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Mosenson J.A.,Loyola University Chicago | Zloza A.,Rush University Medical Center | Zloza A.,Loyola University Chicago | Nieland J.D.,University of Aarhus | And 17 more authors.
Science Translational Medicine

Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell-mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substratebinding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, andmutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo inmice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70i Q435A therapeutically in a different, rapidly depigmentingmodel after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift fromquiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved. Source

Birlea S.A.,Aurora University | Jin Y.,Aurora University | Bennett D.C.,St Georges, University of London | Herbstman D.M.,Florida College | And 11 more authors.
Journal of Investigative Dermatology

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P3.0E-04, odds ratio (OR)1.60; meta-P for rs38069333.1E-03), XBP1 (rs6005863, P3.6E-04, OR1.17; meta-P for rs22695779.5E-09), and FOXP3 (rs11798415, P5.8E-04, OR1.19). Association of GV with CTLA4 (rs12992492, P5.9E-05, OR1.20; meta-P for rs2317751.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions. © 2011 The Society for Investigative Dermatology. Source

Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Ferrara T.M.,Aurora University | And 25 more authors.
Nature Genetics

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10 -8), MC1R (P = 1.82 × 10 -13), a region near TYR (P = 1.57 × 10 -13), IFIH1 (P = 4.91 × 10 -15), CD80 (P = 3.78 × 10 -10), CLNK (P = 1.56 × 10 -8), BACH2 (P = 2.53 × 10 -8), SLA (P = 1.58 × 10 -8), CASP7 (P = 3.56 × 10 -8), CD44 (P = 1.78 × 10 -9), IKZF4 (P = 2.75 × 10 -14), SH2B3 (P = 3.54 × 10 -18) and TOB2 (P = 6.81 × 10 -10). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration. © 2012 Nature America, Inc. All rights reserved. Source

Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Mailloux C.M.,Aurora University | And 15 more authors.
Nature Genetics

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10 8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10-7). © 2010 Nature America, Inc. All rights reserved. Source

Jin Y.,University of Colorado at Denver | Birlea S.A.,University of Colorado at Denver | Fain P.R.,University of Colorado at Denver | Gowan K.,University of Colorado at Denver | And 15 more authors.
Journal of Investigative Dermatology

Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P8.14 × 10 11), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se. © 2011 British Association of Dermatologists. Source

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