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

Abstract

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 (p < 0.0001). 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.The autosomal recessively inherited disease autoimmune polyendocrine syndrome type I (APS I), 1 also called autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), is characterized by organ-specific autoimmunity, mucocutaneous candidiasis, and ectodermal manifestations (1). The gene responsible for the syndrome has been identified recently and named autoimmune regulator (AIRE), coding for a protein with the characteristics of a transcription factor (2, 3).Two of the classical triad of mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency, are required for the clinical diagnosis of APS I(4). Other severe manifestations such as autoimmune chronic active hepatitis, gonadal failure, malabsorption, and insulin-dependent diabetes mellitus may also affect the patients. Furthermore, ectodermal manifestations such as vitiligo, alopecia, and nail and enamel dystrophy are seen frequently (1,5). High titer autoantibodies against affected tissues is a hallmark of APS I. The antigenic structures identified, tissue-specific key enzymes (6 -13), have been shown to be important, some of which seem to act as autoantigens also in other more common autoimmune diseases (14).Vitiligo is a depigmenting skin disorder with a prevalence in the general population of about 1% (15). The etiology is largely unknown, but autoimmune mechanisms are thought to be involved. It is associated with various autoimmune disorders (16) such as insulin-dependent diabetes mellitus (17), thyroid disease (18,19), and pernicious anemia (20,21) and is often a component in autoimmune polyendocrinopathies (4) including APS I (1, 5). Autoantibodies against melanocytes have been reported in patients with vitiligo unrelated to APS I (22, 23), but the major autoantigens in vitiligo are yet to be identified. The possible roles of tyrosinase, tyrosinase-related protein 1 (TPR-1), and tyrosinase-related protein 2 (TPR-2), key enzymes in the synthesis of melanin as well as the melanosomal matrix glycoprotein, pmel17 (24), as melanocyte autoantigens remain largely unresolved. Some studies report frequent immunoreactivity against these proteins in patients wi...

Melia azedarach extract stimulates melanogenesis through increase of tyrosinase-related protein 1 expression in B16F10 mouse melanoma cells

“…It occurs when melanocytes die or are unable to function. The exact cause of vitiligo remains unknown, although studies suggest that it may arise from autoimmune, genetic, oxidative stress, or viral causes (19,20). Exposing the skin to UVB light from UVB lamps is the most common treatment for vitiligo (21).…”

SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

“…Interestingly, ectopic SOX9 expression in the neural crest is sufficient to promote melanocytic differentiation (16), which suggests a role for SOX9 in melanocytic development. An active transcription of SOX9 protein in melanocytes within the skin also has been indirectly suggested by the presence of antibodies against SOX9 in the sera of vitiligo patients (17). Interestingly, the cAMP pathway, which plays a key role in melanocyte differentiation, also has been involved in the control of SOX9 function in chondrocytes (18,19).…”

Cutaneous manifestations of autoimmune polyglandular syndrome type 1 – case report and literature review

“…Kolejną, trzecią z najczęściej obserwowanych dermatoz w zespole APECED jest bielactwo, które występuje znacznie częściej (8-15%) u chorych z tą poliendokrynopatią niż w populacji ogólnej (0,5-2%) [37,38]. Pierwsze ogniska depigmentacji pojawiają się zwykle w pierwszej dekadzie życia (pomiędzy 1. miesiącem życia a 15. rokiem życia) [36].…”

“…zidentyfikowali w surowicy pacjentów z zespołem APECED krążące autoprzeciwciała skierowane przeciwko czynnikom transkrypcyjnym SOX9 i SOX10, które były obecne u 63% badanych pacjentów. Dodatkowo stwierdzili, że zwiększona immunoreaktywność przeciwko anty genom SOX9 i SOX10 koreluje z bielactwem i ły-sieniem plackowatym u pacjentów z tą poliendokrynopatią, natomiast przeciwciała przeciwko SOX10 występują również u pacjentów z bielactwem idiopatycznym, niezwiązanym z zespołami niedoczynności wielogruczołowej [38]. W piśmiennictwie istnieją pojedyncze doniesienia o współistnieniu APS-1 z zapaleniem naczyń, łuszczycą i pokrzywką przewlekłą [40][41][42].…”