinkman–DNA condensation nad thrown around pathogen, membrane disintegration; NETosis- targets in RA- Wegner et al.; Medzhitov- types of inflammation; Para-inflam- Zalli et al. depression associ with increas in inflam markers; raised biomarkers predictive of severe depresion and relapse;
Genetics/stem cells
iPSCs- induced pluropotent stem ells, fibroblasts to stem cells using (Oct3/4; Sox2; c-myc; Klf4)- Takahashi and Yamanaka; Sox2 KO- reduced pluripotent expression- Fong; chimeric mice by injecting embryonic SCs into blastocysts and implant into mothers, mate with normal mouse- normal mice and gene target- Evans; Capecchi; Soresnsen- preamture death in adults has strong genetic backgroun; PTPN gene modultes threshold for T cell tolerance- coealic ; SLE; KO- multiple immune system abnoramlities- Hasegawa;
Regulation of complement
C1 inhibitior- dissocation of C1r:C1s- hereditary angiodema- C2b cleaved into C2 kinin- inc risk of SLE; factor I and co factor H; DAF- C3b; CR1- prevents formation of C3 convertase and breaks down C3b; factor I deficiency- pyogenic pathogens- uncontrolled activation nad depletion; factor I and factor H- atypical haemolytic urameia; factor H gene- age-related macular degenration; C3 glomuleropathy- Gale; eculizumab ameliorates- McGaughan; C5L2- decoy receptor; CD59 inhibits MAC by preventing C9; mutationsin GPI anchors of CD59 and DAF- PNH- intravascular RBC- C3 deposition and MAC on host cells; Tran et al.- positive regulator MafB- on macrophages and monocytes and if deficient results in decreased efferocytosis- reduced activation of complement- increased SLE and glomerular autoimmunity
