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8 - March 12, 2013.docx

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March 12, 2013 – LUPUS SLE – patients usually photosensitive (sun exposure brings out the rash) Skin – inflammation at the epidermal-dermal junction – when stain for Ig and complement, both are deposited at the junction, recruiting inflammatory cells tht cause skin rash Many organs can be involved – inflammation of lining of lung and heart; joint symptoms; one of their relatively more common manifestations is that can affect kidney When look at kidney, inflammation in glomerulus, the filtering apparatus of kidney – when stain the glomerulus with reagents that detect Ig and complement, see deposition of Ig and complement there – recruit inflammatory cells, damaging kidney’s filtering apparatus Lupus characterized by production of many autoantibodies – array of antigens – many of them localize to the nucleus – nucleosomes – fundamental building block of chromatin – RNA associated proteins – antigens directed against various cellular antigens – for example, against surface of red blood cells – tissue damage caused in lupus by autoantibodies that either bind directly to tissues causing inflammatory or bind to antigen in circulation and deposit in organs Immunopathogenesis Genetic disease origin Greater than 20 times higher chance of developing lupus if in family with lupus history Multiple genes required to act in concert to produce lupus – each gene has relativelys mall effect – interaction btw genes that leads to deelop to lupus phenotype Role of environment – Mice models in germ-free enviornments – develop lupus with same kinetics as an ordinary environment Evidence for role of environment – EBV infection stimulate immune system that cross-reacts with nuclear antigens – abundant evidence that lupus patients develop flares of disease following bacterial or virus infections Keratinocyte – skin cells – treated with UV radiation, apoptosis Overlaid keratinocytes with serum from lupus patients – the serum bound to apoptotic blebs – when keratinocytes aptoptoic - _________________ - taken up by macrophages Inviable keratinocytes – recognize antigen if permeabilized cells – if cells were inact, antibodies would have no access to the antigens Vast majority of nuclear antigens that are recognized in lupus are those that are exported to cell surface of aptoptoic cells – how they gain access to immune cells – can be big or small blebs – all antigens seen inlupus are seen on surface of apoptoic cells Another source of nuclear antigens – NETS – when neutrophils undergo cell death – different methods of death One way – neutrophils extrude network of chromatin and neutrophil granule, nmicrobial proteins – this network is called NETs – traps microorganisms and antimicrobial proteins contained within kill microorganisms that are trapped Chromatin is part of this complex – an antigen recognized in lupus – in lupus patients, increased rate of NETosis Decreased degradation of NETS lead to persistence of _________________- Nuclear antigens exposed to immune systems but also some unique properties that lead to activation of immune system Microbial and VIRAL molecules recognized by TLR TLR can also recognize components of mammalian DNA and RNA TLR3, 8, 9, and 7 – 3 recognizes dsRNA; 7 and 8, ssRNA; 9 hypomethylated cpG motifs in dsDNA TLRs – found in endosomal component – prevents activation of TLR by mammalian nucleic acids present in circulation – this is important because TLR are not good at discriminating between mammalian and viral/bacterial RNA/DNA – although TLR9 recognizes CpG motifs in bacteria, when our genome is being transcribed, gets hypomethylated, so have stretches of these motifs in mammalian DNA – when RNA tends to fold upon itself, get not only ssRNA recognized by hairpins that produce dsRNA Normally present in endosomal compartment – stuff in circulation has no access therefore does not lead to activation BUT in lupus patients, have formation of antibodies against either DNA, RNA, or proteins that are complexed with them – get uptake of these antigens through Fc receptors that bind to Ig found to antigens in immune complex – target them to endosomal compartment In lupus, Ig binds to RNA or DNA or proteins that complex to these – DC take up complexes through Fc receptor – directly target these complexes to late endosomal compartments, bind to TLR – lead to activation of dendritic cells In plasmacyte dendritic cells – free RNA and DNA cannot be taken up by DC, but only if in immune complex Produced by activated dendritic cells is IFN alpha Lupus have elevated levels – IFN alpha has short half-life – production of IFN alpha tends to be site- specific – what you can detect is – instead of seeing IFN alpha in serum, can see evidence of reduction of genes in IFN alpha – those cells have seen interferon alph a- known that lupus patients have elevated levels of IFN alpha – and predominantly, this is detected by IFN alpha induced gene expression – levels of IFN alpha and IFN alpha induced gene expression is associated with severity of disease and in animal models of lupus, administer exogenous IFN alpha, can worsen the disease, the kidney disease, earlier mortality Delete IFN alpha, disease better Two clinical trials underway IFN alpha – cytokine with multiple effects on multiple populations – many of the effects tend to enhance immune dysregulation seen in lupus IFN alpha – promotes differentiation of plasmacytoic DC, myeloid dendritic cells, so these cells are capable of taking up antigen and activating autoreactive T cells IFN alpha and IL12 enahnces develppment of TH1 cells and prevents apoptosis of activated T cells So T cells activated by autoantigens could be more presistant Activated T cells could provide help for