Abstract
Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.
Highlights
Systemic lupus erythematosus (SLE) is complex, chronic, autoimmune disease characterized by hyperreactive B cells and the production of pathogenic autoantibodies [1]
To identify unique features amongst Cutaneous lupus erythematosus (CLE) subtypes, weighted gene correlation network analysis (WGCNA) was performed on an initial discovery skin cohort to identify modules of genes correlating with available patient clinical variables: CLASI, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), systemic versus non-systemic disease status, discoid lupus erythematosus (DLE) versus subacute cutaneous lupus erythematosus (SCLE) status, and IFN score
This analysis identified that the cyan module was one of the modules with the strongest correlation with clinical variables and was significantly higher in DLE compared to SCLE status (Figure 1B)
Summary
Systemic lupus erythematosus (SLE) is complex, chronic, autoimmune disease characterized by hyperreactive B cells and the production of pathogenic autoantibodies [1]. While there are consistently observed cellular and molecular features in patients with CLE and/or SLE, such as a type I interferon (IFN) gene signature in the blood and skin [6,7,8,9,10] and peripheral B cell dysfunction [11, 12], the shared and unique molecular and cellular features of ACLE, SCLE, and CCLE remain poorly understood. DLE is more likely to occur without underlying SLE compared to ACLE or SCLE [2, 15], yet it is not clear if the presence or absence of systemic disease is related to the differences observed in cutaneous manifestations of lupus [16]
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