Astier, Anne

Choileain, Siobhan Ni

So, Magdalene

Weller, Belinda

Weyand, Nathan

English

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Altered Regulation of CD46 Expression and Processing in MSCitation for published version:Choileain, SN, Weyand, N, So, M, Weller, B & Astier, A 2010, 'Altered Regulation of CD46 Expression andProcessing in MS' Clinical Immunology, vol 135, pp. S7-S7., 10.1016/j.dim.2010.03.027Digital Object Identifier (DOI):10.1016/j.dim.2010.03.027Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Preprint (usually an early version)Published In:Clinical ImmunologyGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015CD4+ proINS 76-90 (SLQPLALEGSLQKRG) specific T cells usingsoluble fluorescent MHC class II tetramers. Subjects with type1 diabetes (T1D; n=10) and healthy controls (n=8) with highlevels of peripheral proINS -specific T cells were charac-terized by the presence of a “disease-susceptible” polymor-phism in the INS-VNTR gene. Conversely, subjects with a“protective” polymorphism in the INS-VNTR gene had nearlyundetectable levels of proINS tetramer-positive T cells. Usingtetramers to isolate proINS -specific T cells from subjectswith both INS-VNTR genotypes, transcript arrays (Affimetrix)followed by quantitative Q-PCR profiling have identifiedseveral induced pro-apoptotic genes (FASLG, TNF, TNFSF11),and cytokine (IL-2, IFNg, IL-22, IL1B, IL-10, IL-7) andchemokine (CCL22) pathways in controls, but not diabeticsubjects, likely representing a second peripheral mechanismfor maintenance of tolerance to self antigens. These resultsstrongly imply a direct relationship between genetic controlof autoantigen expression and peripheral autoreactivity, inwhich proINS genotype restricts the quantity and quality ofthe potential T cell response.doi:10.1016/j.clim.2010.03.026OR.10. Altered Regulation of CD46 Expression andProcessing in MSSiobhan Ni Choileain1, Nathan Weyand2, Magdalene So2,Belinda Weller1, Anne Astier1. 1University of Edinburgh,Edinburgh, United Kingdom; 2University of Arizona, Tucson,AZThe regulator of complement activity CD46 acts as acostimulatory molecule for T cells and promotes theirdifferentiation into Tr1 cells, secreting notably the anti-inflammatory cytokine IL-10. We previously demonstratedthat CD46 pathway is dysregulated in T cells frompatients withmultiple sclerosis (MS), as IL-10 secretion is impaired. Herein,we have followed CD46 expression upon T cell activation incells from a cohort of healthy donors and patients in the RRMSstage. Upon CD46 activation, we first observed the cleavage ofits ectodomains by MMPs, which is regulated by the TCR. Byhomology to Notch, this generates a C-terminal fragment(CTF) that can be further cleaved by the gamma-secretaseenzymatic complex. Indeed, loss of expression of bothcytoplasmic isoforms occurred after activation, which couldbe partly restored by addition of a gamma-secretase inhibitor.We did not observe a defect in cleavage of CD46 ectodomainin T cells from patients with MS. However, the loss of CD46cytoplasmic tails was not observed in T cells from patients.CD46 processing was required for its functions, as demonstrat-ed by the following results: i) addition of gamma-secretaseinhibitors to T cell culture inhibited IL-10 production by CD46-activated T cells; ii) expression of a pre-cleaved CTF-cyt1fragment of CD46 resulted into increased IL-10 production;iii) our preliminary data suggest that both tails are found in thenucleus of activated T cells. Altogether, this suggests that analtered CD46 processing might be at least partly responsiblefor its defective role in MS.doi:10.1016/j.clim.2010.03.027OR.11. Citrullinated Fibrinogen Stimulates TNFRelease via TLR4 and Citrullinated FibrinogenImmune Complexes Co-stimulate through TLR4 andthe Fc Gamma ReceptorJeremy Sokolove, Xiayan Zhao, William Robinson. StanfordUniversity, Palo Alto, CAExtravasation of fibrin(ogen) is a characteristic pathologicfinding within the RA synovium. Citrullinated proteins havebeen demonstrated at many sites of inflammation andcitrullinated fibrin(ogen) has been consistently identifiedwithin the RA synovium. The presence of anti-citrullineprotein antibodies characterizes RA and has been associatedwith increased RA severity. The innate immune receptorTLR4 is critical in murine models of RA and has beenimplicated in human RA. Several studies have demonstratedTLR4 dependent signaling by non-microbial damage associ-ated molecules including fibrin(ogen). In this study wedemonstrate a dose dependent ability of native and cFb tostimulate macrophage TNF secretion and confirm that thisprocess is TLR4 (and MyD88) dependent. Notably, cFbdisplayed approximately ten-fold increased potency overnative fibrinogen. In-vitro generated cFb containing ICstimulated TNF release at levels significantly above thatseen with cFb alone via a process dependent on thecombination of TLR4 and the Fc gamma receptor. Thisstudy demonstrates that citrullination of fibrinogen dramat-ically increases it's potency on TLR4 mediated TNF releaseand that cFb IC can co-stimulate through TLR4 and the Fcgamma receptor. Given that citrullination is ubiquitous tosites of inflammation, the ability to increase the potency ofan innate damage associated molecule via citrullination ishighly novel with potentially broad generalization to thefield of innate immunity. Additionally, the ability of cFbcontaining IC to co-stimulate TNF release provides apotential pathogenic mechanism for RA associated auto-antibodies in the initiation and propagation of synovialinflammation.doi:10.1016/j.clim.2010.03.028OR.12. Blockade of CD94/NKG2A Prevents EAEJianmei Leavenworth2, Carola Schellack Wenander1,Hye-Jung Kim2, Linrong Lu3, Pieter Spee1, Harvey Cantor2.1Novo Nordisk A/S, Måløv, Denmark; 2Dana-Farber CancerInstitute, Boston, MA; 3Zhejiang University School ofMedecine, Hangzhou, ChinaNK cells are important members of the innate immunesystem that have been implicated in anti-microbial and anti-tumor defense as well as in maintenance of tolerance andcontrol of autoimmune diseases. The activity of NK cells isregulated by a delicate balance of both activating andinhibitory receptors. CD94/NKG2A is an inhibitory receptorexpressed in mice mainly on NK and a subset of CD8+ T cellsrecognizing the non-classical class I molecule Qa-1. Target-ing CD94/NKG2A receptor by blocking its interactionwith Qa-1 by a monoclonal antibody is a new therapeuticapproach to increase NK cell activity in the treatment ofS7Abstracts

Altered Regulation of CD46 Expression and Processing in MS

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