A 47-year-old Vietnamese woman presented with dystrophic fingernails and toenails that had been present since infancy. She also had developed, in the third decade, pretibial pruritus with vesicle ...formation and progressive localized papules and scars. Multiple family members were similarly affected. Physical examination showed lichenoid papules that coalesced into large plaques that were studded with milia over the pretibial areas and 20 nail dystrophy. A biopsy specimen showed milia-like structures and dermal fibrosis. Pretibial epidermolysis bullosa is a rare variant of dystrophic epidermolysis bullosa that shows appreciable clinical overlap with dystrophic epidermolysis bullosa pruginosa. Both disease subsets are characterized by the late age of onset, nail dystrophy, and predominantly pretibial pruritic lichenoid skin lesion; they are associated with glycine substitution mutations in COL7A1.
Plasticity of immune response and immune education are requisite throughout life as the immune system learns to discriminate what is self from non-self to mount proliferative responses against a ...variety of foreign pathogens. T cells that recognize foreign peptides presented in the context of self by antigen presenting cells are able to undergo repeated cell division and secrete the mitogenic cytokine IL-2. In contrast, T cell anergy is a state of non-responsiveness that may serve to limit autoreactive T cell responses. Because anergic cells show a failure to proliferate and produce IL-2, anergy has often been considered a state of failed activation rather than a specifically dedicated regulatory program. To elucidate the molecular mechanisms behind anergy induction, we chose to examine early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 co-stimulation. GRAIL, Gene Related to Anergy in Lymphocytes, is a novel transcript whose expression was markedly induced in anergic T cells. GRAIL is a novel murine type I transmembrane protein that localizes to the endocytic pathway and bears homology to several RING Zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin-ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for regulation of cytokine transcriptional. Induction of GRAIL expression after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins that are essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype. Associated GRAIL phenotypes such as binding to the Ras family GTPase Rit and dramatic alterations in actin-based cell morphology suggest GRAIL activity occurs along non-conventional pathways upstream of IL-2. GRAIL expression and E3 ligase activity may constitute some part of a novel regulatory pathway. Understanding GRAIL function alongside other anergy-associated genes is likely to reveal broader mechanisms for rapidly changing cell fate in diverse cellular contexts.
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