Alteration of epigenetic programs of HSPC underlies the chronic activation of innate cells in SLE

Immune cells are overactivated in people with systemic lupus erythematosus (SLE). While the exact cause is not fully understood, this may be linked to chronically high levels of inflammatory molecules called type 1 interferons (IFN-I). Increased IFN-I activity is one of the key features of SLE, and in 2021, the FDA approved anifrolumab-fnia (Saphnelo®), which blocks IFN-I, for the treatment of SLE. However, many questions remain, including how IFN-I is induced (turned on), which cells produce excess IFN-I, and how people with SLE can have high levels of IFN-I in their bloodstream for years.

Stem cells are cells that can develop into many different types of cells and are the foundation for all organs, tissues, and cells. Hematopoietic and Progenitor Stem Cells (HSPCs) are a type of stem cell that can develop into all types of blood cells, including immune cells like monocytes, dendritic cells, T cells, and B cells. These HSPCs influence the characteristics of mature immune cells. Dr. Barrat will test whether changes in HSPCs might explain the chronic activation and overproduction of IFN-I in mature immune cells in SLE.

Dr. Barrat and his collaborator Dr. Josefowicz previously found that changes in monocytes (a type of white blood cell) from people infected with COVID-19 that are affected with long-COVID, stemmed from alterations in their HSPCs. Similarly, Dr. Barrat will study whether HSPCs in people with SLE serve as “reservoirs” of inflammation-induced changes that reflect the chronic IFN-I response in mature cells. In collaboration with Dr. Mary Crow at HSS, he will conduct an in-depth study of HSPCs from people with SLE with high IFN-I production, those with low IFN-I production, individuals with SLE before and after treatment with anifrolumab, and healthy individuals. He will then analyze mature immune cells to find a link between changes in HSPCs and the disease-related features of these mature cells.

What this means for people with lupus:

Chronic activation of immune cells and overproduction of IFN-I are key features of SLE, but the root cause is not understood. Findings from Dr. Barrat’s study could uncover the underlying cause of these features and identify specific subsets of HSPCs associated with SLE, leading to new therapeutic approaches to better manage the disease.

Multiple autoimmune diseases have been associated with the inability to control the production of type I IFN (IFN-I), and the presence of an IFN-signature has been described in a series of autoimmune conditions, including systemic lupus erythematosus (SLE). A striking aspect of this IFN-signature, is the observation is that these high levels of IFN-I can be sustained for years, suggesting processes that maintain the chronic activation of immune cells, some of which have a fairly short half-life. In a collaborative study with Dr. Josefowicz, a co-investigator on the proposal, we recently described epigenetic changes in monocytes from patients previously infected with SARS-CoV-2 and who developed long-COVID. We showed that these changes did originate from epigenetic alterations in hematopoietic stem and progenitor cells (HSPC) from these patients. HSPCs are long-lived self-renewing precursors to diverse mature immune cells, and it is now recognized that certain stimuli can lead to epigenetic changes in HSPCs that are carried over to mature progeny cells, resulting in an enhanced capacity upon restimulation, a phenomenon termed innate immune memory or trained immunity. Functionally, we observed that HSPC reprogramming following the infection by SARS-CoV-2 had profound impact on the functional response of circulating monocytes. We are now showing in new preliminary data from our collaborator Dr. Niec, that alterations in HSPC subsets also exist in patients with Inflammatory Bowel Disease (IBD), with the presence of unique “pathogenic” HSPC subsets present in excess in IBD patients. In this project, we propose to test the hypothesis that, similarly to what we observed in COVID-19 and IBD, the unique potential of HSPCs to serve as reservoirs of inflammation-induced epigenetic memory will reflect the inflammatory phenotype and chronic IFN-I response found in immune cells in patients with SLE. Specifically, we will use a novel technique developed by the Josefowicz Laboratory to enrich and analyze rare circulating CD34+ HSPC (~0.05% of PBMC) from the blood of SLE patients. This strategy allowed to overcome the impracticalities of obtaining HSPC from bone marrow to study hematopoiesis and epigenetic memory in human disease. We will conduct deep profiling of the CD34+ cells by combined snRNA/ATAC-seq and will study whether alterations in HSPC correlate with pDCs and monocytes functional responses. Patients will be selected in collaboration with Dr. Peggy Crow, a co-investigator, based on the presence of the IFN-I signature and will include patients pre and post treatment with the anti- IFNAR drug Anifrolumab.

Hence, our multi-pronged approach of transcriptional and epigenetic analysis will take us to the root of the inflammatory response in SLE patients which may identify the underlying cause of the IFN-I signature and will provide new opportunities to specifically target disease-associated HSPC subsets for this hard-to-treat disease.