2011.4-7.Skin

Autoreactive T cells are normally eliminated by 1) functional inactivation (anergy) and 2) activationinduced cell death (AICD; directed apoptosis) through death receptor (Fas) signaling. Other authors have reported that activated T cells of lupus patients resist anergy and apoptosis by markedly upregulating and sustaining COX-2 expression [13]. Inhibition of COX-2 caused apoptosis of the anergy-resistant lupus T cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein) [13]. Studies with COX-2 inhibitors and COX-2 deficient mice confirmed that this COX-2/FLIP antiapoptosis program has been used selectively by anergy-resistant lupus T cells, and not by cancer cells or other autoimmune T cells [13]. Notably, the gene encoding COX-2 is located in a lupussusceptibility region on chromosome 1. The same authors also found that selected COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E2 (PGE2) [13]. These findings could be useful in the design of lupus therapies. Our COX-2 data is consistent with expression of this molecule in the context of clinical lupus erythematosus. The ZAP-70 gene encodes an enzyme belonging to the tyrosine kinase protein family; ZAP-70 plays roles in both T lymphocyte development and activation [14]. The ZAP-70 enzyme, which is phosphorylated on its tyrosine residues upon T cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with Src family kinases. Mutations in the ZAP-70 gene result in a form of severe combined immunodeficiency (SCID) syndrome in humans [14]. ZAP-70 expression is also found in a subset of chronic lymphocytic leukemia patients with unmutated Ig genes and a poor clinical course [14]. LAT, a transmembrane adaptor protein expressed in T lymphocytes, natural killer cells and mast cells, is also an important mediator for TCR signaling [14]. Upon TCR engagement, activated ZAP-70 phosphorylates LAT at multiple conserved tyrosine residues within SH2 binding motifs, exposing these motifs as the docking sites for downstream signaling targets [14]. The phosphorylation process in LAT eventually leads to activation of the corresponding signaling pathways [14]. In regard to the positive staining for BAX, the BAX protein is a pro-apoptotic member of the Bcl-2 family of proteins; BAX is found in many cell types [15]. Bax is a cytosolic protein that translocates to the mitochondria and participates in Cytochrome c release in response to apoptotic stimuli [15]. Aberrant expression of BCL-2 family members can inappropriately promote or prevent apoptosis. Increased expression of BAX is associated with the apoptotic loss of neurons in Parkinson’s disease [15]. Given 1) the presence of junctional zone cytoid bodies in many cases of LE and 2) our BAX IHC findings, the role of BAX proapototic molecules in LE warrants further investigation. Based on our findings, the T cells and the cell signaling cascades are actively targeting not only the BMZ, but also skin adnexal structures; thus, the process may the result in dermal scarring and hair loss in some patients with LE. Additional studies are necessary to further explore and define these pathophysiologic possibilities.