UVR Light Causes Exposure of Autoantigens to the Immune System

SCLE and neonatal LE are associated with the presence of antibodies to Ro/SSA and La/SSB (Mond et al. 1989, Sontheimer et al. 1982). The importance of anti-Ro/SSA antibody in the pathogenesis of SCLE is demonstrated by the fact that the lesions of neonatal LE resolve within a few months of onset, likely with the degradation of maternal antibodies (Lee and Farris 1999). These antibodies are necessary but insufficient for the development of SCLE, demonstrating that there are multiple factors required for the development of autoimmunity.

The link between apoptotic cells and the development of autoantibodies was eloquently shown in vitro by demonstrating that during UVB-induced keratinocyte apoptosis, intracellular antigens, including 52-kDa Ro/SSA, ribosomes, calreticulin, and phospholipid complexes, were translocated to two distinct blebs on the cell surface (Casciola-Rosen et al. 1994). Interestingly, during apoptosis, these antigens could be structurally modified by granzyme B, ICE-like proteases, and reactive oxygen intermediates to produce cryptic epitopes that can bind to MHC II molecules and produce an antibody response (Casciola-Rosen and Rosen 1997, Casciola-Rosen et al. 1995,1999).

Studies demonstrate a clonal expansion of T cells from CLE blood and skin, suggesting that lesions may be secondary to antibody-dependent cellular cytotoxicity (ADCC) (Furukawa et al. 1996, Kita et al. 1998). In vitro and in vivo studies show that antibodies from the serum of patients with LE bind to the surface of UVB-irradiated keratinocytes (Furukawa et al. 1990, LeFeber et al. 1984) and that this binding, along with UVB cytotoxicity, increases when using keratinocytes from patients with LE, DLE, or SCLE compared with controls (Furukawa et al. 1999). This increased binding is likely responsible for ADCC to keratinocytes (Furukawa et al. 1994, 1999). Other studies demonstrate that IgG1 anti-Ro/SSA autoantibody can activate complement and ADCC (Bennion et al. 1990). Interestingly, estradiol augments the binding of anti-Ro/SSA and anti-La/SSB antibodies to irradiated keratinocytes, suggesting a link between increased prevalence of SCLE and LE in females (Furukawa et al. 1988). Estrogen likely has a direct effect on the development of autoantibodies, as studies treating lupus-prone mice with tamoxifen have demonstrated a decrease in IgG3 antibodies against DNA and nuclear proteins along with a clinical reduction in proteinuria and a decrease in mortality (Sthoeger et al. 2003).

The exact function of Ro/SSA is unknown, but a recent study demonstrated that it may have a role in cytokine production by activated T cells (Ishii et al. 2003). Recently, a Ro/SSA knockout mouse was developed that was characterized by the development of an autoimmune syndrome with increased sensitivity to light. This suggests that Ro/SSA antibodies may actually contribute to the development of the autoimmune response by allowing cryptic epitopes to be presented to the immune system in response to UV apoptosis (Xue et al. 2003).

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