Project Overview

Dr. Darrah and Dr. Tiniakou: A group of patients with scleroderma (20-45%) makes immune responses against a protein normally present in the body called topoisomerase-I (Topo-I). Patients with these immune responses commonly have fibrosis over a large portion of their skin, scar tissue in the lung, and a higher risk of death. While it is known that these immune responses develop, it is unknown why Topo-I is targeted in these patients or what parts of the Topo-I molecule are driving these responses. A genetic analysis was recently performed on blood samples from African American patients with scleroderma enrolled in the Genome Research in African American Scleroderma Patients (GRASP) cohort, through support from the SRF. Analysis of GRASP and patients from other demographic backgrounds has shown that immune responses to Topo-I are linked to a specific gene called HLA-DPB1*13:01. This gene encodes for a molecule that works by selecting “hot spots” within a protein to present to the immune system and triggering immune responses against the protein. The finding that this specific gene is found in patients with immune responses to Topo-I suggests that it may be involved in picking out the hot spots within the Topo-I protein that patients with scleroderma make immune responses against.

We have developed a technique to identify hot spots within proteins that become targets of the immune system in patients with scleroderma. Our study will use this new technique to identify the hot spots in Topo-I that are presented by HLA-DPB1*13:01 using white blood cells isolated from patients with scleroderma.

How this work will impact patients

The results of this study have the potential to unveil characteristics of the autoimmune response in a severe group of patients with scleroderma. In addition, it may pave the way for new tools for disease monitoring and diagnosis, as well as the development of treatments that specifically block immune responses against Topo-I without knocking down other aspects of the immune system.

Role of the Scleroderma Research Foundation

The SRF has enabled us to translate into reality an idea that originated directly from the GRASP Project. We look forward to working with the SRF to unravel the immunologic role of this molecule in patients with scleroderma.