Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo

Abstract

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 familybased 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 antimelanocyte autoimmune response involved in vitiligo pathogenesis.

Development and Characterization of Proteasome Inhibitors

“…Consequently, the spectrum of the produced peptides is shifted toward peptides that associate with MHC class I molecules with increased affinity (Fruh et al, 1994), implicating a major role of immunoproteasome in antigen presentation. Furthermore, it has been suggested that the immunoproteasome may be involved in some pathological processes, such as diabetes and autoimmune diseases (Casp et al, 2003). However, the exact role of the immunoproteasome remains unclear, caused in large part by the lack of appropriate molecular probes.…”

Could ER Stress Be A Major Link Between Oxidative Stress And Autoimmunity In Vitiligo?

“…Though LMP/TAP gene cluster is located on MHC class II region of chromosome 6, it is involved in antigen presenting function of MHC class I molecule. Different researchers have reported association of LMP7 and TAP1 with vitiligo susceptibility [151]. LMP2 and LMP7 are also involved in the degradation of ubiquitin tagged cytoplasmic proteins to peptides while, TAP1 and TAP2 are involved in transportation of peptides into the endoplasmic reticulum for exposure to nascent MHC class I molecules [150].…”

“…It has been reported that defects in the expression of different components of the MHC class I antigen processing machinery, such as the proteasomal subunits LMP2 and LMP7 and the peptide transporters TAP1 and TAP2, account for impaired MHC class I surface expression [151]. Further, an inappropriate expression or functioning of LMP7 might inhibit antigen processing and presentation, leading to a loss of peripheral tolerance to self-antigens and occurrence of several autoimmune diseases [151]. In this context, Ulianich et al [152] have shown ER stress induced decrease in surface expression of MHC class I in thyroid cells.…”

“…ER stress may result in decreased expression of MHC class I on the cell surface, thereby preventing the recognition of cells by the adaptive and innate immune system [162,163]. It has been reported that defects in the expression of different components of the MHC class I antigen processing machinery, such as the proteasomal subunits LMP2 and LMP7 and the peptide transporters TAP1 and TAP2, account for impaired MHC class I surface expression [151]. Further, an inappropriate expression or functioning of LMP7 might inhibit antigen processing and presentation, leading to a loss of peripheral tolerance to self-antigens and occurrence of several autoimmune diseases [151].…”

Lack of association between catalase gene polymorphism (T/C exon 9) and susceptibility to vitiligo in a Turkish population

“…The complex genetics of vitiligo probably involves multiple susceptibility loci, genetic heterogeneity and incomplete penetrance with gene-gene and gene-environment interactions (Zhang et al, 2005). Increasing number of studies have demonstrated that certain genes are crucial for the development of vitiligo (Le Poole et al, 2001;Arcos-Burgos, 2002;Casp et al, 2002Casp et al, , 2003Zhang et al, 2004a;Jin et al, 2004;Yang et al, 2005). Moreover, more than one genome-wide screen has localized vitiligo susceptibility loci on several chromosomes (Alkhateeb, 2002;Fain et al, 2003;Spritz et al, 2004;Chen et al, 2005).…”