title: Interleukin-2 and subunit alpha of its soluble receptor in autoimmune Addison's disease--an association study and expression analysis.
abstract: Autoimmune Addison's disease (AAD) results from T cell-mediated destruction of the adrenal cortex, commonly accompanied by autoantibodies to 21-hydroxylase (21OH). In order to gain insight into the obscure aetiology of this disease, we investigated the roles of the IL2 and IL2RA genes, encoding interleukin-2 and subunit alpha of its receptor (IL2Ra), respectively. The association of AAD with IL2 and IL2RA polymorphisms (rs6822844, rs2069762, rs3136534, rs11594656, rs3118470 and rs2104286) was tested in 223 patients and 672 healthy controls. Functional studies consisted of gene expression analysis in cultured PBMCs exposed to 21OH and evaluation of serum interleukin by ELISA assays. The frequency of the minor C allele of rs3136534 was significantly decreased in AAD subjects compared to controls (OR 0.71; 95%CI 0.561-0.887; p = 0.003). Only AAD cells responded to 21OH with an elevated IL2 and IL2RA mRNA synthesis (p = 0.004 and p = 0.009 versus controls, respectively), paralleled by increased supernatant levels of both cytokines (p = 0.031 and p = 0.001 versus controls). IL2 mRNA level in 21OH-stimulated AAD PBMCs correlated negatively with age (p = 0.036) and positively with serum antibodies to 21OH (p = 0.006). Carriers of the rs2104286 AA genotype demonstrated higher IL2RA mRNA (p = 0.022) and soluble IL2Ra secretion (p = 0.029) upon 21OH stimulation. Serum interleukin-2 in AAD subjects was significantly higher compared to controls (4.61 ± 4.3 versus 1.71 ± 3.2 pg/mL, p < 0.001), whereas sIL2Ra levels remained similar in both groups (p = 0.885). In conclusion, the study reveals an association between AAD and IL2 locus. It confirms specific 21OH-directed reactivity of the peripheral AAD lymphocytes, which display increased synthesis of interleukin-2 and sIL2Ra.
authors.affiliation: Department of Endocrinology and Metabolism, Poznan University of Medical Sciences , Poznan , Poland .
authors.forename: Marta
authors.initials: M
authors.lastname: Fichna
authors.forename: Magdalena
authors.initials: M
authors.lastname: Żurawek
authors.forename: Eirik
authors.initials: E
authors.lastname: Bratland
authors.forename: Eystein S
authors.initials: ES
authors.lastname: Husebye
authors.forename: Anna
authors.initials: A
authors.lastname: Kasperlik-Załuska
authors.forename: Barbara
authors.initials: B
authors.lastname: Czarnocka
authors.forename: Danuta
authors.initials: D
authors.lastname: Januszkiewicz-Lewandowska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Nowak
mesh_terms: D000224:Addison Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000311:Adrenal Glands / Q000276:immunology / Q000473:pathology; D000328:Adult; D000367:Age Factors; D000483:Alleles; D001323:Autoantibodies / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D012995:Solubility; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D013255:Steroid 21-Hydroxylase
keywords: 21-hydroxylase; adrenal insufficiency; interleukin-2; interleukin-2 receptor subunit alpha; polymorphism