Alopecia and vitiligo in autoimmune polyendocrine syndrome type I

Sammanfattning: Autoimmune polyendocrine syndrome type I (APS I) is a recessively inherited disease caused by mutations in a recently identified gene, AIRE, on human chromosome 21. APS I patients are affected by autoimmune destruction of multiple endocrine glands and other organs as well as ectodermal structures. By use of high-titer organs-specific autoantibodies from patients withAPS I we have studied the antigenic structures targeted in hair follicles and skin that are related to alopecia areata and vitiligo. Through immunofluorescence staining of human scalp tissue with 39 APS I patients, we identified immunoreactivity against differentiating keratinocytes in the hair follicle correlating with alopecia totalis (p<0.0001). A human scalpcDNA library was then constructed and by immuno-screening of the in vitro expressed tissue-specific proteins, with sera from APS I patients with both alopecia and vitiligo, we subsequently identified two major autoantigens. These were tyrosine hydroxylase (TH), the key enzyme in dopamine synthesis, and the transcription factor SOX9, structurally homologous with SOX10. Out of 94 APS I patients, 44% showed the TH immunoreactivity, correlating with alopecia areata (p<0.024), and 22% of 91 patients showed immunoreactivityagainst SOX9 and SOX10 correlating with vitiligo (p<0.0001). Both SOX9 and SOX10 expression was detected in hair follicle and epidermal melanocytes. One out of 20 sera from patients with Parkinson's disease displayed immunoreactivity against TH isoforms 2 and 4. By DNA alignment analysis, we identified an epitope of 10 amino acids present in these iso-enzymes and potentially related to the reactivity found in this patient. These 10 amino acids showed high homology with the RNA polymerase subunit P3 of the Influenza A virus.In conclusion, we have identified the transcription factors SOX9 and SOX10 as vitiligo autoantigens and tyrosine hydroxylase as an autoantigen related to alopecia areata in APS I. We have also shown that patients with APS I have immunoreactivity against a hair follicle keratinocyte autoantigen associated with alopecia totalis. Additionally. we present data supporting the hypothesis of molecular mimicry in a subgroup of patients with Parkinson'sdisease.