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Wayne T. McCormack, Ph.D.
Associate Professor Department of Pathology, Immunology and Laboratory Medicine University of Florida College of Medicine Gainesville, Florida Research Abstracts |
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GENES OF THE LMP/TAP CLUSTER ARE ASSOCIATED WITH THE HUMAN AUTOIMMUNE
DISEASE VITILIGO Genes
within the class II region of the major histocompatibility complex (MHC),
including genes involved in antigen processing and presentation, have been
reported to be associated with several autoimmune diseases. We report here that
the LMP/TAP gene region is significantly associated with vitiligo,
a disorder in which biochemical defects and/or autoimmune destruction cause
melanocyte loss and resulting skin depigmentation. Case/control analyses
revealed genetic association of vitiligo in Caucasian patients with an early age
of onset with the
transporter associated with antigen processing-1 (TAP1) gene. A
family-based association method revealed biased transmission of specific alleles
from heterozygous parents to affected offspring for the TAP1 gene, as
well as for the closely linked LMP2 and LMP7 genes encoding
subunits of the immunoproteasome. No association with vitiligo was found for the
MECL1 gene, which encodes a third immunoproteasome subunit and is
unlinked to the MHC class II region. These results suggest a possible role for
the MHC class I antigen processing and/or presentation pathway in the anti-melanocyte
autoimmune response involved in vitiligo pathogenesis. |
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Presented at the annual meeting of the American Association of Immunologists, New Orleans, LA, April 20-23, 2002 ANTIGEN PROCESSING AND
PRESENTATION GENES IN VITILIGO SUSCEPTIBILITY Vitiligo is characterized by progressive skin depigmentation due to autoimmune destruction of epidermal melanocytes. As suggested for other autoimmune diseases, vitiligo susceptibility may involve both target organ-specific genes and immune response genes. The MHC class II genomic region has become very important in the study of the genetics of autoimmunity, with statistically significant associations reported between many of the genes in this region and autoimmune diseases. Case-control and family-based association studies were performed for several genes in the MHC class II region involved in antigen processing and presentation, including Low Molecular weight Polypeptide 2 and 7 (LMP2 and LMP7) and Transporter associated with Antigen Processing 1 and 2 (TAP1 and TAP2) using control and vitiligo patient populations. We report significant genetic association between LMP7 and TAP1 genes and vitiligo susceptibility, suggesting that improper antigen processing and or presentation may play a role in vitiligo pathogenesis. In vitro studies of LMP2, LMP7, TAP1, and TAP2 gene and protein expression in patient and control antigen presenting cells are being conducted, to provide further evidence for involvement of antigen processing and/or presentation in vitiligo susceptibility. (Supported by the National Vitiligo Foundation, NIH T32 AR 07603, and the UF Center for Immunology and Transplantation) Abstract published in FASEB J. 16(5):A1219, 2002 |
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GENETIC ASSOCIATION OF THE CATALASE GENE (CAT)
WITH VITILIGO SUSCEPTIBILITY Vitiligo susceptibility is a complex genetic trait that may involve genes important for melanin biosynthesis, response to oxidative stress, and/or regulation of autoimmunity, as well as environmental factors. We report here case-control and family-based association studies for the catalase gene (CAT) in vitiligo patients. The CAT gene was selected as a candidate gene due to the reduction of catalase enzyme activity (EC 1.11.1.6) and concomitant accumulation of excess hydrogen peroxide observed in the entire epidermis of vitiligo patients. One of three CAT genetic markers studied was found to be informative for genotypic analysis of Caucasian vitiligo patients and control subjects. Both case/control and family-based genetic association studies of the T/C single nucleotide polymorphism in exon 9 of the CAT gene, which is detectable with the restriction endonuclease BstX I, suggest possible association between the CAT gene and vitiligo susceptibility. The observations that T/C heterozygotes are more frequent among vitiligo patients than controls and that the C allele is transmitted more frequently to patients than controls suggest that linked mutations in or near the CAT gene might contribute to a quantitative deficiency of catalase activity in the epidermis and the accumulation of excess H2O2. The CAT gene may therefore be a susceptibility gene in some vitiligo patients, further supporting the epidermal oxidative stress model for vitiligo pathogenesis. Full
text article available on-line as HTML document or PDF document from Blackwell
Synergy |
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Presented at the annual meeting of the Pan-American Society for Pigment Cell Research, Minneapolis, MN, June 14-17, 2001 GENETICS OF VITILIGO SUSCEPTIBILITY: ASSOCIATION STUDIES OF IMMUNE
