Gene functions
|
Mission To study cellular and molecular background of the autoimmune disease APECED which belongs to the Finnish disease inheritage. Our goal is by understanding the regulation of immunological tolerance to reveal the mechanisms of common autoimmune diseases. |
|
Research APECED autoimmune disease Autoimmune diseases, like type I diebetes, celiakia, multiple sclerosis and rheumatoid arthritis, are common diseases, with environmental and multigenic background. Our group studies a rare recessively inherited autoimmune disease APECED, which is caused by mutations in one single gene. Thus it is an unique and important study model for autoimmune diseases and immunological tolerance. Genotype-phenotype relationships in APECED APECED patients typically have variable spectrum of symptoms, even within one single family. By analyzing more than 100 APECED patients we found that AIRE genotype slightly, but HLA II alleles more distinctly, affects the appearance of certain disease components. This indicates that even if APECED is a monogenic disease other genes modify the disease phenotype. AIRE protein and molecular pathogenesis of APECED APECED is caused by mutations in AIRE gene located in the chromosome 21. This gene directs the synthesis of AIRE protein. When expressed transiently in cell cultures AIRE protein was located both in cytoplasm and in nucleus, where it formed distinct dots. We determined the consequences of several APECED mutations at cellular and biochemical levels and found that the mutations could lead into abnormal subcellular location and into defects in homo- or heteromultimerization and transactivation functions of AIRE. This analysis also revealed multiple functions of the different AIRE domains. Currently we are analyzing the AIRE containing molecular complexes as well as the regulation of promoter of the AIRE gene. AIRE and immunological tolerance We (Leena Peltonen) have produced a AIRE knock-out mouse model for APECED, which provides an exellent opportunity to study the role of Aire in development and maintenance of immunological tolerance and homeostasis in central and peripheral organs. Further, these mice enable us to explore the possibilities to develop therapeutic approaches for autoimmune diseases. Research group Ismo Ulmanen, Principal investigator, Ph.D.,
docent
Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J. (2002) AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. 87(6):2568-74. Halonen, M., Kangas, H., Rüppell, T., Ilmarinen, T., Ollila, J., Kolmer, M., Vihinen, M., Palvimo, J., Saarela, J., Ulmanen, I., Eskelin, P. (2004) APECED-causing mutations in AIRE reveal the functional domains of the protein. Human Mutation 23(10): 245-257. Ilmarinen T., Eskelin P., Halonen M., Rüppell T., Kilpikari R., Duran Torres G., Kangas H. and Ulmanen I. (2005) Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Human Mutation, 26(4):322-31. Ulmanen I, Halonen M, Ilmarinen T, Peltonen L. (2005) Monogenic autoimmune diseases – lessons of self-tolerance. Current Opinion in Immunology, Dec;17(6):609-15. Ilmarinen T., Melen K., Kangas H., Julkunen I., Ulmanen I, and Eskelin P. (2006) The monopartite nuclear localisation signal of autoimmune regulator mediates its nuclear import and interaction with multiple importin - molecules. The FEBS Journal, 273:315-324. Pöntynen N, Miettinen A, Arstila T.P, Kämpe O, Alimohammadi M,
Vaarala O, Peltonen L, Ulmanen I. (2006) Aire deficient mice do not
develop the same profile of tissue-specific autoantibodies as
APECED patients. Journal of Autoimmunity, in press. |
Additional information  Docent Ismo Ulmanen e-mail: firstname.lastname@ktl.fi |