Viral-Associated Trichodysplasia: Characterization of a Novel Polyomavirus Infection With Therapeutic Insights

Background Viral-associated trichodysplasia of immunosuppression is a rare cutaneous eruption that is characterized by follicularly based shiny papules and alopecia with characteristic histopathologic findings of abnormally anagen follicules with excessive inner root sheath differentiation. Prior reports have described the histopathologic characteristics on vertical sections; however, to our knowledge, immunohistochemical analysis of polyomavirus proteins has not been previously performed. Observations We discuss the thorough diagnostic evaluation and therapy of an unusual case of viral-associated trichodysplasia due to a newly described human polyomavirus that occurred in a patient with post-treatment chronic lymphocytic leukemia and an abnormal white blood cell count. Unique to our study is the immunohistochemical staining for the polyomavirus middle T antigen, which demonstrated positive staining of cellular inclusions within keratinocytes that compose the inner root sheath. Further evaluation with scanning electron microscopy and polymerase chain reaction analysis of viral DNA confirmed the presence of the virus. Treatment with topical cidofovir resulted in dramatic clinical improvement and hair regrowth. Conclusions Several tools, including immunohistochemical staining for the polyomavirus middle T antigen, can be used to identify the pathogenic virus associated with viral-associated trichodysplasia. This case highlights the utility of multiple diagnostic modalities and a robust response to a topical therapeutic agent, cidofovir

Increased expression of ceruloplasmin in the retina following photic injury

PURPOSEOxidative stress plays a role in the photic injury model of retinal degeneration and in age-related macular degeneration. Our preliminary microarray analysis of retinal gene expression upon photic injury suggested increased expression of ceruloplasmin, a ferroxidase that could reduce retinal oxidative stress. Patients with acerul oplasminemia have retinal degeneration, indicating that ceruloplasmin is necessary for maintenance of retinal health. The purpose of this study was to determine whether retinal ceruloplasmin is upregulated following photo-oxidation, to localize ceruloplasmin protein, and to determine which ceruloplasmin isoform is present in the retina.METHODSBalb/c mice were exposed to bright white light for seven hours. TUNEL labeling was used to detect photoreceptor apoptosis. At several intervals after the light injury, retinal ceruloplasmin was studied by quantitative PCR, immunohistochemistry, and western analysis. Expression of the secreted and expression of the membrane-anchored glycosyl phosphatidyl inositol (GPI) linked forms of ceruloplasmin were assesed in rat retina using primers specific for each form. Vitreous ceruloplasmin was detected by immunohistochemistry in Balb/c mouse eyes and by western analysis of aspirated vitreous from post-mortem human eyes.RESULTSRetinal ceruloplasmin mRNA was upregulated eight-fold following photic injury. Ceruloplasmin protein was detected throughout normal retinas by immunohistochemistry, with a specific increase in Muller cell labeling following photic injury. Western analysis confirmed an increase in ceruloplasmin protein following photic injury and revealed eight-fold more ceruloplasmin protein in normal retina than in brain. The mRNAs for both the secreted and GPI linked forms of ceruloplasmin were detected by RT-PCR in the retina. Ceruloplasmin protein was detected by western analysis of normal human vitreous and was increased in mouse vitreous following photic injury.CONCLUSIONSCeruloplasmin, a retinal ferroxidase, is upregulated at the mRNA and protein levels upon light damage. The increased protein is primarily in Muller cells. Ceruloplasmin is considerably more abundant in retina than in brain. The retina expresses both the GPI-linked and secreted forms of ceruloplasmin, and since vitreous ceruloplasmin increases following photic injury, some of the retinal ceruloplasmin may be secreted into the vitreous. Ceruloplasmin may protect the retina from oxidative stress by decreasing the amount of ferrous iron available to produce reactive oxygen species

Ceruloplasmin/Hephaestin Knockout Mice Model Morphologic and Molecular Features of AMD

PURPOSE: Iron is an essential element in human metabolism but also is a potent generator of oxidative damage with levels that increase with age. Several studies suggest that iron accumulation may be a factor in age-related macular degeneration (AMD). In prior studies, both iron overload and features of AMD were identified in mice deficient in the ferroxidase ceruloplasmin (Cp) and its homologue hephaestin (Heph) (double knockout, DKO). In this study, the location and timing of iron accumulation, the rate and reproducibility of retinal degeneration, and the roles of oxidative stress and complement activation were determined. METHODS: Morphologic analysis and histochemical iron detection by Perls' staining was performed on retina sections from DKO and control mice. Immunofluorescence and immunohistochemistry were performed with antibodies detecting activated complement factor C3, transferrin receptor, L-ferritin, and macrophages. Tissue iron levels were measured by atomic absorption spectrophotometry. Isoprostane F2α-VI, a specific marker of oxidative stress, was quantified in the tissue by gas chromatography/mass spectrometry. RESULTS: DKOs exhibited highly reproducible age-dependent iron overload, which plateaued at 6 months of age, with subsequent progressive retinal degeneration continuing to at least 12 months. The degeneration shared some features of AMD, including RPE hypertrophy and hyperplasia, photoreceptor degeneration, subretinal neovascularization, RPE lipofuscin accumulation, oxidative stress, and complement activation. CONCLUSIONS: DKOs have age-dependent iron accumulation followed by retinal degeneration modeling some of the morphologic and molecular features of AMD. Therefore, these mice are a good platform on which to test therapeutic agents for AMD, such as antioxidants, iron chelators, and antiangiogenic agents

Ionizing Radiation Selectively Reduces Skin Regulatory T Cells and Alters Immune Function

<div><p>The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth’s magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstrate that radiation, both homogeneous and inhomogeneous, induces inflammation with resultant specific loss of regulatory T cells from the skin. This results in a hyper-responsive state with increased delayed type hypersensitivity in vivo and CD4⁺ T cell proliferation in vitro. The effects of inhomogeneous radiation to the skin of astronauts or as part of a therapeutic approach could result in an unexpected enhancement in skin immune function. The effects of this need to be considered in the design of radiation therapy protocols and in the development of countermeasures for extended space travel.</p></div

CD164 and FCRL3 Are Highly Expressed on CD4+CD26 − T Cells in Sézary Syndrome Patients

Sézary syndrome (SS) cells express cell surface molecules also found on normal activated CD4 T cells. In an effort to find a more specific surface marker for malignant SS cells, a microarray analysis of gene expression was performed. Results showed significantly increased levels of mRNA for CD164, a sialomucin found on human CD34+ hematopoietic stem cells, and FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from SS patients compared with healthy donors (HD). Flow cytometry studies confirmed the increased expression of CD164 and FCRL3 primarily on CD4+CD26- T cells of SS patients. Importantly, a statistically significant correlation was found between an elevated percentage of CD4+CD164+ T cells and an elevated percentage of CD4+CD26- T cells in all tested SS patients but not in patients with mycosis fungoides and atopic dermatitis or HD. FCRL3 expression was significantly increased only in patients with high tumor burden. CD4+CD164+ cells displayed cerebriform morphology and their loss correlated with clinical improvement in treated patients. Our results suggest that CD164 can serve as a marker for diagnosis and for monitoring progression of cutaneous T-cell lymphoma (CTCL)/SS and that FCRL3 expression correlates with a high circulating tumor burden