Pathophysiology of cutaneous lupus erythematosus

Abstract

The pathophysiology of cutaneous lupus erythematosus (CLE) encompasses the complex interactions between genetics, the environment, and cells and their products. Recent data have provided enhanced understanding of these interactions and the mechanism by which they cause disease. A number of candidate genes have been identified which increase the risk of developing CLE. Ultraviolet radiation, the predominant environmental exposure associated with CLE, appears to initiate CLE lesion formation by inducing apoptosis, precipitating autoantigen presentation, and promoting cellular production of specific cytokines. Autoantibodies are a well-known entity in CLE, but their exact role remains unclear. Finally, cells ranging from native skin cells to innate and adaptive immune cells produce cytokines and other molecules and play specific roles in lesion formation and perpetuation. Native skin cells implicated in CLE include keratinocytes and endothelial cells. Innate immune cells crucial to CLE pathophysiology include dendritic cells and neutrophils. The primary adaptive immune cells thought to be involved include Th1 cells, Th17 cells, cytotoxic T cells, and invariant natural killer T cells. Though the pathophysiology of CLE has yet to be fully characterized, current research provides direction for future research and therapies.

Fig. 1

Keratinocytes (KCs) produce cytokines and pro-inflammatory molecules in response to ultraviolet (UV) radiation and other damage. These cytokines recruit and activate members of the innate immune system, including macrophages, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Endothelial cells also recruit cells from the innate immune system through adhesion molecules and glycosaminoglycans (GAGs). Endogenous DNA from apoptosis and neutrophil extracellular traps enhance cytokine production by pDCs. pDCs produce interferon (IFN)-α, which recruits members of the adaptive immune system, including Th1 and cytotoxic T cells (CTLs). Th1 cells produce IFN-γ that activates macrophages and CTLs and upregulates its own production. CTLs prime KCs and other cells for apoptosis through granzyme B (GrB), which activates caspases in the target cells. KCs recruit invariant natural killer T cells (iNKTs) through enhanced expression of the antigen-presenting molecule CD1d. iNKTs produce IFN-γ among other cytokines. Various immune cells promote differentiation and activity of Th17 cells through the production of IL-6. Th17 cells produce IL-17. Activity of these cells and cytokines lead to lesion formation and perpetuation characteristic of cutaneous lupus erythematosus. MMP, matrix metalloproteinase; TLR, Toll-like receptor