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