RESPONSE GENES Vitiligo is characterized by progressive depigmentation of the skin thought to be caused by melanocyte autodestruction due to metabolic defects and/or autoimmune attack. The association of vitiligo with other autoimmune disorders suggests that genetic susceptibility to autoimmunity may involve both target organ-specific genes and immune response genes. We have used case-control and family-based association methods to examine the possible role of candidate vitiligo susceptibility genes. PCR-based methods were used to genotype 552 patients and family members and 184 controls for single nucleotide polymorphisms or microsatellite markers located within each candidate gene. Allele and genotype frequencies for Caucasian patients and controls were compared by c 2 analysis in the case/control study, and the transmission disequilibrium test was used to seek confirmation. Further analyses of several candidate genes associated with melanocyte biology (PAH, TYR, TRP1, TRP2, TH, GCH1, NF1, KIT, and PAX3) that were reported last year have led to the conclusion that they are not associated with vitiligo susceptibility in our patient population. We have also examined the role of candidate immune response genes (APS-1, CD4, CD28, CD59, CTLA-4, ICAM-1, IL-1b, IL-1Ra, LMP-2, LMP-7, MCP, MECL1, TAP1, TAP2, and TNF-a), which were selected based on reported differences in expression in vitiligo patients and/or suggested roles in other autoimmune diseases. Genetic association with vitiligo was suggested by markers for the CD28/CTLA4 and LMP/TAP gene regions. These studies provide evidence for genetic association of candidate immune response genes with vitiligo, and support an autoimmune etiology of vitiligo in some patients. (Supported by the National Vitiligo Foundation) Abstract published in Pigment Cell Research 14(3):231, 2001 |
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Presented at the annual meeting of the American Association of Immunologists, Orlando, FL, March 31 - April 4, 2001 Genetic Association Studies of
Immune Response Genes and Vitiligo Susceptibility Vitiligo is characterized by progressive skin depigmentation due to autoimmune destruction of epidermal melanocytes. As suggested for other autoimmune diseases, vitiligo susceptibility may involve both target organ-specific genes and immune response genes. We examined the role of candidate immune response genes in conferring genetic susceptibility to vitiligo using case/control association. The candidate genes APS-1, CD4, CD28, CD59, CTLA-4, ICAM-1, IL-1b, IL-1Ra, LMP-2, LMP-7, MCP, and TNF-a were selected based on reported differences in expression in vitiligo patients and/or suggested roles in other autoimmune diseases. PCR-based methods were used to genotype 552 patients and family members and 184 controls for single nucleotide polymorphisms or microsatellite markers located within each candidate gene. Allele and genotype frequencies for Caucasian patients and controls were compared by c 2 analysis in the case/control study, and a family-based association method (transmission disequilibrium test) was used to seek confirmation. Additional markers in the LMP/TAP region will also be reported. Genetic association with vitiligo was suggested by a microsatellite marker for CD28, located near the diabetes susceptibility locus IDDM12, and by a RFLP marker for LMP-7. (Supported by the National Vitiligo Foundation) Abstract published in FASEB J. 15(4):A323, 2001 |
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Presented at the annual meeting of the Pan-American Society for Pigment Cell Research, College Station, TX, June, 2000 MELANOCYTE GENES AND VITILIGO SUSCEPTIBILITY: A CASE-CONTROL
ASSOCIATION STUDY Vitiligo is characterized by progressive depigmentation of the skin due to
autoimmune destruction of epidermal melanocytes and/or their auto-destruction
due to toxic melanin biosynthesis metabolites. The association of vitiligo with
other autoimmune disorders suggests that genetic susceptibility to autoimmunity
may involve both target organ-specific genes and immune response genes. We have
used case-control association to examine the possible role of ten candidate
vitiligo susceptibility genes associated with melanocyte biology: phenylalanine
hydroxylase (PAH), tyrosinase (TYR), tyrosinase-related protein-1 (TRP1),
tyrosinase-related protein-2 (TRP2), tyrosine hydroxylase (TH), GTP
cyclohydrolase 1 (GCH1), catalase (CAT), neurofibromin (NF1), c-kit (KIT), and
Waardenburg syndrome 1 (PAX3). DNA was isolated from peripheral blood leukocytes
of 460 vitiligo patients and family members and 184 Caucasian control subjects
with no history of autoimmunity. Samples were genotyped using PCR-based methods
for single nucleotide polymorphisms (SNP), restriction fragment length
polymorphisms (RFLP), or microsatellite markers located within each candidate
gene. The frequencies of each allele and genotype in ~180 Caucasian vitiligo
patients and control subjects were compared by chi-square analysis for 17
genetic markers. Among the tyrosinase gene family members, genetic association
was suggested only for TYR by one of three genetic markers. Similarly,
association was suggested by one of four genetic markers for PAH. Single genetic
markers suggested association with CAT and TH. No association was suggested by
markers for TRP1, TRP2, GCH1, NF1, KIT, or PAX3. These studies provide
preliminary evidence for genetic association of several candidate genes with
vitiligo. (Supported by the National Vitiligo
Foundation) |
