Nils Landegren

Severe illness from infectious diseases affects only a small fraction of exposed individuals, with genetic factors playing a role, but much of this variability remains unexplained. During the COVID-19 pandemic, ~10% of critically ill patients were found to harbor autoantibodies that block type I interferons, revealing cytokine autoantibodies as a key factor in infection susceptibility. However, current means to identify cytokine autoantibodies are limited, and their broader role in infectious diseases is likely underestimated, leaving individuals at risk undiagnosed and without specific treatment.This project aims to identify cytokine autoantibodies with pathogenic roles in infectious diseases. Leveraging our established methodology and access to unique patient cohorts, we will screen for autoantibodies against over 200 cytokines in blood samples from thousands of patients with viral, bacterial, fungal, and parasitic diseases. Identified autoantibodies will undergo functional characterization to assess their impact on immune responses and disease severity. Additionally, we will investigate whether type I IFN autoantibodies may have a protective role in systemic autoimmune diseases driven by IFN overactivation, investigating their presence and functional effects in patients with SLE.The findings could have a significant clinical impact by identifying cytokine autoantibodies with causative roles in disease, guiding prevention strategies and treatment.

Severe illness from viral infections affects only a small fraction of exposed individuals, with genetic factors playing a role, but much of this variability remains unexplained. During the COVID-19 pandemic, ~10% of critically ill patients were found to harbor autoantibodies that block type I interferons, revealing cytokine autoantibodies as a key factor in infection susceptibility. However, current means to identify cytokine autoantibodies are limited, and their broader role in viral diseases is likely underestimated, leaving individuals at risk undiagnosed and without specific treatment.This project aims to identify cytokine autoantibodies with pathogenic roles in viral diseases. Leveraging our proven high-throughput screening platforms and access to unique patient cohorts, we will analyze blood samples from thousands of individuals with over 20 different viral illnesses to detect autoantibodies against a panel of more than 200 cytokines. Identified autoantibodies will undergo functional characterization to assess their impact on immune responses and disease severity. Furthermore, we will evaluate a cost-effective approach to cytokine autoantibody diagnostics based on dried blood spots with potential for population-level screening.The findings could have a significant clinical impact by identifying cytokine autoantibodies with causative roles in viral disease, guiding prevention strategies and treatment, and strengthening preparedness for future pandemics.

In recent years, it has become increasingly clear that the immune system's ability to react against tumor cells constitutes an important protection against cancer. However, this defense can also result in attacks on healthy organs and cause serious so-called paraneoplastic disease states. Paraneoplastic pemphigus is a serious disease that involves both skin and mucous membranes. The disease often debuts with blistering in individuals with as yet undetected cancer. There is therefore a great need for reliable diagnostic markers that can enable early diagnosis so that the underlying cancer can be detected without delay. I intend to characterize immune responses and identify new diagnostic blood markers in tumor-associated autoimmune skin diseases. The studies are initially focused on paraneoplastic pemphigus and then expanded to a larger group of blistering diseases. Serum samples are examined for immunoreactivity against a panel of thousands of proteins following methodology I developed in previous studies. The results will then be used to develop a test that can support the clinical diagnosis of autoimmune skin diseases and detect cases of undetected cancer. The study will provide knowledge about immunological mechanisms underlying severe paraneoplastic syndromes and enable improved diagnostics. The project aims to develop a diagnostic tool to detect undiagnosed cancer in patients with new-onset bladder-forming diseases, with the aim that more individuals with cancer will have the opportunity for curative surgical treatment. The study may also allow for a broader understanding of how the immune system protects against cancer, and thus gain importance for cancer treatment more generally.

Women face a four-fold higher risk of developing an autoimmune disease compared to men. Sex differences in immune-mediated disorders are well-documented, but have remained poorly understood and are not taken into account in current therapies. To improve treatment of sex-biased autoimmune disorders I believe it will be essential to gain a much deeper understanding of fundamental factors controlling sex differences in the human immune system. The present proposal applies two uniquely informative human model systems to determine the separate roles of sex hormones and sex chromosomes in immune regulation. First we will investigate how the immune system is transformed during female-to-male and male-to-female sex change, utilizing samples collected in a multicenter study that I am coordinating. A combination of broad-scale technologies will be applied to follow dynamics provoked by sex hormone transition in peripheral blood immune cells, autoimmune reactivity, plasma proteins, and gut microbiota. As a complementary model to capture effects mediated by sex chromosomes, we will study mosaic individuals harboring immune cells with both female and male karyotypes in peripheral blood. Single cell transcriptomic analysis will be used to compare these cell populations, thereby revealing the influence of chromosomal sex in an otherwise fixed genetic and hormonal background. These model systems will be combined with population-based studies - taking advantage of new data on sex hormone levels and sex chromosome karyotypes in 500,000 women and men (UK Biobank), which will allow us to determine how these factors ultimately influence the risk of autoimmune disease. I believe this novel approach will offer groundbreaking insights into the biology of sex differences of human immune systems, thus providing a foundation for development of new treatment strategies for sex-biased autoimmune disorders.