Autoantigens in Vitiligo Identified by the Serological Selection of a Phage-Displayed Melanocyte cDNA Expression Library

Vitiligo is an acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented macules resulting from the loss of cutaneous melanocytes. Although the exact cause of vitiligo remains obscure, autoimmunity may play a role in the development of the disease. The present study was undertaken to investigate the applicability of phage display technology to identify B-cell autoantigens in vitiligo. A melanocyte cDNA phage display library was subjected to rounds of enrichment with vitiligo patient IgG. Subsequently, enriched IgG-binding peptides representing putative autoantigens were identified by sequencing their encoding cDNAs. Radioimmunoassays were used to confirm the immunoreactivity of vitiligo patient (n=61) and control (n=28) sera to several of the putative autoantigens. Non-segmental vitiligo patient sera (n=53) were positive for antibody (Ab) reactivity to gamma-enolase (8%); alpha-enolase (9%); heat-shock protein 90 (13%); osteopontin (4%); ubiquitin-conjugating enzyme (15%); translation-initiation factor 2 (6%); and GTP-binding protein, Rab38 (15%). Ab reactivity to at least one of the previously unknown autoantigens was detected in 51% of patients with non-segmental vitiligo. In contrast, Ab reactivity in a group of patients with segmental vitiligo (n=8) was not demonstrated. Overall, the study indicated that the targets of autoantibodies in vitiligo patients can be revealed by employing the methodology of phage display

Environmental requirements for three sea pen species: relevance to distribution and conservation

The aim is to determine the environmental requirements, estimate the extent of suitable habitat for three sea pen species, and assess the implications for marine protected areas (MPAs). The sea pen Funiculina quadrangularis and the habitat associated with two further sea pen species, Virgularia mirabilis and Pennatula phosphorea, are of key conservation importance and are recommended for protection within MPAs. This study models their potential distributions using the MAXimum ENTropy algorithm and assesses these in relation to five possible marine protected areas (pMPAs) proposed for Scottish waters. Metrics relevant to assessing the efficacy of MPAs are also presented. Four environmental variables of prime importance for predicting the presence of all three species of sea pen were identified: mud, minimum salinity, depth, and gravel. The habitat suitability index increased with mud content. The modelled distribution of F. quadrangularis indicated a deeper distribution than V. mirabilis or P. phosphorea and was not present in sediment with gravel content above 30%. Pennatula phosphorea had the smallest area of suitable habitat, while V. mirabilis had the largest. The percentage predicted suitable area for each species that was encompassed by the five pMPAs ranged from 11% for F. quadrangularis to 15% for P. phosphorea. Some of the largest areas predicted as suitable for F. quadrangularis lay outside the pMPAs. The model results indicated differences in the environmental requirements of the three species of sea pen that can be linked to the autecology of each species. Patch sizes, calculated from a binary output of the model, were used to estimate the degree of habitat fragmentation, thereby giving a partial assessment of the adequacy criterion for these pMPAs. The results suggest that potential MPAs within the study area cover sizeable areas of potential sea pen habitat. However, further areas suitable for F. quadrangularis could be considered

The Transcription Factors SOX9 and SOX10 Are Vitiligo Autoantigens in Autoimmune Polyendocrine Syndrome Type I

Vitiligo is common in the hereditary disorder autoimmune polyendocrine syndrome type I (APS I). Patients with APS I are known to have high titer autoantibodies directed against various tissue-specific antigens. Using sera from APS I patients for immunoscreening of a cDNA library from human scalp, we identified the transcription factors SOX9 and SOX10 as novel autoantigens related to this syndrome. Immunoreactivity against SOX9 was found in 14 (15%) and against SOX10 in 20 (22%) of the 91 APS I sera studied. All patients reacting with SOX9 displayed reactivity against SOX10, suggesting shared epitopes. Among the 19 patients with vitiligo, 12 (63%) were positive for SOX10 (p0.0001). Furthermore, three of 93 sera from patients with vitiligo unrelated to APS I showed strong reactivity against SOX10, which may indicate a more general role of SOX10 as an autoantigen in vitiligo

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo.

BACKGROUND Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05×10−23) and class II molecules (P=4.50×10−34), PTPN22 (P=1.31×10−7), LPP (P=1.01×10−11), IL2RA (P=2.78×10−9), UBASH3A (P=1.26×10−9), and C1QTNF6 (P=2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07×10−15) and GZMB (P=3.44×10−8), and in a locus containing TYR (P=1.60×10−18), encoding tyrosinase. CONCLUSIONS We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma

Common variants in FOXP1 are associated with generalized vitiligo

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)

Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae.

Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype

Selective reduction of CO₂ to a methanol equivalent by B(C₆F₅)₃-activated alkaline earth catalysis

Treatment of β-diketiminato Mg and Ca amidoborane compounds with B(C6F5)3 induces hydride elimination and formation of alkaline earth hydrido-tris(pentafluorophenyl)borate derivatives. Both species react with CO2 to provide formate complexes, one of which has been structurally characterised, and may be applied to the highly selective reductive hydroboration of CO2 with pinacolborane (HBpin) to provide the methanol equivalent, CH3OBpin

Graves Hyperthyroidism After Stopping Immunosuppressive Therapy in Type 1 Diabetic Islet Cell Recipients With Pretransplant TPO Autoantibodies

OBJECTIVE — After an initially successful islet cell transplantation, a number of patients return to C-peptide negativity, and therefore immunosuppressive therapy is discontinued. Some are then found to have developed Graves disease. We examined the risk of Graves disease after immunosuppression. RESEARCHDESIGNANDMETHODS — Immunosuppressive therapy was stopped in 13 type 1 diabetic islet cell recipients who had received one course of antithymocyte globulin and maintenance doses of mycophenolate mofetil and a calcineurin inhibitor. None had a history of thyroid disease. RESULTS — In four patients, clinical Graves hyperthyroidism was observed within 21 months after discontinuation and 30–71 months after the start of immunosuppressive therapy. All four patients exhibited a pretransplant positivity for thyroid peroxidase (TPO) autoantibod-ies, while the nine others were TPO negative pre- and posttransplantation. CONCLUSIONS — Type 1 diabetic recipients of islet cell grafts with pretransplant TPO autoantibody positivity exhibit a high risk for developing Graves hyperthyroidism after immu-nosuppressive therapy is discontinued for a failing graft. Diabetes Care 32:1817–1819, 2009 I slet cell transplantation has beenshown to reproducibly achieve meta-bolic correction in nonuremic type 1 diabetic patients (1,2). However, in the years following transplantation, several of them return to C-peptide negativity and thus to a discontinuation of their immu-nosuppressive therapy (2)