Ultraviolet (UV) light is intricately linked to the functional status of the cutaneous immune system. In susceptible individuals, UV radiation can ignite pathogenic inflammatory pathways leading to allergy or autoimmunity. In others, this same UV radiation can be used as a phototherapy to suppress pathogenic cutaneous immune responses. These vastly different properties are a direct result of UV light's ability to ionize molecules in the skin and thereby chemically alter them. Sometimes these UV-induced chemical reactions are essential, the formation of pre-vitamin D 3 from 7-dehydrocholesterol, for example. In other instances they can be potentially detrimental. UV radiation can ionize a cell's DNA causing adjacent pyrimidine bases to chemically bond to each other. To prevent malignant transformation, a cell may respond to this UV-induced DNA damage by undergoing apoptosis. Although this pathway prevents skin cancer it also has the potential of inducing or exacerbating autoreactive immune responses by exposing the cell's nuclear antigens. Ultavioletinduced chemical reactions can activate the immune system by a variety of other mechanisms as well. In response to UV irradiation keratinocytes secrete cytokines and chemokines, which activate and recruit leukocytes to the skin. In some individuals UV-induced chemical reactions can synthesize novel antigens resulting in a photoallergy. Alternatively, photosensitizing molecules can damage cells by initiating sunburn-like phototoxic reactions. Herein we review all types of UV-induced skin reactions, especially those involving the immune system. KeywordsUltraviolet radiation; skin; phototoxic reaction; photoallergic reaction; phototherapy; atuoimmunity The basic principles of lightAlthough light is commonly thought of as something visible, in physics light actually refers to all electromagnetic radiation. The frequency, wavelength, and energy of an electromagnetic wave are related to one another with wavelength being inversely proportional to both frequency and energy (Figure 1). The huge spectrum of electromagnetic radiation can therefore be organized conceptually by decreasing wavelength into radio waves, microwaves, terahertz Author to whom correspondence should be sent: Emanual Maverakis, M.D., 3301 C Street, Sacramento, CA 95816, Phone: (916) 734-6111, Fax: (916) 843-9444, emaverakis@yahoo.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript radiation, infrared radiation, visible light, UV radiation, X-rays, and gamma rays (Fi...

Mutations in the nucleophosmin gene (NPM1 mut ) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1 mut . In the present study, we were able to demonstrate both CD4 ؉ and CD8 ؉ T-cell responses against NPM1 mut . Ten peptides derived from wild-type NPM1 and NPM1 mut were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients.Tetramer assays against the most interesting epitopes were performed and Cr 51 -release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4 ؉ T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1 mut induced CD8 ؉ T-cell responses. A total of 33% of the NPM1 mut AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4 ؉ T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8 ؉ and CD4 ؉ T cells. The results of the present study show that NPM1 mut induces specific T-cell responses of CD4 ؉ and CD8 ؉ T cells and therefore is a promising target for specific immunotherapies in AML. (Blood. 2012;120(6):1282-1289) IntroductionMutations in the nucleophosmin 1 gene (NPM1 mut ) represent some of the most common gene mutations in acute myeloid leukemia (AML). 1,2 Falini et al first described the abnormal cytoplasmic localization of the NPM1 protein caused by mutations in exon 12 of the gene. 3 In AML patients with normal cytogenetics, the incidence of NPM1 mut was reported in up to 60% of the patients. 1-3 NPM1 constitutes an important prognostic marker, especially in the context of FMS-related tyrosine kinase internal tandem duplication (FLT3-ITD). In more than 90% of AML patients harboring NPM1 mut , the 3 different NPM1 mut types (A, B, and D) were found. 1,2,4-6 AML patients harboring an NPM1 mut without an FLT3-ITD mutation showed improved survival when treated with intensive chemotherapy. 2 Most AML patients with NPM1 mut seem not to benefit from an allogeneic stem cell transplantation as a first-line treatment. 2,7 However, this issue remains to be elucidated in the context of minimal residual disease detection 8 and the coexistence of other molecular markers. The functional role of NPM1 mut for the improved clinical outcome remains to be elucidated. Immune responses may contribute to clinical outcome by lysis of residual leukemic cells through specific T cells after chemotherapy. Leukemia-associated antigens (LAAs) can be targeted by the immune system in a specific manner, leading to the hypothesis that the expression of LAAs might also influence the clinical outcome of AML patients. mRNA expression of at least 1 of the 3 LAA, receptor for hyaluronic acid-mediated motility (RHAMM), preferentially expressed antigen in mela...

Hypoxia is a condition in which cells, tissues, or organisms are deprived of sufficient oxygen supply. Aerobic organisms have a hypoxic response system, represented by hypoxia-inducible factor 1-α (HIF1A), to adapt to this condition. Due to publication bias, there has been little focus on genes other than well-known signature hypoxia-inducible genes. Therefore, in this study, we performed a meta-analysis to identify novel hypoxia-inducible genes. We searched publicly available transcriptome databases to obtain hypoxia-related experimental data, retrieved the metadata, and manually curated it. We selected the genes that are differentially expressed by hypoxic stimulation, and evaluated their relevance in hypoxia by performing enrichment analyses. Next, we performed a bibliometric analysis using gene2pubmed data to examine genes that have not been well studied in relation to hypoxia. Gene2pubmed data provides information about the relationship between genes and publications. We calculated and evaluated the number of reports and similarity coefficients of each gene to HIF1A, which is a representative gene in hypoxia studies. In this data-driven study, we report that several genes that were not known to be associated with hypoxia, including the G protein-coupled receptor 146 gene, are upregulated by hypoxic stimulation.

Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet's syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.