The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells.

The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4(+) or CD8(+) T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage.

Geometric border as a marker for melanoma diagnosis: Study of 200 consecutive melanocytic lesions.

The ABCD rule has long been proposed as a guidance for malignant melanoma (MM) diagnosis. We aimed to define a new simple, straightforward tool that could be useful in early melanoma detection and must be validated in further studies. We conducted a prospective historic cohort study of 200 melanocytic lesions classifying them according to the presence of geometric borders. Sixty-four percent of the MM and 31% of the melanocytic nevi presented with geometric borders. Lesions with two straight borders that formed a noncurvilinear angle presented a 2.1-fold higher risk of being malignant after excision. When comparing melanomas with geometric and nongeometric border, we found a tendency toward better prognostic markers in the geometric lesions. Lesions located in the extremities and melanoma subtype SSM were more common in the geometric group. Regarding pathologic features, a deeper Breslow (mean, 3.8 vs 1.4 mm), presence of ulceration (25% vs 5%) and a higher number of mitosis was found in the nongeometric group. On the other hand, more regression was found in the geometric group while both groups showed similar degree of lymphovascular infiltration. We propose geometric border as another clinical criterion to take into account when suspecting MM, which must be validated in further studies. The ABCDE rule could be completed with a G for geometry.

Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma.

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor ß (TGF-ß). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-ß antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.

Pemphigus foliaceus worsened by drugs in a patient with psoriasis, responding to adalimumab.

Pemphigus foliaceus is a blistering autoimmune disease related to the production of autoantibodies against desmoglein 1. We present a patient with psoriasis and pemphigus foliaceus aggravated by enalapril and amlodipine intake, with successful response of both conditions to adalimumab therapy.

El pénfigo foliáceo es una enfermedad autoinmune ampollosa debida a la producción de autoanticuerpos frente a la desmogleína 1. Presentamos el caso de un paciente con psoriasis y pénfigo foliáceo agravado por enalapril y amlodipino, con buena respuesta de ambas patologías a la terapia con adalimumab.Pemphigus foliaceus is a blistering autoimmune disease related to the production of autoantibodies against desmoglein 1. We present a patient with psoriasis and pemphigus foliaceus aggravated by enalapril and amlodipine intake, with successful response of both conditions to adalimumab therapy.

El pénfigo foliáceo es una enfermedad autoinmune ampollosa debida a la producción de autoanticuerpos frente a la desmogleína 1. Presentamos el caso de un paciente con psoriasis y pénfigo foliáceo agravado por enalapril y amlodipino, con buena respuesta de ambas patologías a la terapia con adalimumab.

Eccrine squamous syringometaplasia secondary to cutaneous extravasation of docetaxel: report of three cases.

Eccrine squamous syringometaplasia is characterized by the metaplasia of cuboidal epithelial cells of the eccrine sweat ducts into squamous epithelial cells. It has been associated with several conditions including chemotherapy-related bilateral dermatitis, an entity that can take place in body areas rich in eccrine glands, as well as in acral erythema related to chemotherapy. Only a few cases because of cutaneous extravasation of chemotherapy have been previously reported. We report three cases of eccrine squamous syringometaplasia secondary to extravasation of docetaxel.

Calcineurin sets the bandwidth for discrimination of signals during thymocyte development.

At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.

Unexpected slow recovery of seagrass leaf epiphytes after the impact of a summer heat wave and concomitant mucilage bloom.

The epiphytes of seagrass leaves constitute a peculiar community, comprised of a number of species specialized for this living substrate. Several studies report on the response of epiphytes to different pressures but no information exists about the effects of summer heatwaves, which have become frequent events in the last decades. This paper represents the first attempt to investigate the change in the leaf epiphyte community of the Mediterranean seagrass Posidonia oceanica due to the heatwave occurred in summer 2003. Thanks to a series of data collected seasonally between 2002 and 2006, and punctual data in the summers of 2014 and 2019, we assessed the change over time in the leaf epiphyte community. Temperature data trends were analysed through linear regression, while multivariate analyses (i.e., nMDS and SIMPER) were applied to cover data in order to assess changes over time in the epiphyte community. As a whole, the two most abundant taxa were the crustose coralline alga Hydrolithon and the encrusting bryozoan Electra posidoniae, which displayed the highest average cover values in summer (around 19%) and spring (around 9%), respectively. Epiphytes proved to be sensitive to temperature highs, displaying different effects on cover, biomass, diversity and community composition. Cover and biomass exhibited a dramatic reduction (more than 60%) after the disturbance. In particular, Hydrolithon more than halved, while E. posidoniae dropped sevenfold during summer 2003. While the former recovered comparatively quickly, the latter, as well as the whole community composition, apparently required 16 years to return to a condition similar to that of 2002.