Polyglandular Autoimmune (PGA) Syndromes and associations to sarcoidosis

Abstract: Polyglandular Autoimmune (PGA) syndrome type II in idiopathic Addison's disease: In a retrospective study of idiopathic Ad-dison's disease (median age at diagnosis 32.5 years, range 8-62; median observation time 17 years, range 0.5-41), 50% met the criteria for PGA syndrome type II. In PGA syndrome type II, 73% had ATD and 41% had IDDM. The full triad was present in 14%. The sequence of appearance differed between ATD and IDDM in relation to Addison's disease. All pa-tients with ATD preceding Addison's disease, almost 50%, had Graves' disease. On the other hand, Hashimoto thy-roiditis did not develop prior to Addison's disease in any of the patients. In contrast to previous reports, IDDM preceded Addison's dis-ease in almost all patients and developed at a young age. Sarcoidosis: A novel association between PGA syndrome type III (ATD and IDDM), coeliac disease and sarcoidosis was presented and the report of an additional identical case in a series of 78 Swedish patients with sarcoidosis further supported its existence. In 78 patients with sarcoidosis (34 females, 44 males, median age at diagnosis 31 years, range 16-75, median observation time 120 months, range 1-468), 47.4% demonstrated at least one organ specific autoimmune phenomenon, defined as the presence of antibodies and/or clinical autoimmune disease. Endocrine autoimmunity was seen in 19.2% of the patients with sarcoidosis and overt clinical disease in 12.8% (thyroid autoimmunity in 16.7%, overt ATD in 10.2%). Despite a frequency of 37.4% of gastrointestinal immune reactivity (gastric autoimmunity in 24.2%, gluten-associated immune reactivity in 15.4%) only two patients with clinical gastrointestinal disease (pernicious anaemia, coeliac disease) were found of which one with the novel disease constellation of PGA syndrome type III, coeliac disease and sarcoidosis. The frequency of PGA syndromes ranged from 5% in clinical forms to 40% in serological forms. The reason for the discrepancy in the expression of clinical autoimmune disease between the endocrine autoimmunity and the gastrointestinal immune reactivity groups might be HLA related. HLA-DRB1'02, '14, -DQB1'0602, '0503, previously associated with chronic sarcoidosis in Scandinavian patients, were particularily frequent in the group with associated autoimmune manifestations and gastrointestinal immune reactivity, while patients with sarcoidosis and thyroid autoimmunity/ATD presented with haplotypes (DRB1'03, '04 - DQB1'0201, '0301, '0302 –DRB1'12) usually associated with the corresponding autoimmnune diseases. In sarcoidosis-associated thyroid autoimmunity, ATD-specific immunogenetic factors prevail, overriding the associations of -DRB1'02, '14 and -DQB1'0602, '0503 in clinical situations dominated by sarcoidosis. S-ACE levels were significantly increased in sarcoidosis associated with autoimmune manifestations compared to isolated sarcoidosis and the ACE-gene DD-genotype, encoding for the highest s-ACE levels, was significantly increased in autoimmunity-associated sarcoidosis X-ray stage III (theoretically with major granuloma mass). The high frequency of associated autoimmunity in sarcoidosis supports a role for this disease in the manifestation of autoimmunity. Our findings support the hypothesis that different immunogenetic profiles exist in sarcoidosis indicative of distinct clinical subgroups. Possibly, the role of HLA class II genes in sarcoidosis is related to their function as antigen-presenting molecules. HLA class II presentation of a putative sarcoidosis-specific antigen in conjunction with the high S-ACE levels encoded by the DD genotype in autoimmunity-associated sarcoidosis might be of vital importance, modulating the immune response, possibly leading to a chronic form of sarcoidosis with serological abnormalities and a slow or no progression to clinical autoimmune disease.