High Ro52 Expression in Spontaneous and UV-Induced Cutaneous Inflammation

Abstract

Ro52 is an E3 ubiquitin ligase with a recently identified regulatory role in inflammation. The protein is targeted by autoantibodies in rheumatic diseases, and Ro52 autoantibodies are specifically associated with cutaneous lupus erythematosus (CLE) and photosensitivity. The aim of this study was to investigate cutaneous Ro52 expression in CLE patients and to examine whether UVR might modulate Ro52. Ro52 expression was assessed by immunohistochemistry in biopsies derived from CLE lesions (n=25), nonlesional (n=7), and healthy control skin using four anti-Ro52 mAbs generated by us. Ro52 expression was also analyzed in psoriatic, lichenoid, and eczematous lesions. It was increased in the epidermis of spontaneous CLE lesions as compared with unaffected skin of patients and healthy controls. High epidermal Ro52 expression was also observed in other inflammatory dermatoses investigated. Ro52 was upregulated in experimentally photoprovoked CLE lesions as observed by immunohistochemistry in sequential biopsies, which was confirmed in vitro both at the mRNA and protein levels by exposing cultured patient-derived primary keratinocytes to UVR. In conclusion, Ro52 expression is upregulated in keratinocytes in inflammatory skin conditions and in response to UVR. High Ro52 expression might lead to the breaking of tolerance and the generation of Ro52 autoantibodies in genetically susceptible subjects. Further, the upregulation of Ro52 in keratinocytes after sun exposure might also be a triggering factor for skin lesions in patients with Ro52 antibodies.

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

“…Spontaneous SLE has been linked to alterations in expression (57) and activation of TLR7/9 (17, 18), dysregulation of the cytosolic sensors p202 and AIM2 (24,25), and polymorphisms (21) and heightened expression in TRIM21 (22). We now define that defective degradation of FcγR-bound cargo in the lysosome is a critical upstream event that overburdens the phagolysosome.…”

“…Polymorphisms in the sensor that recognizes cytoplasmic IgG (tripartite motif containing 21; TRIM21; ref. 21), and heightened expression of TRIM21 (22) and its regulated genes (22,23), have been identified in SLE patients. Further, two cytosolic sensors that recognize dsDNA (p202 and absent in melanoma 2; AIM2) have been implicated in type 1 interferon (IFN) production in murine lupus (24,25).…”

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

“…A large number of TRIM genes are induced by type I or type II IFNs (e.g., during viral or bacterial infections) (20,21). Interestingly, some TRIM genes are also overexpressed in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, suggesting that TRIM proteins participate in the pathogenesis of these diseases (22)(23)(24). Trim21 is induced by both type I and type II IFNs and is overexpressed in patients with systemic lupus erythematosus and Sjögren's syndrome compared with healthy controls (23,24).…”

“…Interestingly, some TRIM genes are also overexpressed in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, suggesting that TRIM proteins participate in the pathogenesis of these diseases (22)(23)(24). Trim21 is induced by both type I and type II IFNs and is overexpressed in patients with systemic lupus erythematosus and Sjögren's syndrome compared with healthy controls (23,24). The molecular mechanisms regulating Trim21 expression are unknown, but because Trim21 is induced by IFNs we hypothesized that transcription factors activated by IFN signaling control Trim21 expression.…”

Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: A randomized, vehicle-controlled, double-blind study

“…24 Meanwhile this testing regimen has received much attention because phototesting is not only an optimal way to evaluate photosensitivity in patients with CLE, but the reproducibility of inducing skin lesions by UVA and UVB irradiation makes it an ideal model for several experimental approaches, which allow the study of inflammatory and immunologic events that take place before and during lesion formation. [25][26][27][28] Most interestingly, the phototesting studies showed that the development of skin lesions in patients with CLE is characterized by a latency period for up to 3 weeks in contrast to other photodermatoses, such as polymorphous light eruption (PLE). 24 Therefore, most patients with CLE are not aware of the link between sun exposure and their disease and deny any effect of UV irradiation on the induction or outcome of their cutaneous lesions.…”