Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity

Abstract

SUMMARYKeratinocyte cytotoxicity is an important component of the immunopathology of photosensitive lupus erythematosus, and antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be an important mechanism by which autoantibodies, especially those specific for SS-A/Ro, can induce keratinocyte damage in models of photosensitive lupus. We provide further evidence that keratinocytes from patients with photosensitive lupus show significantly greater ultraviolet radiation (UVR)-induced cytotoxicity, and that ADCC of these targets is especially enhanced by autologous patient's serum or by anti-SS-A/Ro þ sera. Keratinocytes from normal uninvolved skin of 29 patients with cutaneous lupus erythematosus (LE) were grown in cell culture and tested as targets in cytotoxicity experiments in vitro. Cultured keratinocytes from patients with systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE) showed significantly greater cytotoxicity following UVR treatment than did keratinocytes from normal adult controls or from neonatal foreskins (P < 0·01). The same cultures also showed greater UVR-induced binding of IgG from fractionated anti-SS-A/Ro þ preparations. ADCC experiments were also performed using keratinocytes cultured from patients with SLE, SCLE, discoid lupus erythematosus (DLE), and normal controls. When keratinocytes were incubated in autologous serum plus a standard mononuclear cell effector population, the percentage of ADCC observed was significantly greater in cultures containing keratinocytes and sera from the SLE and SCLE patients (P < 0·001). When cultured keratinocytes were added to different IgG antibody probes, plus standard mononuclear effector populations, greater ADCC was seen using the anti-SS-A/Ro probe and keratinocytes from patients with SLE or SCLE. With normal human neonatal keratinocyte targets, the anti-SS-A/Ro probe induced greater ADCC than that seen with anti-ssDNA or normal human serum. We have shown that keratinocytes from patients with some forms of lupus erythematosus (SLE and SCLE) show greater cytotoxicity in vitro when irradiated with UVR, and greater susceptibility to ADCC whether the antibody source is their own serum or an anti-SS-A/Ro probe.

The pathophysiology of photosensitivity in lupus erythematosus

“…The ability of ultraviolet light to induce apoptotic death in suprabasal keratinocytes has been recognized for many years and these cells were called ''sunburn cells'' by morphologists (89). However, cultured keratinocytes from patients with SLE and SCLE show significantly greater cytotoxicity following UV exposure than keratinocytes from normal adult controls (67,69). There are a number of different ways whereby UV light can induce cell death in keratinocytes.…”

Two Approaches to the Study of a Controversial Relationship: Cutaneous Photosensitivity and Anti-Ro/SS-A Autoantibodies

“…However, there are many studies that indicate a positive relationship between anti-Ro Aabs and CP, like the ones which measure the binding of sera containing antiRo Aabs from patients to self-derived irradiated keratinocytes [18][19][20]. These studies were always performed with sera which were tested by various techniques to be only specific for one autoantigen, among 4 or 5 different ones.…”

“…It has been demonstrated that UVr driven apoptotic keratinocytes relocate RNPs towards the cell membrane [15,16] and this event could, on a first instance, induce the production of Aabs [17]. Subsequently these circulating Aabs could bind to the apoptotic keratinocytes' membrane, producing Aabs mediated cytotoxicity, finally leading to an unwanted inflammatory response, which under normal conditions would not take place [18]. These events are proposed to be relevant in the generation of cutaneous damage in SAPs patients.…”

Phototherapy for mycosis fungoides in a patient with coincident systemic lupus erythematosus

“…Five cases have previously been reported in the skin. [1][2][3][4][5] Here we report a case occurring in the skin of the forehead.…”

“…However, it has been reported that the percentage of the SLE patients who are photosensitive to ultraviolet radiation is only 60%. 4 It has also been reported that UVA1 is beneficial in several cases. 5 In our patient, phototherapy did not cause a flare of the SLE.…”