GRONINGEN, The Netherlands—Sunlight exposure can trigger new cutaneous lesions or lead to increased disease activity in patients with systemic lupus erythematosus (SLE). Dutch researchers reported recently that lupus patients clear ultraviolet (UV)-damaged, apoptotic keratinocyte "sunburn cells" normally from the dermis but that some lupus patients develop inflammatory lesions near accumulations of apoptotic keratinocytes and that these lesions resemble typical lupus skin lesions.¹

These results and related studies throw into sharper relief three basic questions about the connection between sunlight, rash, and lupus exacerbation, Melanie K. Kuechle, MD, and Keith B. Elkon, MD, comment in an editorial.²

"Is there an intrinsic keratinocyte ‘malresponse' to UV that drives inflammation and do apoptotic cells have anything to do with it? Is UV-induced apoptosis relevant to the recruitment of plasmacytoid [dendritic cells] DC? What roles do autoantibodies play in this process?" ask Dr. Kuechle, of the division of dermatology, and Dr. Elkon, with the division of rheumatology, both at the University of Washington School of Medicine, in Seattle.

Clearance of UV-Damaged Skin Cells Effective but Odd in Lupus Patients

The research study by Esther Reefman, MD, of the department of rheumatology and clinical immunology at Groningen University Medical Center, in The Netherlands, examined whether delayed or altered clearance of apoptotic cells after UV irradiation leads to inflammation in the skin of SLE patients. Dr. Reefman and colleagues exposed 15 SLE patients and 13 control subjects to a standardized dose of UVB light, then analyzed sequential skin biopsies over the next 10 days for numbers of apoptotic cells, T-cells, macrophages, and deposition of immunoglobulin and complement. They also compared the cutaneous lesions seen in the research subjects to the skin lesions of 20 SLE patients, with regard to apoptotic cells and infiltrate.

"Clearance rate of apoptotic cells after irradiation did not differ between patients and controls," Dr. Reefman reports. "Influx of macrophages in dermal and epidermal layers was significantly increased in patients compared with controls. Five out of 15 patients developed a dermal infiltrate that was associated with increased epidermal influx of T cells and macrophages but not with numbers of apoptotic cells or epidermal deposition of immunoglobulins....Inflammatory lesions in these patients were localized near accumulations of apoptotic keratinocytes similar [to those] seen in the majority of [lupus erythematosus] LE skin lesions. In vivo clearance of apoptotic cells is comparable between SLE patients and controls. However, the presence of inflammatory lesions in the vicinity of apoptotic cells...suggests that these lesions result from an inflammatory clearance of apoptotic cells."

The researchers suspect that, at least in a subset of lupus patients, the inflammation produced by a single dose of UVB might "represent early LE skin lesions in which apoptotic cells play an inducing role"; these patients developed infiltrates and inflammatory lesions in the vicinity of apoptotic cells, and colocalization of inflammatory lesions and apoptotic cells was often seen in LE skin lesions. The UV-induced infiltrates are interesting, since clearance of apoptotic cells by phagocytes "is usually an antiinflammatory event," the authors write. They suggest that in the patients who developed such infiltrates, the clearance of apoptotic cells was by an inflammatory process.

Drs. Kuechle and Elkon raise the possibility of a deficiency of a p53 response gene. "UVB light induces multiple forms of organelle and genotoxic injury resulting in DNA strand breaks as well as the generation of pyrimidine dimers. Single-stranded breaks are sensed by the ATR (ataxia telangiectasia and rad3 related) kinase, which orchestrates repair pathways and activation of p53. P53, in turn, leads to cell cycle arrest followed by DNA repair or apoptosis," they explain. They suggest that abnormalities in this complex pathway of sensing and repair might result in new skin lesions and systemic worsening of lupus activity.

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References

1. Reefman E, de Jong MCJM, Kuiper H, et al. Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus? Arthritis Res Ther. 2006;8:R156 (doi:10.1186/ar2051).
2. Kuechle MK, Elkon KB. Shining light on lupus and UV. Arthritis Res Ther. 2007;9:101 (doi:10.1186/ar2100).