E. Helen Kemp

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo

BACKGROUNDnGeneralized 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.nnnMETHODSnTo 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.nnnRESULTSnWe 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=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.nnnCONCLUSIONSnWe 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.

Autoimmune aspects of vitiligo.

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact cause of the condition remains to be established, an autoimmune aetiology has been suggested and several observations support this theory. These will be the topic of discussion in this review. In brief, the disease is frequently associated with other disorders which have an autoimmune origin such as autoimmune thyroiditis and insulin-dependent diabetes mellitus. Furthermore, circulating antibodies and T lymphocytes which react against melanocyte antigens are present in the sera of a significant proportion of vitiligo patients compared with healthy individuals. Immunosuppressive therapies which are reasonably effective in treating the condition, well-studied animal models of the disease as well as the association of vitiligo with MHC antigens, all add credence to the hypothesis that immune mechanisms play a role in the development of vitiligo

Immunological pathomechanisms in vitiligo

Vitiligo is a depigmenting disorder characterised by the loss of melanocytes from the cutaneous epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses frequently observed in vitiligo patients have led to the suggestion that, in some cases, the condition has an autoimmune component. Briefly, circulating autoantibodies and autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. In addition, vitiligo is often associated with other disorders that have an autoimmune origin, including Hashimotos thyroiditis, Graves disease, type 1 insulin-dependent diabetes mellitus and Addisons disease. Furthermore, effective use of immunosuppressive therapies to treat vitiligo, the association of vitiligo with certain major histocompatibility complex antigens, and evidence from animal models of the disease have all added credence to the hypothesis that immune reactions play a role in vitiligo pathogenesis. This review presents and discusses the evidence for immunological pathomechanisms in vitiligo.

An insertion/deletion polymorphism in the gene encoding angiotensin converting enzyme is not associated with generalised vitiligo in an English population.

Vitiligo is an acquired hypomelanotic skin disorder characterised by circumscribed depigmented macules resulting from the loss of functional melanocytes from the cutaneous epidermis and autoimmunity has been suggested to play a role in the pathogenesis of the disease. Recently, an insertion/deletion (I/D) polymorphism of a 287-base pair repetitive sequence in intron 16 of the angiotensin converting enzyme (ACE) gene has been associated with autoimmune disease and with the development of vitiligo. In this study, the distribution of ACE gene I/D genotypes was investigated in a population of 106 English patients with generalised (non-segmental) vitiligo and 174 ethnically matched healthy controls using a restriction fragment length polymorphism-polymerase chain reaction genotyping method. No significant difference in the frequencies of II, ID and DD genotypes was detected between vitiligo patients and control subjects (P=0.35). The same result was evident for the genotype distribution in vitiligo patients with an autoimmune disease and for those without when compared with controls (P=0.33 and P=0.53, respectively). In addition, the results indicated that the D allele was not significantly over-represented in the group of patients with vitiligo compared with controls (P=0.42) and that this was also the case for patients with and without associated autoimmunity (P=0.40 and P=0.62, respectively).

Autoantibodies as diagnostic and predictive markers of vitiligo.

Vitiligo is an acquired hypomelanotic disorder characterised by circumscribed depigmented macules resulting from the loss of functional melanocytes and of melanin from the epidermis. Large population surveys have shown a prevalence ranging from 0.38 to 1.13% and, in 50% of cases, the condition begins before the age of 20 years. More women than men are referred with vitiligo, although the incidence of the disorder is not believed to be sexlinked. Familial cases of vitiligo are common, indicating a hereditary factor: between 6 and 38% of vitiligo patients have family members with the disease. However, studies have indicated that vitiligo is not transmitted by a simple mendelian mechanism and its inheritance pattern is more consistent with a polygenic trait. Although, at first, vitiligo might be viewed as a minor disorder, the impact on patients’ self-esteem and social interactions can be devastating, particularly in patients with deeply pigmented skin. Three major hypotheses for the pathogenesis of vitiligo have been proposed. The neural hypothesis suggests that the accumulation of a neurochemical substance such as a toxin released from nerve endings decreases melanin production as a result of damage to melanocytes. The biochemical hypothesis implicates the accumulation of toxic intermediate products of melanin synthesis, the breakdown of free radical defence and the build-up of excessive quantities of hydrogen peroxide in the selfdestruction of pigment cells. An autoimmune aetiology has also been proposed to explain the depigmentation characteristic of vitiligo. The frequent association of vitiligo with autoimmune diseases, together with studies demonstrating that many vitiligo patients have autoantibodies and autoreactive T lymphocytes against melanocyte antigens, add support to the theory. Other possible causes of vitiligo have been proposed, including stress, infections, genetic factors, melatonin receptor dysfunction, and impaired melanocyte migration and/or proliferation. It is possible that these different causal factors can act independently or together to yield the same effect, namely the disappearance of melanocytes from the skin and this is proposed in the convergence theory. For example, autoimmunity might arise as a secondary phenomenon following the auto-destruction of melanocytes. This might then amplify the damage to pigment cells. Clinically, two large subsets of vitiligo are distinguished: focal/segmental vitiligo and non-segmental vitiligo. Focal vitiligo presents with a limited number of small lesions while segmental vitiligo is typified by an asymmetric dermatomal distribution of depigmented macules. Non-segmental vitiligo corresponds to all generalised, usually symmetrical, forms including acrofacial vitiligo. The course of the disease is unpredictable but is often progressive with phases of stabilised depigmentation. An extending vitiligo with enlarging macules or the development of new lesions is classified as the active form of the disease. Different pathogenic mechanisms could account for the various clinical types of vitiligo: the neural theory is more usually related with segmental vitiligo whereas the autoimmune hypothesis is thought to be involved in the generalised form of the disorder. Indeed, non-segmental vitiligo is characterised by an association with autoimmune disease and unstable results after autologous melanocyte grafting. The autoimmune phenomena of vitiligo are currently well investigated in terms of both cellular and humoral reactivity and are extensively reviewed. Autoantibodies to melanocytes have been detected in significant numbers of vitiligo patients, although the exact contribution they have to vitiligo pathogenesis remains unresolved. Pigment cell antibodies might result from a genetic predisposition to immune dysregulation at the T-cell level. Alternatively, cross-reacting antigens expressed either on other target cells or on infecting

First report of anti-calcium-sensing receptor antibodies in a patient with Sjögren's syndrome and primary hypoparathyroidism

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