The Journal of pathology
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The Journal of pathology · Dec 2004
Granulocyte-derived elastase and gelatinase B are required for dermal-epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid.
Epidermolysis bullosa acquisita (EBA) and bullous pemphigoid (BP) are two clinically and immunologically distinct autoimmune subepidermal blistering skin diseases associated with IgG autoantibodies against the dermal-epidermal junction. BP antibodies are directed against the hemidesmosomal antigens BP180 and BP230, and those in patients with EBA target type VII collagen, a major component of anchoring fibrils. While the pathogenetic mechanisms of subepidermal blistering in BP have been previously studied using a passive transfer mouse model, the effector pathways of blister formation in EBA are largely unknown. ⋯ A combination of broad-range protease inhibitors as well as inhibitors of serine and matrix metalloproteases completely abolished dermal-epidermal separation induced by EBA or BP autoantibodies. When characterizing the proteases involved more specifically, selective inhibition of human leucocyte elastase or gelatinase B/MMP-9 was also found to result in suppression of blistering. These findings strongly suggest that elastase and gelatinase B are essential for granulocyte-mediated proteolysis resulting in dermal-epidermal separation in EBA and BP patients' skin.
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The Journal of pathology · Dec 2004
Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer.
Pre-operative 5-fluorouracil (5-FU)-based chemoradiotherapy in locally advanced rectal cancer (UICC-II/III) may significantly reduce local tumour mass. Response to pre-operative treatment, however, varies significantly. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are thought to be important predictors for the efficiency of 5-FU-based treatment. ⋯ For the DPD gene, no significance was found at all. In conclusion, this study shows that TS gene expression in a pretreatment biopsy predicts the response of local rectal cancer to neo-adjuvant 5-FU-based chemoradiotherapy in a high percentage. Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied.
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The Journal of pathology · Nov 2004
ReviewAstrocyte intermediate filaments in CNS pathologies and regeneration.
Astroglial cells are the most abundant cells in the mammalian central nervous system (CNS), yet our knowledge about their function in health and disease has been limited. This review focuses on the recent work addressing the function of intermediate filaments in astroglial cells under severe mechanical or osmotic stress, in hypoxia, and in brain and spinal cord injury. Recent data show that when astrocyte intermediate filaments are genetically ablated in mice, reactive gliosis is attenuated and the course of several CNS pathologies is altered, while the signs of CNS regeneration become more prominent. GFAP is the principal astrocyte intermediate filament protein and dominant mutations in the GFAP gene have been shown to lead to Alexander disease, a fatal neurodegenerative condition in humans.
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The Journal of pathology · Sep 2004
Early-onset gastric carcinomas display molecular characteristics distinct from gastric carcinomas occurring at a later age.
Gastric cancer is thought to result from a combination of environmental factors and accumulation of specific genetic alterations, and consequently mainly affects older patients (>50 years of age). Fewer than 10% of patients present with the disease before 45 years of age and these young patients are thought to develop carcinomas with a different molecular genetic profile from that of sporadic carcinomas occurring at a later age. Forty early-onset gastric carcinoma resection specimens were characterized for microsatellite instability (MSI) and loss of heterozygosity status using 22 polymorphic microsatellite markers. ⋯ No correlation was observed between non-functional E-cadherin and the histological type of the tumours analysed. Finally, Epstein-Barr virus was not detected in any of the cases analysed. On the basis of these results, early-onset gastric carcinomas appear to have characteristics distinct from gastric carcinomas occurring at a later age.
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The Journal of pathology · Jul 2004
Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2).
Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a new coronavirus, SARS-CoV. Pulmonary involvement is the dominant clinical feature but extra-pulmonary manifestations are also common. Factors that account for the wide spectrum of organ system involvement and disease severity are poorly understood and the pathogenesis of SARS-CoV infection remains unclear. ⋯ Moreover, the interaction between SARS-CoV and the immunological or lymphoid system remains to be defined. It is clear that we are only at the dawn of our understanding of the pathogenesis of SARS. As our knowledge of the pathogenic mechanisms improves, a more rational approach to therapeutic and vaccine development can be designed in order to combat this new and fatal human disease.