Scleroderma, or systemic sclerosis, is an autoimmune disease characterized by abnormalities in the blood vessels, thickening and scarring of the skin and internal organs, and abnormal development of immune responses to proteins normally present in the body. Typically, our immune response is programmed to fight infections and cancer, but in the case of autoimmune diseases like scleroderma, specific immune cells called T cells misdirect the attack towards healthy tissues and proteins normally found in our bodies. These T cells are activated by specific “hot spots” within proteins called peptides, which are presented by scaffolds known as HLA molecules. The role of HLA molecules is to activate T cells against the particular peptides they present in order to initiate a specific immune response. These HLA molecules are highly diverse in the human population and are often used clinically – for example, to screen for compatibility and safety in transplant patients.
A subset of patients with scleroderma who have more severe lung and skin disease, as well as a higher rate of death, develop immune responses to a protein called Topoisomerase, or “Topo” for short. In this study, researchers at Johns Hopkins sought to identify the importance and role of these HLA molecules and which peptides within Topo they present. The goal of the study was to shed light on why and how the immune system attacks healthy tissues in patients with scleroderma, despite the fact that they possess diverse HLA molecules. These peptide-HLA complexes could ultimately be used as tools to diagnose, monitor, and even treat the disease.
Why was this done?
In patients with scleroderma, the immune system mistakenly attacks healthy tissues. However, the presentation of peptides within the Topo protein by HLA molecules, a key step in the initiation of an autoimmune response, has not been studied in scleroderma. Therefore, Hopkins researchers sought to identify these peptides in order to understand how Topo erroneously becomes a target of the immune system in patients with diverse genetic backgrounds.
How was this study done?
Immune cells were isolated from the blood of patients with Topo-positive scleroderma followed at the Johns Hopkins Scleroderma Center. These cells were then incubated with Topo protein, during which the cells chopped up the protein and selected peptides to present on their HLA molecules. These peptides were subsequently isolated and analyzed. Finally, in order to determine the biological and clinical relevance of the identified peptides, the research team investigated whether patients with Topo-positive scleroderma had T cells that recognized these peptides and whether this T cell response correlated with any clinical features of scleroderma, such as skin or lung disease.
What were the major findings?
The researchers analyzed whether peptides from the Topo protein were commonly presented between patients with different HLA molecules and whether those HLA molecules shared features that might allow for the generation of scleroderma in individuals with diverse genetic backgrounds. The study revealed that a common group of Topo peptides was presented by diverse HLA molecules and activated patient T cells, in addition to identifying important similarities between the HLA molecules possessed by Topo-positive patients. They thus identified features on both sides of the peptide-HLA interaction that contributed to the presentation of common Topo peptides, which may explain why patients with different genetic backgrounds can develop the same autoimmune response. This study additionally demonstrated that the patients who possessed T cells against the majority of those peptides had more severe interstitial lung disease (ILD).
What is the impact of this work?
This is the first study to identify biologically and clinically relevant features of the peptide-HLA interaction that may contribute to the development of shared immune responses and lung disease among scleroderma patients – an important step toward our understanding of the pathogenesis of scleroderma. These findings additionally have the potential to inform new diagnostic tools and treatments for this complex and poorly understood disease, which is currently lacking in definite diagnostic criteria and safe, effective therapies.
This research was supported by:
- Rheumatology Research Foundation
- Jerome L Greene Foundation
- Scleroderma Research Foundation
- NIH P30 Bayview Immunomics Core Facility
Tiniakou E, Fava A, McMahan ZH, Guhr T, O’Meally RN, Shah AA, Wigley FM, Cole RN, Boin F, Darrah E. Arthritis Rheumatol. 2020 Mar 12. doi: 10.1002/art.41248. [Epub ahead of print]