Eva Kosek

Background: A growing body of evidence suggests an increasing prevalence of autoimmune diseases in the general population. The reason for this increase is unknown and cannot be explained by genetic factors only.Aims: The current study will investigate whether exposure to environmental contaminants, i.e. the exposome, can be linked to an increased risk for autoimmune diseases and chronic pain state, and their role in disease progression.Methods: We will analyze the causal relationship between the exposome and genetics, sex, and other known risk factors in large multiple sclerosis case-control cohorts (&gt

7,400 subjects), and nested case-control and prospective studies within the EpiHealth cohort (25,104 individuals) to explore if an interaction between the genetic profile and the exposome is relevant to develop an autoimmune disease. We will use our in-house high-resolution mass spectrometry infrastructure and computational expertise in the field.Impact: We expect this project to significantly advance our knowledge of the exposome´s role in developing an AID, its role in the disease progression and the pathophysiology of multiple sclerosis, and in chronic pain states. This may lead to recommendations for stricter regulations to minimize exposure to certain chemicals and how prevent the development of intractable chronic pain.

Fibromyalgia (FM) is a common chronic disorder characterized by widespread musculoskeletal pain, hypersensitivity, and fatigue. The causes of pathology in FM remain unknown and this gap in knowledge underlies the lack of therapeutic options. The common view is that FM is a CNS disease. However, new research points to an involvement of the peripheral nervous system. We recently discovered that transfer of antibodies (IgG) from FM patients to mice induces several aspects of the disease, including widespread pain. We found that FM IgG binds to satellite glial cells (SGC) in both human and mouse dorsal root ganglia (DRG) and that binding intensity to SGCs correlates with FM disease severity.Our preliminary data show striking cellular changes in skin biopsies from FM patients and that transfer of FM IgG to mice induces cellular changes in skin and mitochondrial dysfunction in DRG cells. Based on our this we aim to: 1. Characterize the cell landscape in human fibromyalgia skin using single cell RNA sequencing and advanced imaging. 2. Examine if IgG from FM patients induce cellular changes in mouse skin and how this correlates to induction of pain-related behaviors. 3. Investigate what aspects of mitochondrial function is affected by FM IgG mitochondrial in DRG and skin and it relates to pain.Our project will provide new insights peripheral mechanisms underpinning FM symptoms and potentially to pave the way for new treatment strategies for sub-populations of individuals with FM.

Fibromyalgia (FM) is a chronic pain condition characterized by widespread pain and tenderness. It affects 2-4% of the population and predominantly women. There are indications that environmental factors are of importance for the development of FM, which is the focus for the present project. We will take an holistic approach and investigate the exposome, encompassing the totality of exposures, of FM patients.   To measure the exposome we will use modern analytical chemistry methods and evaluate the data with bioinformatics tools, e.g. machine learning. We will use mass spectrometry to chemically profile hundreds of blood samples from FM patients and matched healthy controls. From the gathered data we will create exposome profiles that reflect the totality of exposures in these subjects. Through statistical multivariate methodologies we will compare the exposome profiles of the groups and evaluate the differences to conclude if there are underlying molecular mechanisms related to exposures of importance for FM. The project involves a high level of method development that will be of value for the greater exposome research community.        We anticipate that this project will result in new and increased knowledge on FM, specifically whether and how environmental exposures are involved. The results may be of importance in the treatment of FM and for recommendations regarding diet and other exposures in the development of FM.

Recently, we reported autoreactive IgG antibodies (FM IgG) in fibromyalgia (FM) patients. The overarching aim of this clinical study is to investigate how FM IgGs are related to symptoms and pathophysiological mechanisms. We profit from our new method to quantify FM IgG. First, in an existing cohort, associations between FM IgG levels and symptom severity are determined and related to proteomics, metabolomics and lipidomics. Second, associations between FM IgG and previously reported FM-related structural and functional pathology of C fibers as well as the newly discovered ultra-fast conducting A fibers (A-HTMRs) will be studied using skin biopsies and microneurography. Finally, given neuroinflammation and cerebral glia activation in FM, potential FM IgG related CNS mechanisms will be examined by assessing blood-brain-barrier integrity (DCE-MRI), cerebrospinal fluid (CSF) IgG concentrations and intrathecal IgG production (IgG index). These findings will be analyzed in relation to neuroinflammation (proinflammatory substances in CSF) and sleep disturbance (polysomnography). The project is a collaboration between 3 Swedish universities, with subjects (n =300) recruited in Stockholm and Uppsala in 2023-25 and meta-data analysis with drafting of manuscripts in 2026-27. The research will fundamentally improve our understanding of FM and facilitate development of objective diagnostic tools, use of immunomodulatory treatments and development of totally new biological treatments.