SLEisadevastatingsystemicautoimmunediseaseofunknownetiologythatpresentswithadiversearrayofclinical symptoms and afflicts over 1.5 million Americans. Numerous risk factors have been identified, and it is generally accepted that SLE can result from a spectrum of immunoregulatory defects. However, one of the key events is a breach in tolerance of autoreactive B cells and their development into autoantibody producing plasma cells. Nucleic acidbindingToll-likereceptors(TLRs)havebeenfoundtoplayacriticalroleintheproductionofautoantibodiesand disease development in all animal models of SLE that have been examined to date. Intriguingly, in these same models, TLR9 appears to play both a protective and disease promoting role;? TLR9 is required for the production of anti-dsDNA autoantibodies, but surprisingly, TLR9KO autoimmune-prone mice develop much more severe clinical disease than their TLR9-sufficient counterparts. Previously, we have reported that activation of autoreactive B cells with TLR9 dependent DNA-containing immune complexes causes rapid proliferation followed by cell death while activation with TLR7 dependent RNA-containing immune complexes leads to plasma cell differentiation. The exact basis for this bifurcation in B cell differentiation is still under investigation. We have preliminary evidence that TLR9 uniquelyregulatestheNF-k?BpathwaybypromotingIk?Ba?degradationandexpressionofIk?Bz?.Ik?Bz?isanimportant transcription factor that regulates the levels of pro-inflammatory (IL6, IL12) and anti-inflammatory cytokines (IL10). Recently, the expression of Ik?Bz? has been linked to the immunometabolite itaconate. Interestingly, TLR9KO B cells showadecreasedoxygenconsumptionratecomparedtoWTBcellsafterimmunecomplexactivationsuggestinga role for TLR9 in the regulation of metabolism. Putting these findings together, we hypothesis that TLR9 plays a key roleinmetabolicreprogrammingofautoreactiveBcellsandsubsequentmodulationofimportantsignalingpathways.
In Aim1, wewillexploretheroleofTLR9inincreasingcellularmetabolisminimmunecomplexactivatedBcellsand its inhibitory effect on plasma cell differentiation.
In Aim 2, we will explore the pathways by which TLR9 dependent metabolic reprogramming modulates the NF-k?B pathway downstream of B cell receptor crosslinking. Based on our hypothesis, we expect to identify key roles for itaconate and Ik?Bz? in plasma cell differentiation. Overall, the studies outlined in this application should provide important insights regarding the metabolic requirements of autoreactive B cells and its influence on B cell fate decisions. The findings from these studies may lead to the discovery of new therapeutictargetsforSLE.
PROPOSALNARRATIVE SystemicLupusErythematosus(SLE)isacommonanddevastatingautoimmunedisease,characterizedby dysregulatedactivationofautoreactiveBcellsbyintracellularantigenslikeRNAandDNA,whichactivateToll- likereceptors(TLR)7andTLR9.Despitetheiridenticalsignalingcascadesinmacrophages,TLR9signalingin BcellsseemstoinhibitplasmacelldifferentiationwhileTLR7promotesit,suggestingabifurcationofsignaling cascadesdownstreamofTLR7andTLR9,whichmayexplainpartoftheobservedprotectiveroleofTLR9in SLE.Inthisproposal,weareexploringhowTLR9modulatesNF-k?Bsignalingbymetabolicreprogramming anditseffectonplasmacelldifferentiation?insightsthatmayleadtothediscoveryofnewtargetsformuch neededtherapeuticsinSLE.
