Targeting the CXCR3 Chemokine Axis in Cutaneous Lupus
The study and what it means for patients:
“Some patients with lupus develop a form of the disease that primarily affects the skin – cutaneous lupus. We are trying to determine what attracts harmful immune cells into patients’ skin and whether existing drugs can keep the cells out to prevent damage. These results could lead to clinical trials to test these drugs in patients with cutaneous lupus.”
In patients with lupus, immune cells mistakenly attack the body’s tissues. The skin is their main target in people who have the cutaneous type of the disease. Earlier studies suggested that molecules known as chemokines trigger immune cells to infiltrate the skin, but the source of these molecules wasn’t clear. Using samples from the blisters on participants’ skin, we will identify the specific cells that produce the chemokines. To go one step further and test a possible therapeutic approach, we will then treat mice that develop lupus skin symptoms with several drugs known to inhibit the effects of the chemokines in different ways. Some of these drugs are approved for treating other diseases, such as rheumatoid arthritis. Our findings could indicate whether these drugs should be tested in patients with cutaneous lupus and may also enable researchers to develop new drugs that block the chemokines but have fewer side effects.
Cutaneous lupus erythematosus (CLE) is a chronic autoimmune skin disease characterized by inflammation that predominates on sun-exposed skin. In addition to the morbidity of cutaneous lupus alone, skin manifestations indicate a predisposition for developing systemic lupus erythematosus (SLE), which also has devastating health consequences, including kidney and brain involvement leading to renal failure and neurologic disease. Understanding the pathophysiology of CLE will lead to better diagnostics and identify new treatment targets for both skin-limited and systemic disease. The CXCR3 chemokine ligands are upregulated in lesional skin from lupus patients, and they are likely responsible for recruitment of lymphocytes into the skin. However, the cellular sources of CXCR3 ligands and their contributions to lupus pathogenesis are unknown. Finding the sources of the ligands is important, as recent data that I generated revealed that the cell-specific context of CXCR3 chemokine expression in the skin determines whether the ligands will provide a pro-inflammatory or anti-inflammatory signal during the progression of vitiligo. Further, we found that identifying the cellular sources of these chemokines allows for more targeted treatment options with potentially higher efficacy. Preliminary data from gene expression analysis on human CLE skin samples reveal that CXCR3 ligands are indeed elevated in the skin, with different cell-specific gene signatures present in the different CLE subtypes. In this proposal, we will examine CXCR3 expression in cutaneous lupus patients using a novel suction blister biopsy technique, and will determine which cells produce CXCR3 ligands in the skin. To reveal the functional significance of this, we will use a novel CLE mouse model developed by Dr. Rothstein to target CXCR3 and its ligands in different cell types. Lastly, we will determine the usefulness of therapies targeting the CXCR3 chemokine axis, including JAK inhibitors and neutralizing antibodies, in our CLE mouse model. In total, this project will reveal the cell-specific chemokine context of CXCR3 ligands in CLE, which will provide important insight into the pathogenesis and may ultimately allow for identification of novel biomarkers and targeted therapeutic options.