AbstractsMedical & Health Science

New insights in Autoimmune Polyendocrine Syndromes 1 and 2

by Nicolas Kluger

Institution: University of Helsinki
Department: Institute of Clinical Medicine, Department of Dermatology, Venereology and Allergology
Year: 2015
Keywords: endocrinology
Record ID: 1130276
Full text PDF: http://hdl.handle.net/10138/153326


Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene located on chromosome 21 (21q22.3). AIRE deficiency causes a loss in central immune tolerance, leading to the failure to eliminate autoreactive T cells in the thymus and allowing their escape to the periphery. Because of a founder effect, APECED is particularly prevalent in Finland (1/25,000) but is observed worldwide with variable prevalence. APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine autoimmune diseases such as primary hypoparathyroidism, adrenal insufficiency, primary hypogonadism, type 1 diabetes, hypothyroidism, and hypophysitis. They may also develop additional nonendocrine autoimmune diseases, such as alopecia areata/totalis, vitiligo, gastro-intestinal (GI) diseases, keratitis or tubulointerstitial nephritis (TIN). In addition, the patients typically develop a variety of serum tissue-specific autoantibodies, which are predictive of the development of autoimmune disease and anticytokine antibodies such as those against type I interferons and Th17-related interleukin IL-17 and IL-22. The aim of this thesis was to study such manifestations of APECED that have not been well characterized before and also, to study health-related quality of life among Finnish APECED and Addison s disease/APS2 patients. We evaluated the clinical GI features and searched for novel markers of GI dysfunction in a Finnish cohort of 31 APECED patients. The main upper GI symptoms were dysphagia and retrosternal pain (45%) and the lower GI symptoms were constipation (48%), diarrhoea (45%) and malabsorption (16%). Previously, L-amino-acid decarboxylase (AADC) and tryptophan hydroxylase type 1 (TPH-1) antibodies have been demonstrated in APECED. AADC antibodies were found in 51% and TPH-1 antibodies in 39% of all patients. Also, a T cell response to AADC was detected in 43%. One third of the patients had autoimmune enteropathy (AIE)-related 75 kDa antigen (AIE-75, 33%) and villin (29%) autoantibodies, and antibodies against brush borders and Paneth cells (PCs) were detected in 29% and 20%, respectively. Mucosal intestinal IL-17 expression was decreased or negative in 77% of the intestinal samples. Duodenal chromogranin A and serotonin expression was absent or decreased in 50% and 66% of the patients, respectively. Of the clinical symptoms, constipation correlated with negative serotonin staining (p less than 0.05) and with AADC antibodies (p = 0.019). Importantly, we found a correlation between autoantibodies against AADC, which are critical for serotonin and DOPA synthesis, and constipation. Constipation was also associated with a lack of serotonin expression in the enteroendocrine cells (EECs). Paneth cells (PCs) were lacking in the duodenum in 20% of our intestinal samples, even though this was not associated with GI symptoms. In this Finnish APECED patient cohort, 17% (5/30) had moderate-to-severe renal failure,…