Apoptosis and Redistribution of the Ro Autoantigen in Balb/c Mouse Like in Subacute Cutaneous Lupus Erythematosus

Abstract

In subacute cutaneous lupus eryhematosus (SCLE) the cutaneous antigens constitute the main source of Ro and La autoantigens. The aim of this investigation was to demonstrate if UV light increases the availability of Ro autoantigen in the skin, also the blocking effect of Ac-DEVD-CMK a caspase inhibitor was assessed. For this purpose newborn Balb/c mice were UVB irradiated (5–30 mJ/cm2) equivalent to a moderate to severe sunburn. Animals were injected with monoclonal anti-Ro antibodies from SCLE patients. Apoptosis was also induced by anti-Fas antibody injection. Skin samples were examined by direct immunofluoresence, by TUNEL, and the expression of caspase 3 by RT-PCR. Major findings of present studies were: 1. UVB irradiation and anti-Fas induced apoptosis of keratinocytes. 2. Apoptosis redistribute the Ro antigen on cell surface and is better triggered by Ro antibody. 3. The caspase 3 inhibitor Ac-DEVD-CMK decreases the availability of Ro autoantigen in epidermis and prevents deposition of anti-Ro. In conclusion, the caspase pathway would be blocked to avoid anti-Ro deposition along skin; this finding would be a prospect in the treatment of SCLE patients.

The Caspase Pathway as a Possible Therapeutic Target in Experimental Pemphigus

“…The Ac-DEVD-CMK peptide has previously been used in lupus experimental models to prevent apoptosis and tissue damage by antibody deposition [26, 27]. Here, we extend these previous observations to pemphigus and confirm the hypothesis that caspases inhibition can prevent blistering in pemphigus [10, 12, 13].…”

Ro60 and La ribonucleoproteins become self-aggregated by cell stress

“…The stress induces changes of the cytoskeleton which is of particular importance because the actin-based cytoskeleton is a sensitive monitor of extra cellular stimuli (26,27). Is well established that stress increases the availability of intracellular antigens on cell surface, in consequence the autoantibodies trigger better antigens produced under cellular stress (28,29), present results confirm this notion, and suggest that the Ro and La redistribution is associated to the cytoskeleton modification; another interesting observation suggest that Ro and La suffer conformational changes and aggregates form transitory complexes with the cytoskeleton proteins through HSP70. As support to our Ro ad La proteins tagged another experimental model have been demonstrated that under UV irradiation Ro and La are shuttled to cell membrane associated to calreticulin and HSP proteins, the transport is executed by the cytoskeleton (30)(31)(32).…”

Pathogenic effects of maternal antinuclear antibodies during pregnancy in women with lupus

“…46 These experiments demonstrated the pathogenic effects of anti-Ro antibodies, suggesting that antibody deposition induces ADCC cytotoxicity, leading to the inflammation and apoptosis of keratinocytes, which release intracellular Ro antigens, creating a pathophysiological loop. 47,48 The cardiac manifestations of NL include variable degrees of CHB, which is manifested as intrauterine bradycardia or low heart rates at birth. These anomalies persist for days or months, depending on the extent of the blockade, and when fibrosis of the atrial node is present, the blockage is permanent.…”