Background/Purpose: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases with distinct clinical and immunopathological features. Epigenetic modifications, particularly DNA methylation, contribute to immune dysregulation in these diseases. While SLE is characterized primarily by type I interferon (IFN) pathway activation, RA involves complex inflammatory pathways. Both are complex human diseases which share synovitis as a feature. Understanding ancestry-specific methylation patterns in immune cell subsets may elucidate disease mechanisms and explain differences in disease severity and response.

Methods: We performed genome-wide DNA methylation profiling using Infinium MethylationEPIC v1.0 on sorted B cells, monocytes, and T cells from Black (24 SLE and 21 RA), First American (22 SLE and 27 RA), and White (25 SLE and 24 RA) female patients with SLE or RA and with age-matched healthy controls (n=30/ancestry). Probes above the limit of detections based on negative controls and samples with < 1% poor-quality probes were retained for subsequent analyses. Additionally, probes associated with known single nucleotide polymorphisms were also excluded. Differentially methylated regions were identified and analyzed with respect to immune pathways and ancestry.

Results: Overall, the differences observed in SLE and RA highlight methylation signatures that are unique to both diseases (Fig 1). In SLE, B cells and monocytes from Black and First American patients exhibited significant hypomethylation in type I Interferon (IFN) response genes (MX1, IFITM2, IFITM1, IFI44L), consistent with IFN hypersensitivity, a signature absent in White patients (Fig 1 B&C). First American T cells demonstrated hypermethylation of Toll-like receptor (TLR) response genes (MYD88 and TLR9)., whereas White and Black T cells showed no significant changes in these pathways. In contrast, RA patients showed distinct methylation patterns: White monocytes displayed uniquely hypermethylated regions related to vitamin B12 metabolism (LMBRD1 and MMADHC), and T cells exhibited hypermethylation in TLR-related genes (MYD88, TLR9, JUN, and IRF7). AI and Black RA patients displayed minimal methylation alterations in these immune cell types. These findings underscore divergent epigenetic regulation between SLE and RA, with SLE marked by IFN pathway dysregulation predominantly in Black and First American ancestries, and RA characterized by metabolic and TLR pathway methylation changes primarily in WHITE patients (Fig 1).

Conclusion: Ancestry-specific DNA methylation signatures in SLE and RA distinct immune pathway involvement. The pronounced type I IFN hypomethylation in Black and First American SLE patients contrasts with the unique methylation of vitamin B12 and TLR-related genes in White RA patients. These results highlight the necessity of incorporating ancestry and disease context in epigenetic studies to better understand autoimmune pathogenesis and guide personalized therapeutic strategies.

A, Circular Manhattan plot showing distinct methylation profiles among different genetic ancestries between SLE and RA patients when compared to HC for B, T, and monocytes. B. Differential methylated region analyses for each sorted immune cell population. C. Gene set enrichment analyses of hyper- and hypomethylated genetic regions revealed different cellular pathways unique to disease and genetic ancestry within all three sorted immune cells.

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/dna-methylation-signatures-in-systemic-lupus-erythematosus-and-rheumatoid-arthritis-highlight-divergent-immune-pathways/