Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.     

Bathing suit ichthyosis: Two Burmese siblings and a review of the literature

Bathing suit ichthyosis (BSI) is a subtype of autosomal recessive congenital ichthyosis (ARCI) characterized by the development of large platelike scales mainly limited to the trunk. It is caused by temperature sensitive variants in transglutaminase 1, encoded by the gene TGM1. We describe a rare case of intrafamilial variation in phenotypic expressivity in two Burmese siblings with BSI that demonstrates the heterogeneity of the disorder within the same family and even in the same individual across time. We also present a concise review of the genotypic spectrum of BSI from 54 cases reported in the literature as evidence that both environmental and additional genetic factors can significantly alter the clinical phenotype.     

抗肿瘤药物对~(125)I-纤维蛋白原与白血病细胞P388和HL60结合的抑制作用

肿瘤转移是肿瘤患者致死的关键。肿瘤转移涉及很多复杂的过程和机制[1] 。对它们的深入研究将有助于我们了解肿瘤转移过程 ,找出有针对性的治疗方法 ,对提高临床肿瘤的治疗效果有很重要的作用。肿瘤转移与血液系统 ,尤其是与纤维蛋白和纤维蛋白原关系已引起人们长期的关注。纤维蛋白与纤维蛋白原是肿瘤组织的主要基质 ,已经被认为通过下列 3条途径帮助肿瘤转移形成 :①凝结成自身网络帮助肿瘤细胞在上面吸附 ,以利于肿瘤细胞扩增和转移 ;②在肿瘤细胞表面形成包被以抵消宿主淋巴细胞对肿瘤细胞的攻击 ;③帮助肿瘤血管的形成[2 ,3 ] 。因此 ,…     

Ultrastructure and immunohistochemistry of the lateral prostate in aged rats

Ultrastructural, histological, and immunohistochemical studies were performed on lateral prostates of 1) aged rats from different strains, 2) rats permitted different levels of sexual activity, and 3) castrated rats. Antibodies against the following proteins were used as immunohistochemical markers: SVS II from seminal vesicle, LP 28 from lateral prostate, acid phosphatase isoenzymes from ventral prostate, transglutaminase from coagulating gland, and a commercial monoclonal antibody against cytokeratin. SVS II is a marker of lateral prostatic secretion, while immunoreactions to LP 28 and acid phosphatase (pI 7.1) were cytoplasmic. In aged animals the amount of intracellular secretion is decreased, and focally metaplastic transformation can be visualized by using immunohistochemical markers. Epithelial ultrastructure varied considerably with experimental conditions. Intensive sexual activity resulted in increased polymorphism and increased number of secretory granules within the glandular cells, while castration was followed by a rapid loss of secretory material. Also, in rats older than 10 months, a reduction in the number of secretion granules was common. The epithelium developed a positive immunoreaction to transglutaminase antibodies that were not observed in juvenile glands. Cells, presumably macrophages, which had an intense immunoreactivity for transglutaminase, were increased in number both within and outside the prostatic acini of aged rats. The possible interaction between secretory SVS II, a substrate of transglutaminase, the release of this enzyme from macrophages or its reflux from coagulating glands, the spontaneous cellular exfoliation that is due to decreased androgen levels, and dietary noxae may be of importance in the development of lateral prostatic nonbacterial inflammation in aged rats.     

组织型谷氨酰胺转氨酶在肿瘤生物学中的作用

组织型谷氨酰胺转氨酶是一种多功能酶，不仅可以催化多种蛋白质形成交联分子稳定细胞外基质，而且可以调节肿瘤生长、细胞分化、细胞凋亡和细胞黏附。本文就该酶的一般特性及在肿瘤生物学中的作用进行综述。     

Immunoglobulin, complement and epidermal transglutaminase deposition in the cutaneous vessels in dermatitis herpetiformis

BACKGROUND: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteristic serological markers for DH, these antibodies do not bind to normal papillary skin structures. AIMS: To test the possibility of IgA immune complex precipitation within the vessel walls as a first step in the pathogenesis of skin symptoms, we analysed immunoglobulin, complement, and epidermal TG deposition along the vascular system of DH skin. METHODS: Punch biopsy specimen were taken from 116 DH patients' skin, and evaluated for the presence of vascular immune precipitates by direct immunofluorescence. Skin samples from 16 DH patients were also studied for tissue and epidermal TGs. RESULTS: In 74 (64%) of the 116 DH skin studied, significant vascular staining accompanied the DH-specific granular IgA fluorescence (IgA and C3 in 39 patients; IgA alone in 18; IgA, C3 and IgM together in five; IgM alone in 12). In most cases (92%), the precipitates were detected in the small vessels of the papillary dermis; however, a subpapillary vascular fluorescence was also observed in a few patients (8%). Skin IgA colocalized with epidermal TG in the vessel walls and within the scattered papillary peri- and intervascular DH bodies. Tissue TG did not colocalize either with the immunoglobulins or with the complement precipitates of the dermis. Furthermore, we could not detect keratinocyte TG in the DH bodies nor in the vessel walls. CONCLUSIONS: These findings support possible immune complex precipitation in the vessel walls of DH skin and further confirm the significance of epidermal but not tissue TG in the pathomechanism of skin symptoms.     

Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease

Dermatitis herpetiformis (DH) is an itchy blistering skin disease with predilection sites on elbows, knees, and buttocks. Diagnosis is confirmed by showing granular immunoglobulin A deposits in perilesional skin. DH is one manifestation of coeliac disease; the skin symptoms heal with gluten free diet (GFD) and relapse on gluten challenge. Of the first-degree relatives, 5% may be affected by either condition. Tissue transglutaminase (TG2) is the autoantigen in coeliac disease and epidermal transglutaminase (TG3) in DH. Both diseases conditions exhibit TG2-specific autoantibodies in serum and small bowel mucosa; patients with DH have IgA-TG3 in the skin. There are some divergencies between these two phenotypes. One-fourth of DH patients do not have small bowel mucosal villous atrophy, but virtually all have coeliac-type inflammatory changes. The skin symptoms respond slowly to GFD. The incidence of coeliac disease is increasing, whereas the opposite is true for DH. A female predominance is evident in coeliac disease, while DH may be more common in males. Coeliac disease carries the risk of small intestinal T-cell lymphoma; in DH B-cell lymphomas at any site may prevail. Adult coeliac disease carries a slightly increased elevated mortality risk, whereas in DH, the relative mortality rate is significantly decreased.

• Key messages

• Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease; both conditions are genetically determined and gluten-dependent.

• Gastrointestinal symptoms and the degree of villous atrophy are less obvious in dermatitis herpetiformis than in coeliac disease. Both show tissue transglutaminase (TG2) specific autoantibodies in serum and small bowel mucosa. In addition, TG3-targeted IgA antibodies are found in the skin of DH patients

• Both conditions carry an increased elevated risk of lymphoma, in coeliac disease small intestinal T-cell lymphoma, in dermatitis herpetiformis mainly B-cell lymphoma at various sites.

• Coeliac disease is currently eight times more common that DH; the incidence of DH is decreasing in contrast to that of coeliac disease, where it is increasing.

     

Mucosal Molecular Pattern of Tissue Transglutaminase and Interferon Gamma in Suspected Seronegative Celiac Disease at Marsh 1 and 0 Stages

Background/Aim:In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNγ). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNγ-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs).Results:Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15–25 (26 patients: group B), and 0–15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNα-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4.Conclusions:Our results suggest that tTG- and IFNγmRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15–25 (Marsh 0), suggesting the possibility of a “gray zone” inhabited by patients which should be closely followed up in gluten-related disorders.