Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation in many organs. Dermatitis is one of the most common manifestations of SLE, which requires constant treatment to control lesions. Lupus dermatitis can cause scarring and disfigurement in patients. Little is known about its pathogenesis. MRL-lpr and MRL+/+ mice that develop multi-organ inflammation have been used to study mechanisms of SLE. We have adopted this model to investigate pathogenesis of lupus dermatitis. Skin has a specialized immune system that includes specialized dendritic cells called Langerhans cells (LC) and specialized 34 T cells called dendritic epidermal T cells (DETC). LCs and DETC reside side by side in the skin. It is unclear how these two immune cells interact in vivo and whether impairments in these interactions contribute to the development of lupus dermatitis. LCs constantly migrate to carry skin antigens to skin draining lymph nodes, where they are believed to tolerize skin-reactive T cells and prevent autoimmunity. Guided by our preliminary data, we hypothesize that impaired migration of LC is a major mechanism that drives the development of lupus dermatitis. To test this hypothesis, we will first assess the migratory capacity of LC in lupus dermatitis-prone mice using newly generated Langerin (Lang)-eGFP knock-in MRL mice that express enhanced green fluorescent protein [eGFP] driven by a langerin promoter, which allows a clear detection of LC. To evaluate the role of LC in the development of lupus dermatitis, we will use newly generated Lang- DTR.eGFP knock-in MRL mice in which LC can be ablated in a time-specific manner. These mice will be used to test the specific hypothesis that impaired LC migration contributes to the development of lupus dermatitis. We will then begin to delineate mechanisms underlying impaired LC migration in lupus. Guided by our preliminary data, we will test the hypothesis that CD1d regulates LC migration and development of lupus dermatitis although through activation of skin 34 DETC and not in a traditional role of stimulating natural killer T cells. We will investigate whether 34 DETC in fact represent a novel subset of CD1d-reactive T cells, and CD1d-binding glycolipids increase 34 DETC, improve LC migration, and ameliorate lupus dermatitis. Our goal in this application is to understand how various immune cells in the skin interact to regulate the development of immune-mediated inflammation. The knowledge gained will have major implications for the development of new therapies to boost organ-specific immunity via specialized 34 T cells that reside in tissues.
Lupus dermatitis is an autoimmune-mediated damage to skin, which can cause significant scarring, disfigurement and morbidity. This application will investigate mechanisms involved in the development of lupus dermatitis. In particular, the application will focus on patho-physiological roles of skin dendritic cells, which will have important implications for vaccination and other inflammatory diseases that involve skin.
|Lam, Larry; Halder, Ramesh C; Montoya, Dennis J et al. (2015) Anti-inflammatory therapies of amyotrophic lateral sclerosis guided by immune pathways. Am J Neurodegener Dis 4:28-39|
|King, Jennifer K; Philips, Rachael L; Eriksson, Anna U et al. (2015) Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease. J Immunol 195:464-76|
|Yang, J-Q; Kim, P J; Halder, R C et al. (2013) Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus. Clin Exp Immunol 173:18-27|
|Singh, Ram Raj; Yang, Jun-Qi; Kim, Peter J et al. (2013) Germline deletion of ýý2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus. Arthritis Res Ther 15:R47|
|Jacinto, J; Kim, P J; Singh, R R (2012) Disparate effects of depletion of CD1d-reactive T cells during early versus late stages of disease in a genetically susceptible model of lupus. Lupus 21:485-90|
|Yang, Jun-Qi; Kim, Peter J; Singh, Ram Raj (2012) Brief treatment with iNKT cell ligand ýý-galactosylceramide confers a long-term protection against lupus. J Clin Immunol 32:106-13|
|Khanna, Dinesh; Saggar, Rajeev; Mayes, Maureen D et al. (2011) A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum 63:3540-6|
|Yang, Jun-Qi; Wen, Xiangshu; Kim, Peter J et al. (2011) Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner. J Immunol 186:1512-20|
|Divekar, Anagha A; Khanna, Dinesh; Abtin, Fereidoun et al. (2011) Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis. Clin Immunol 141:293-303|
|Divekar, Anagha A; Dubey, Shweta; Gangalum, Pallavi R et al. (2011) Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu. J Immunol 186:924-30|
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