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J Drugs Dermatol ; 16(7): 701-704, 2017 Jul 01.
Article in English | MEDLINE | ID: mdl-28697224

ABSTRACT

INTRODUCTION: Epidermodysplasia verruciformis (EV) is a rare inherited dermatosis characterized by increased susceptibility to human papilloma virus infection. Acquired EV occurs in patients with compromised cell-mediated immunity, such as patients with HIV and transplant recipients. Optimal management of acquired EV has not yet been established, as cases are rare and are due to a variety of underlying conditions. Additionally, no distinctions have been made between different immunosuppressive medications and their respective link to EV. METHODS AND RESULTS: We report a patient with systemic lupus erythematosus who developed EV while on azathioprine and prednisone. The patient's lesions resolved completely after she was switched from azathioprine to mycophenolate mofetil. Her lesions recurred when her immunosuppressive regimen was again changed from mycophenolate mofetil to methotrexate. A review of the literature revealed azathioprine to be related to other cases of acquired EV. DISCUSSION: This case indicates a possible link between specific immunosuppressive drugs and the development of EV, allowing for new EV treatment considerations. In this case and previous cases, azathioprine is indicated as being particularly linked with the development of EV, while mycophenolate mofetil may be an immunosuppressive option that is less likely to induce EV in patients predisposed to this condition. J Drugs Dermatol. 2017;16(7):701-704.


Subject(s)
Azathioprine/adverse effects , Epidermodysplasia Verruciformis/chemically induced , Epidermodysplasia Verruciformis/diagnosis , Immunosuppressive Agents/adverse effects , Female , Humans , Middle Aged
4.
JCI Insight ; 1(8): e86434, 2016 06 02.
Article in English | MEDLINE | ID: mdl-27699266

ABSTRACT

Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22-producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.


Subject(s)
Carcinoma, Squamous Cell/chemically induced , Cyclosporine/pharmacology , Immunosuppressive Agents/pharmacology , Interleukins/metabolism , Skin Neoplasms/chemically induced , Animals , Cell Line, Tumor , Humans , Mice , Receptors, Interleukin/metabolism , Interleukin-22
5.
J Biol Chem ; 286(27): 24150-8, 2011 Jul 08.
Article in English | MEDLINE | ID: mdl-21602279

ABSTRACT

Loss-of-function mutations in the proton-coupled folate transporter (PCFT, SLC46A1) result in the autosomal recessive disorder, hereditary folate malabsorption (HFM). Identification and characterization of HFM mutations provide a wealth of information on the structure-function relationship of this transporter. In the current study, PCR-based random mutagenesis was employed to generate unbiased loss-of-function mutations of PCFT, simulating the spectrum of alterations that might occur in the human disorder. A total of 26 mutations were generated and 4 were identical to HFM mutations. Eleven were base deletion or insertion mutations that led to a frameshift and, along with similar HFM mutations, are predominantly localized to two narrow regions of the pcft gene at the 5'-end. Base substitution mutations identified in the current study and HFM patients were largely distributed across the pcft gene. Elimination of the ATG initiation codon by a one-base substitution (G > A) did not result in a complete lack of translation at the same codon consistent with rare non-ATG translation initiation. Among six missense mutants evaluated, three mutant PCFTs were not detected at the plasma membrane, one mutation resulted in decreased binding to folate substrate, and one had a reduced rate of conformational change associated with substrate translocation. The remaining PCFT mutant had defects in both processes. These results broaden understanding of the regions of the pcft gene prone to base insertion and deletion and inform further approaches to the analysis of the structure-function of PCFT.


Subject(s)
Mutation , Proton-Coupled Folate Transporter/metabolism , HeLa Cells , Humans , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/metabolism , Mutagenesis , Proton-Coupled Folate Transporter/genetics , Structure-Activity Relationship
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