Pittelkow, Mark R.

Background In addition to its fundamental functions in mediating the survival, proliferation, and migration of keratinocytes, increasing evidence suggests that the amphiregulin-epidermal growth factor receptor pathway has a major impact on cutaneous inflammation. Transgenic expression of amphiregulin in the epidermis of mice induces skin pathology with striking phenotypic similarity to that of psoriasis. Prominent T-cell and dendritic cell infiltrates are observed in the lesional skin from these mice. Objective In this study, we aimed to identify more fully the effect of amphiregulin on keratinocytes and T cells during cutaneous inflammation through examining relevant cytokines in the lesional skin as well as in human keratinocyte culture. Methods Using a multicytokine enzyme-linked immunosorbent assay, we found that amphiregulin directly induces the production of monocyte chemoattractant protein-1, interleukin-α, and interleukin-8 from keratinocytes in vitro. In addition, we examined the cutaneous expression of T-cell cytokines in amphiregulin transgenic mice compared with wild-type mice using quantitative polymerase chain reaction, which demonstrated upregulation of interferon-γ, vascular endothelial growth factor, and interleukin-4 in amphiregulin transgenic mice. Results and Conclusion Our study suggested that amphiregulin in the epidermis not only induces keratinocyte proliferation but also induces T-cell activation through a complex circuit of proinflammatory cytokines. Elucidating the role of amphiregulin on the generation, interactions, and balance among T-cell subsets will advance the understanding of psoriasis pathogenesis.

Although the primary function of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the regulation of calcium and phosphorus metabolism, it also regulates the growth and differentiation of several different cell types. Recent work suggests that 1,25(OH)2D3 regulates cellular growth by altering the synthesis of growth factors and growth factor responses.

The present study was undertaken to investigate the presence of C-type natriuretic peptide (CNP) immunoreactivity in cultured human vascular endothelial cells and in human plasma. CNP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and by radioimmunoassay. With the utilization of gel permeation chromatography, this immunoreactivity proved to be consistent with the higher molecular weight CNP-53. CNP immunoreactivity was also present in human plasma (n = 22) at low picogram concentrations (6.5 +/- 0.2 pg/ml) by specific radioimmunoassay. This immunoreactivity was consistent with the lower molecular weight CNP-22 by gel permeation chromatography. These findings suggest that the vascular endothelium may be the site of CNP production. The isolation of different molecular forms of CNP in tissue and plasma may be consistent with a storage form of the peptide in endothelial cells CNP-53, while CNP-22 circulates in plasma. In summary, the present study is consistent with CNP being a peptide of endothelial cell origin.

The endothelium is the production site of several potent vasoactive substances that modulate vascular tone and growth. The present study was undertaken to investigate the presence and secretion of atrial natriuretic peptide (ANP) immunoreactivity from vascular endothelial cells. ANP immunoreactivity was present in cultured human aortic endothelial cells by both immunohistochemical staining and radioimmunoassay. ANP immunoreactivity was also detectable in culture medium from human aortic endothelial cells in low picogram concentrations. These findings suggest that vascular endothelium is a site of ANP production and secretion of ANP. There was a differential distribution of ANP and endothelin-1 (ET-1), with a higher ANP concentration in cell extracts and a higher ET-1 concentration in cell culture media. Although ANP has been conceived as a circulating endocrine hormone, these findings are consistent with ANP functioning also as an autocrine and paracrine modulator in the regulation of vascular tone and growth.

Introduction. The phenomenon of graft-versus-host disease, a solid organ transplant recipient, is a rare development with a very poor prognosis. Case Presentation. A 40-year-old woman with type 1 diabetes developed cutaneous graft-versus-host disease following second pancreas transplantation. Conclusion. The development of a nonspecific rash in the early posttransplant period following a pancreas transplant warrants suspicion for graft-versus-host disease.

AbstractThis viewpoint highlights major, partly controversial concepts about the pathogenesis of pemphigus. The monopathogenic theory explains intra‐epidermal blistering through the “desmoglein (Dsg) compensation” hypothesis, according to which an antibody‐dependent disabling of Dsg 1‐ and/or Dsg 3‐mediated cell–cell attachments of keratinocytes (KCs) is sufficient to disrupt epidermal integrity and cause blistering. The multipathogenic theory explains intra‐epidermal blistering through the “multiple hit” hypothesis stating that a simultaneous and synchronized inactivation of the physiological mechanisms regulating and/or mediating intercellular adhesion of KCs is necessary to disrupt epidermal integrity. The major premise for a multipathogenic theory is that a single type of autoantibody induces only reversible changes, so that affected KCs can recover due to a self‐repair. The damage, however, becomes irreversible when the salvage pathway and/or other cell functions are altered by a partnering autoantibody and/or other pathogenic factors. Future studies are needed to (i) corroborate these findings, (ii) characterize in detail patient populations with non‐Dsg‐specific autoantibodies, and (iii) determine the extent of the contribution of non‐Dsg antibodies in disease pathophysiology.

AbstractBackgroundPublished case series describe lenalidomide as an effective treatment of refractory cutaneous lupus erythematosus (CLE).ObjectivesThe present study aimed to further characterize lenalidomide use in the treatment of CLE.MethodsA retrospective review of patients treated with lenalidomide for CLE from January 1, 2000, to December 17, 2014, was conducted.ResultsEight of the nine patients (89%) were women. Their median age at initiation of lenalidomide was 62 years (range: 41–86 years). Subtypes of CLE included discoid lupus erythematosus (DLE) (n = 6), lupus panniculitis (n = 2), and subacute CLE (n = 1). Before the initiation of lenalidomide, all patients had been previously treated unsuccessfully or were intolerant to at least one antimalarial and one immunosuppressive agent. With lenalidomide, five patients achieved a complete response (CR), two a partial response, and two had no response (lupus panniculitis). Time to initial response (dose range: 2.5–10.0 mg/d) varied from 2 weeks to 3 months; the median time to CR in five patients was 3 months (range: 3–6 months). The median duration of lenalidomide therapy was 12 months (range: 2–67 months). The median duration of follow‐up was 48 months (range: 20–103 months). Adverse effects included mild leukopenia; one patient had deep vein thrombosis of unclear etiology during a hospitalization. No patients developed or showed progression of systemic LE while receiving lenalidomide.ConclusionsLenalidomide was effective for the treatment of CLE (particularly DLE) but not for the treatment of lupus panniculitis in this series.

Purpose Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. Patients and Methods Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. Results ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). Conclusion The addition of cell adhesion–linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.