ABSTRACT
Common pathophysiological mechanisms are thought to promote the cutaneous and systemic manifestations
of lupus. Thus a better understanding of the factors that promote CLE are likely to provide important insights as
far as the pathogenesis of SLE. Nevertheless, it is also likely that tissue specific effector mechanisms account
for the diverse clinical presentations exhibited by SLE patient populations. Since 75% of SLE patients exhibit
skin lesions of some sort, and UV exposure of the skin is often associated with lupus flares, it is surprising that
there have been relatively few mechanistic studies that address initiation, progression and recurrence of CLE.
One reason for this gap is that murine models available for the study of CLE have been limited – despite the
numerous murine models of SLE, models that accurately reflect the central features of CLE are much more
limited. We have now develop an inducible model of lupus like skin inflammation (LLSI), initiated by T cell
transfer, that recapitulates many of the features of CLE. These include a prominent role for skin-infiltrating
IFN¿-producing Th1 cells, excessive keratinocyte death, autoantibody deposition at the dermal/epidermal
border, increased expression of CxCL9, CxCL10, CxCL11, CCL8, and accumulation of pDCs in the skin. There
are also mechanistic similarities between our LLSI model and other inducible as well as genetically
programmed murine models of SLE; they all depend on the expression of TLR7 and are exacerbated by the
absence of TLR9. Therefore our LLSI mice provide a novel, rapid and reproducible system for exploring the
effector mechanisms responsible for the induction and regulation of cutaneous lupus. This application will
focus on TLR9 and FasL. As mentioned, TLR9 negatively regulates the development of both cutaneous and
systemic lupus, but whether TLR9 works passively by simply competing with TLR7 for access to the
endosomal trafficking chaperone Unc93B1, or actively by inducing molecules dependent on a TLR9 signaling
cascade that limit inflammation, has not been addressed. We have also recently shown that the development
of skin lesions is completely dependent T cell FasL expression, but whether FasL promotes disease indirectly
by inducing cell death and creating cell debris and/or directly by inducing the production of pro-inflammatory
cytokines is unresolved. Interplay between TLR9 and FasL may be an important amplification loop in LLSI -
TLR ligands induce upregulation of Fas and FasL generates cell debris that can activate endosomal TLRs. We
propose to address the questions by using gene-targeted mice with discriminating mutations for both in vitro
and in vivo (LLSI) studies. In Aim 1, we will use mice that express normal levels of a form of TLR9 that cannot
engage MyD88, and in Aim 2, we will use mice that express a Caspase 8 mutation which removes the
Caspase 8 autocleavage site and thereby prevents FasL-induced apoptosis but not chemokine production.
Together, these studies should help identify the most effective therapeutic strategies for targeting TLR9 and
FasL pathways to prevent or ameliorate the development of cutaneous lupus.