No abstract

Cicatricial pemphigoid is a heterogeneous group of autoimmune subepidermal blistering diseases associated most commonly with autoantibodies to bullous pemphigoid (BP)180 and less frequently with those to laminin 5 or type VII collagen. In addition, a few cases have been described with autoantibodies to the beta4 subunit of alpha6beta4 integrin. We describe a patient with extensive disease of ocular, oral, pharyngeal, laryngeal and genital mucous membranes that healed with scarring of conjunctivae. IgG autoantibodies bound to the dermal-epidermal junction on direct immunofluorescence (IF) microscopy and to the epidermal side of 1 mol L(-1) NaCl-split skin on indirect IF microscopy. Our patient's circulating IgG recognized a 205-kDa protein in extracts of 293T cells transfected with the beta4 subunit of alpha6beta4 integrin and in the cell extract of DJM-1 cells. Our patient's IgG and IgA autoantibodies also reacted with full-length BP180 derived from epidermal extracts and the ectodomain of BP180 (LAD-1) derived from culture supernatant of keratinocytes. In addition, a weak IgG reaction with BP230 was noted. The disease rapidly responded to dexamethasone-cyclophosphamide pulse therapy, and immunoblot reactivity to both beta4 integrin and BP180 decreased according to disease activity.

Background Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 ( TREX2 ) locus in laryngeal ( n = 256) and colorectal cancer cases ( n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). Results Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts ( p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 ( p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients ( p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. Conclusions The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies. Electronic supplementary material The online version of this article (10.1186/s13148-019-0666-5) contains supplementary material, which is available to authorized users.

Quantitative histochemistry (scanning microphotometry) was used to determine the activities of the mitochondrial enzymes NAD-linked isocitrate dehydrogenase (EC 1.1.1.41), L-glutamate dehydrogenase (EC 1.4.1.3) and GABA transaminase (EC 2.6.1.19) in various layers of the hippocampus (middle one third) of young (3-4 months old) and memory-impaired aged rats (28-30 months old). For comparison, determinations of cytochrome c oxidase (EC 1.9.3.1) as a marker for mitochondria and energy metabolism were also performed. The study showed that there was a layered reaction pattern in the hippocampus and that the cellular distribution and the levels of enzyme activity were different. However, the activities of the different enzymes (excepting GABA transaminase and cytochrome c oxidase) were significantly correlated in the hippocampus in both age groups. Age-dependent changes were only observed for NAD-linked isocitrate dehydrogenase and GABA transaminase (significant increases of activities in some layers of the hippocampus, preferentially in the terminal field of the perforant path). From the present study it is concluded that, 1. the enzymatic complement of mitochondria in neurons and glia depends upon layer specific metabolic processes of the hippocampus (also with respect to glutamatergic and GABAergic terminal fields) indicating a layer specific interaction of the enzymes studied to produce or catabolize glutamate and GABA, and 2. the age dependent changes of the studied enzymes are very restricted.

Cicatricial pemphigoid is an autoimmune subepidermal blistering disease of the skin and mucous membranes. We report on eight patients in whom the clinical diagnosis was confirmed by direct immunofluorescence. The patients' age averaged 69 years; seven were female and one male. Initial symptoms were erosions of the oral mucous membranes in four patients, skin blisters in three patients, and in one patient an ocular involvement was the first manifestation of the disease. Indirect immunofluorescence on NaCl-split human skin revealed circulating IgG antibodies binding to the roof of the artificial blister in three patients. Immunoblotting of epidermal and dermal extracts disclosed binding of IgG antibodies of one of these patients to an epidermal 230-kD protein, whereas IgA-antibodies showed no specific binding. In four of five patients with a strong ocular involvement IgA deposits were found by direct immunofluorescence. These studies were done on biopsies of perilesional skin or oral mucous membranes, and they were positive in one patient even before the first ocular lesions appeared. Therefore, finding of IgA deposits by direct immunofluorescence may be taken as a prognostic criterion allowing selection of the proper treatment. We treated six patients with a dexamethasone-cyclophosphamide pulse therapy, while two patients received dapsone orally. The involvement of skin and oral mucous membrane responded well to both regimens, whereas the ocular lesions were progressive, except in one patient. On the basis of our eight cases, we discuss both options and limitations in the treatment of cicatricial pemphigoid and review new aspects of the pathogenesis of this disease.