Nils Landegren research group
The immune system provides critical protection against invading organisms but can also give rise to detrimental responses against our own bodies. Autoimmunity is now one of the leading causes of morbidity world-wide. Our team performs broad-scale analysis of autoimmune responses to understand disease mechanisms and provide better means for diagnostics. We also have a particular focus on the striking and poorly understood sex differences in risks for autoimmune diseases.
Proteome-wide autoimmunity studies
Autoimmune responses can ultimately be defined at the molecular level by the specific interaction between T- or B-cell receptors and distinct self-molecules. While the T-cell response in many cases mediates tissue-damage, the humoral response can be explored to identify novel immune targets and for diagnostic applications. In our studies of autoimmune disorders we combine several tools for explorative proteome-wide autoantibody studies, including high-throughput screening of large cohorts and diagnostic assessment of patients.
There are increasing data to suggest that cytokine autoantibodies may be an important mechanism behind immune dysregulation and infectious disease susceptibility, alongside genetic defects in the immune system. One such striking example is the findings of type I interferon autoantibodies in patients who develop critical COVID-19. We have ongoing collaborations to explore the roles of cytokine autoantibodies in autoimmunity syndromes as well as in COVID-19 and adverse vaccine response thereto. For these purposes we have developed a targeted screening panel that allows us to broadly assess cytokine autoantibodies in a high-throughput fashion.
Sex differences in autoimmunity
Women face a four-fold higher risk of developing an autoimmune disease, whereas men tend to suffer worse outcomes of infections such as COVID-19. Such sex differences in immunity have remained poorly understood, and are not taken into account in current clinical management.
The overarching aim our SEXimmune project is to dissect the biological basis for sex differences of human immune systems by assessing the separate roles of sex hormones and genetics. The studies are conducted in close collaboration with clinical partners and research teams, and with SciLifeLab. One of our approaches is to study individuals who are initiating treatment with cross-sex hormones for gender reassignment. By comparing samples collected before and after start of hormone treatment we can study the direct effects of sex hormones in a fixed genetic background. Multiple technologies are combined to broadly assess dynamics of immune phenotypes and functional responses. In a complementary approach focusing on genetic factors, we are studying patients whose cells are mosaic for sex chromosome karyotypes. This allows us to compare immune cells with female vs male karyotypes from the same individual, and thus to assess the genetic component of sex differences in cell-based immunity in the same hormonal environment. These two model systems are combined with population-level studies, taking advantage of recently collected data on sex hormone levels and sex chromosome aberrations for 500,000 women and men in UK Biobank. This allows us to study hormonal and genetic factors influencing risks of developing autoimmune diseases and severe COVID-19.
Our research is supported by the European Research Council, the Swedish Research Council, the Swedish Cancer Society, Göran Gustafsson Foundation, and Cornell foundation, amongst others.