Genetic and serological characteristics of tissue-specific autoimmune disease

The immune system has evolved to protect us from infectious disease and not to overreact to our own tissues or commensal flora. Immune system attack directed against self-tissue is referred to as autoimmune disease, a group of diseases that affect more than 5% of the population. Hypothyroidism and type 1 diabetes are well-known examples, resulting from the destruction of the thyroid gland, and of the insulinproducing beta cells in the pancreatic islets, respectively. Autoimmunity is also the predominant cause of primary adrenal failure, known as Addison’s disease, where the adrenal cortex is destroyed by the immune system. All four studies in this thesis were aimed to improve our understanding of autoimmune disease in terms of genetic risk factors, serological biomarkers, and tolerance mechanisms. Despite its high heritability, little is known about the genetic background of Addison’s disease. Paper I and II address the heritable risk factors in Addison’s disease and discover novel genetic risk variants. Early recognition of the rare syndrome autoimmune polyendocrine syndrome type I (APS1) is essential for prevention of its potentially lethal complications. By identifying four previously undiagnosed patients with APS1, Paper III is a proof-of-concept study showing that serological screening of patients with Addison’s disease can identify otherwise undiagnosed APS1 patients. Paper IV studies peripheral immune tolerance by investigating the serologic repertoire in patients with mutations in FOXP3, lacking regulatory T lymphocytes. Autoantibodies against a set of structurally unrelated enterocyte antigens are demonstrated, including tissue-specific nuclear receptors. In summary, this thesis takes on several aspects of autoimmunity. Both genetic, serological and clinical studies are integrated to explore new characteristics of tissue-specific autoimmune disease. LIST OF SCIENTIFIC PAPERS I. Eriksson D*, Bianchi M*, Landegren N, Nordin J, Dalin F, Mathioudaki A, Nordling Eriksson G, Hultin-Rosenberg L, Dahlqvist J, Zetterqvist H, Karlsson Å, Hallgren Å, Farias F. H. G, Murén E, Ahlgren K. M, Lobell A, Andersson G, Tandre K, Dahlqvist S. R, Söderkvist P, Rönnblom L, Hulting A. -L, Wahlberg J, Ekwall O, Dahlqvist P, Meadows J. R. S, Bensing S, Lindblad-Toh K, Kämpe O†, Rosengren Pielberg G. † *† Equal contributions Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison’s disease Journal of Internal Medicine, 2016, 280(6): 595–608. II. Eriksson D, Bianchi M, Landegren N, Dalin F, Skov J, HultinRosenberg L, Mathioudaki A, Nordin J, Hallgren Å, Andersson G, Tandre K, Dahlqvist S, Söderkvist P, Rönnblom L, Hulting A-L, Wahlberg J, Dahlqvist P, Ekwall O, Meadows J, Lindblad-Toh K, Bensing S, Rosengren Pielberg G, Kämpe O Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison’s disease Manuscript in revision. III. Eriksson D, Dalin F, Nordling Eriksson G, Landegren N, Bianchi M, Hallgren Å, Dahlqvist P, Wahlberg J, Ekwall O, Winqvist O, Catrina SB, Rönnelid J, The Swedish Addison Registry Study Group, Hulting AL, Lindblad-Toh K, Alimohammadi M, Husebye E. S, Knappskog P. M, Rosengren Pielberg G, Bensing S, Kämpe O Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1 Journal of Clinical Endocrinology and Metabolism, 2018, 103(1): 179-186. IV. Eriksson D, Bacchetta R, Gunnarsson H. I, Chan A, Barzaghi F, Ehl S, Hallgren Å, van Gool F, Sardh F, Laakso S. M, Rönnblom A, Ekwall O, Mäkitie O, Bensing S, Husebye E. S, Anderson M, Kämpe O, Landegren N Patients deficient in regulatory T cells target enterocyte antigens Manuscript