autoantibody production – IFN alpha can enhance BCR- dependent activation and impairs B cella poptopsis – tend to lead to more activation of self-reactive cells and persistence of these cells in circulation – directly Enhance expression and secretion of BAFF – B cells activation factor that leads to enhanced survival of autoreactive cells if high levels of BAFF Nuclear antigens are also unique in that they can directly activate B cell in absence of T cell In lupus, have B cells in circulation that are specific for DNA or specific for RAN or specific for anything bound to RNA/DNA – RNA never present as free RNA, what is present is nucleosome or chromatin complex; DNA bound to protein or histone DNA bound to histone leads to activation of histone – any antigen complexed to dsDNA can be activated by interaction with DNA with TLR9 in B cell – similar things are true for B cells that recognize RNA or RNA-associated antigen – present as RNA complex with smRNP, ro, or lo So Ro-specific B cells will bind to complex and the RNA in the complex will lead to activation of B cell through TLR7 – so B cells require two signals, but when recognize nuclear antigen, the second signal does not require from T cell; the nuclear antigen can be the second signal – UNIQUE PROPERTIES Immune defects lead to loss of tolerance If healthy, aptoptoic debris is rapidly cleared by predomaintly bmacrophages – almost never see aptoptic cells unless there is defect in clearing them Macrophages – when take up apoptic cells, have natural set point that causes them to secrete anti- inflammatory cytokines – when macrophages take up aptoptoic debris –s ecrete TGF beta and When aptoptic debris is not efficiently taken up, those aptoptic cells move to late apoptotic phase or necrotic phase – now they can be taken up by macrophages that are pro-inflammatory Macrophages distinguish between late and early aptoptic cells – if aptoptic cells at late stage, taken up by pro-infmallatory macrophages Role of complement in immune system C1q bound efficiently to surface of aptoptic cells – aptoptic keratinocytes – overlaid with C1q and overlaid withantibody with C1q – on surface of aptoptic blebs – C1q bound to surface of apoptotic blebs promotes clearance/uptake by macrophages – mice were generates that were deficient in C1q – mice had increased production of autoantibodies – immune complex mediated glomerulonephritisi Normally do not see apoptoic bodies – but increased numbers of apoptotic bodies – so impaired clearance of apoptotic debris – multiple models that if knock out these molecules, impair clearance of apotoptic debris – all of these models facilitate development of lupus in genetic background Knockout capacity to degrade DNA – when cells that undergo apoptogos, get NETs, if knockout DNAse I, development of lupus – DNAse I has role in degradation of NETs in circulation Known that people that lack C1q have high prevalence of lupus – few individuals with this – few hundred but almost all of these individuals develop lupus – suggest that a rare allele that leads to development of lupus is one that leads to deficiency of C1q In addition to genetic defects that impair clearance of aptoptic debris – a number of genetic defecs that lead to heightened reseponse – heightened TLR response, tend to promote development of lupus TLR response is fine-tuned – if interrupted, tend to promote development of lupus – several genetic polymorphisms – that really impact on tLR responses promoting development of lupus Yaa allele first described in BXSB strain – only the males get disease – the Yaa gene on Y chromosome – shown to markedly enhance lupus if cross onto variety of genetic backgrounds that are associated with increase phenotype of lupus Yaa gene consisted of a translocation of a region from the X chromosome onto the Y chromosome – in the middle of this translocation is TLR7 Effects of the Yaa gene – Yaa gene increases the dose of TLR7, so twice the levels Response of B cells in these mice to imiquimod that stimulates TLR7 – markedly enhanced response to stimulation through TLR7 but no enhanced response through CPG through TLR9 and D is showing no change in CPG response but response to ligands for TLR7 – because TLR7 recognizes RNA Increased production of antibodies against proteins complexed with RNA or RNA itself and because those antigens tend to be not homogeneously distributed through nucleus – when look at pattern of antibodies on ANA – speckled patterns – TLR7 transgenic mice have high levels of TLR7 – lupus – speckled patterns of ANA ANA – antinuclear antibodies – fix and permeabilize cells, overly with serum from patient or mouse, treate with antibodies that recognize the nucleus – see fluorescent pattern at nuclei – the pattern tells you what the specificity is – homogenous pattern – A number of people see if TLR – if knockout molecules downstream of TLR9 – ameliorate development of lupus – TLR signalling plays important role in the development of lupus Identification of a number of polymorphisms through GWAS studies that act by impacting on TLR signalling TNFAIP3 – negative regulator of TLR signalling – in lupus, risk allele is associated with decreased regulation, enhanced signalling IRAK1 – downsream of TLR signalling – expressed at high levels – higher levels associated with increases with TLR signalling TNIP is negative regulator – low levels are associated with enhanced signalling – allele associated with lupus – the same principles that were identified in mice – also important role in humans!!! Is presentation or persitance of abototic debris sufficient to produce lupus? NO Aptoptoic debris pulsed dendritic cells – immunize healthy mice with this apoptotic debris – if provide source of autoantigens, will these mice become sick –
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