Apoptosis Genes and Photosensitivity in Lupus

Apoptosis is a form of programmed cell death, over 6-48 h, that is characterized by cell shrinkage and nuclear condensation in response to the activation of the enzyme caspase 3 (Elkon 1997, Salmon and Gordon 1999). On early apoptotic keratinocytes, Casciola-Rosen (1997) reported the formation of surface blebs, which are highly enriched with several lupus autoantigens, including Ro/SSA; in genetically susceptible individuals, expression of this autoantigen is proposed to initiate an autoantibody response. Multiple stimuli, including UVR, cytokines, cytotoxic T cells, and cytotoxic drugs, are capable of inducing apoptosis (Arnold et al. 1999, Danno and Horio 1982, Elkon 1997, Haake and Polakowska 1993, Stone et al. 1998). The Fas transmembrane glycoprotein receptor (Fas, encoded by TNFRSF6) has an intracellular death domain that initiates a cascade of events when Fas binds external Fas ligand, leading to death of the cell by apoptosis. In normal human skin, Fas is found mainly in the basal layer of the epidermis; expression then gradually diminishes toward the stratum granulo-sum. The specific role of Fas and Fas ligand in human CLE is still a matter of debate, but both molecules are expressed on infiltrating cells around blood vessels and hair follicles (Fushimi et al. 1998,Nakajima et al. 1997). Consistent with this co-expression of Fas and Fas ligand around hair follicles, apoptotic cells in this region were found (Nakajima et al. 1997).

In murine models, the Fas/Fas ligand axis may be involved in LE. Mice that are homozygous for the Ipr (lymphoproliferation) recessive mutation accumulate large numbers of CD3+ CD4- CD8- T cells, which lead to the induction or acceleration of systemic autoimmunity (Kono and Theofilopoulos 1997, Takahashi et al. 1994). The Ipr mutation on mouse chromosome 19 causes a point mutation in Fas that abolishes its ability to transduce the apoptotic signal.A recent study of MRL/n (control) mice found that they develop LE-like skin lesions later in life than the closely related MRL/lpr (homozygous) mice (Furukawa et al. 1996). In humans,the Fas gene is located on chromosome band 10q24.1 (Inazawaet al. 1992). Huang et al. (Huang et al. 1999) examined a Fas polymorphism, the MvaI RFLP (MvaI*1/ MvaI*2, caused by an A/G SNP at the -670 nucleotide position) in 103 Caucasian patients with SLE and found that MvaI*2 homozygosity was significantly higher in patients with photosensitive SLE, but polymorphic Fas loci have not yet been examined by association or linkage in CLE.

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