Nils Landegren research group
Our immune systems are protecting us against invading organisms, but it can also give rise to detrimental responses directed against our own bodies. Autoimmunity is one of the leading causes of morbidity world-wide. Our team performs large-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 profiling
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 responses in many cases mediate tissue-damage, the humoral responses can be explored to identify novel immune targets and allow diagnostic applications. In our studies of autoimmune disorders we combine several tools for explorative proteome-wide autoantibody studies and high-throughput screening of large cohorts.
Cytokines enable coordination between cells, and they are critical for functional responses against pathogens. Mutations in genes encoding cytokines or their receptors are a well-known reason for infectious disease susceptibility. We now realize that autoantibodies blocking cytokines is yet another mechanism broadly influencing susceptibility to infections by viruses, bacteria, and fungi. The recent finding of type I IFNs autoantibodies as an explanation for a severe course of COVID-19 is a pertinent example. Our research aims at identifying cytokine autoantibodies underlying infectious disease susceptibility and to support new treatments. In our ongoing collaborations we study patients with COVID-19 and other infections, as well as adverse vaccine reactions and hyperinflammatory conditions. For these purposes we have developed a targeted assay to broadly assess cytokine autoantibodies in high-throughput.
Insights in the ability of the immune system to elicit tumor-specific immune responses that protect against cancer is growing rapidly. However, the immune system can also engage in misdirected attacks on healthy tissues – in what is referred to as paraneoplastic autoimmune syndromes. Knowledge of the involved immunological events is critical for understanding, diagnosing and treating these often very severe syndromes. Furthermore, since paraneoplastic manifestations often present in individuals whose cancers have not yet been diagnosed, there is a valuable opportunity to search for reliable biomarkers of paraneoplasia, in order to initiate investigations for occult malignancy. In our ongoing collaborations we are characterizing autoantibody reactivities in patients with cancer and severe autoimmune manifestations such as skin blistering.
Sex differences in autoimmunity
Women face a four-fold higher risk of developing autoimmune disease, whereas men tend to suffer worse outcomes of infections such as COVID-19. Sex differences in immunity have remained poorly understood, and are not taken into account in current clinical management.
The overarching aim of my ERC-funded SEXimmune project is to dissect this 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 at Karolinska Institutet, and with SciLifeLab. As one part of this work we are studying women and men who are initiating treatment with cross-sex hormones for gender reassignment. By sampling individuals before, during and after hormonal reassignment we are able to study direct effects of sex hormones on the immune system. Multiple technologies are combined to broadly assess the dynamics of immune phenotypes and functional responses over the course of hormone treatment. In a complementary approach with the focus on genetic factors we study and compare immune cells from patients with different sex chromosome aberrations. We hope that this work will enable better understanding of sex differences in immune-related diseases and treatments better tailored to each sex.
Our research is supported by the European Research Council (ERC), the Swedish Research Council, the Swedish Cancer Society, Göran Gustafsson Foundation, and Cornell foundation, amongst others.