Systemic sclerosis (SSc) is a devastating multisystem autoimmune disorder affecting the connective tissue. Cutaneous fibrosis is the most characteristic feature of SSc and is believed to result from the inappropriate activation of dermal fibroblasts by immune mediators and other growth factors produced by infiltrating inflammatory cells, predominantly T cells. In previous studies, we found that dysregulated production by peripheral blood effector CD8+ T cells of the profibrotic cytokine IL-13 correlates with the extent of skin fibrosis and is associated with defects in the molecular control of IL-13 production, such as increased expression of the transcription factor GATA-3. The following are our most recent results. Firstly, we found that IL-13 and CD8+ T cells are highly expressed in the skin lesions of early SSc patients. Secondly, we established that increased numbers of CD8+ T cells expressing skin homing receptors and producing IL-13 are found in the peripheral blood of SSc patients compared to normal controls. Finally, we demonstrated that CD8+ T-cell supernatants from SSc patients induce collagen production by normal skin fibroblasts and that this is inhibited by the addition of an anti-IL-13 antibody. Our preliminary results show that CD8+ T cells in the sclerotic skin of SSc patients express markers of cytotoxicity, such as Granzyme B, and are therefore potentially cytotoxic. Furthermore we show that GATA-3 is also highly expressed by inflammatory cells in the sclerotic skin where it may be associated with the overproduction of IL-13. This evidence supports the central hypothesis of this proposal, that CD8+ T cells are involved in the onset of cutaneous systemic sclerosis by aberrant production of pro-fibrotic IL-13 and cytotoxic damage.
The Specific Aims are designed to establish the unique role of CD8+ T cells in the pathogenesis of SSc and to elucidate the cellular and molecular mechanisms leading to tissue damage and fibrosis in SSc (Aims 1) and to target molecular pathways that could prevent or reverse the process (Aim 2). Since currently there is no therapy that slows or reverses the natural progression of this disabling and often fatal disease, understanding the pathogenic mechanisms of SSc at a molecular level will reveal new therapeutic targets for developing more specific diagnosis and treatment. 1

Public Health Relevance

Systemic sclerosis (SSc) has the highest case fatality rate among the connective tissue diseases. Currently, no therapy has proven effective in modifying the course of the disease, a reflection of the complex pathogenesis of SSc. Identifying the mechanisms underlying the disease is a priority for research efforts. This project aims to establish the cellular and molecular mechanisms underlying autoimmune processes leading to tissue damage and fibrosis in SSc. We expect that our proposal will lead to the development of novel therapeutic strategies aimed at targeting cells involved in the pathogenesis of SSc and the cytokines they produce, with particular emphasis on the molecular pathways governing the expression of pro-fibrotic IL-13.

Agency
National Institute of Health (NIH)
Type
Small Research Grants (R03)
Project #
1R03AR065755-01A1
Application #
8769486
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Mancini, Marie
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213