Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease for which specific etiologic agents remain largely unclear. Several lines of evidence suggest that gene-environment interactions leading to inhibition of DNA methylation and overexpression of methylation-sensitive immune genes contribute to SLE development and progression [1,2]. Although SLE has traditionally been referred to as a disease of reproductive-age women, recent epidemiologic evidence upends this perception as overly simplistic [3]. Whereas Black women experience peak SLE incidence in their 20s, highest incidence for White women generally occurs in their 50s (around the average age of menopause) and for men in their 70s [[4], [5], [6], [7]]. One interpretation is that aging is an integral component of SLE risk, albeit unevenly expressed across groups. The accelerated development of SLE in Black women is compatible with the “weathering hypothesis”, which depicts the concept of faster, stress-related biological aging in historically marginalized groups [8,9].

DNA methylation is an epigenetic mechanism that silences gene expression by promoting a chromatin configuration inaccessible to transcription factors. In dividing T cells, suppression of DNA methylation—through direct inhibition of DNMT1 methyltransferase, or reduction of PkC-δ signaling by oxidative stress or agents associated with drug-induced lupus—converts normal CD4+ T cells into autoreactive, cytotoxic, and proinflammatory T cells that can cause lupus-like disease in animal models [[10], [11], [12]]. CD70, a B cell costimulatory ligand encoded by the CD70 gene (also known as TNFSF7), has been depicted as hypomethylated and overexpressed in T cells both in lupus and when treated with lupus-inducing drugs [13,14]. Its overexpression leads to increased B cell co-stimulation and concomitant immunoglobulin overproduction. Prior studies of DNA methylation in lupus have been limited by relatively small sample sizes in tertiary care settings and lack diversity reflective of the general population. While methylation of CD70 has not been detailed in association with age, CD70 gene expression in T lymphocyte subsets has been correlated with age in healthy persons, and CD70-expressing T cells from elderly persons demonstrate increased susceptibility to apoptosis [15].

We have performed a population-based, immunoepidemiology study characterizing CD70 DNA methylation patterns in T lymphocyte subsets in SLE and controls. Methylation, in contrast to gene expression, has the potential to serve as a more stable marker of environmental insults or alterations at this gene. As such, we have interrogated CD70 methylation associations with age and race, which may have implications related to weathering and SLE expression.