Sepsis and Septic Arthritis in the Presence of Rheumatic Autoimmunity: Immunomonitoring and Immunomodulatory Intervention Strategies
Immunology
Final Report Abstract
Sepsis is a life-threatening dysregulation of the immune system that is triggered by infection, leading to end organ damage. This condition is highly complex and remains insufficiently understood to date. Sepsis occurs almost exclusively in individuals with pre-existing conditions. In this context, rheumatoid arthritis represents an important risk factor, and the project described here aimed to generate insights into the immunological processes occurring during the interaction between chronic inflammatory disease and infection. To this end, a mouse model of collagen-induced arthritis (CIA) was employed in combination with Group A Streptococcus (GAS) infection. The cellular mediators of immune derailment were analyzed in multiple organs using flow cytometry. While the general health status of animals with and without pre-existing joint disease appeared comparable after 24 hours, only CIA mice exhibited significant bacterial burdens in the blood, liver, and spleen. This highlights for this early stage of infection an increased risk for sepsis in animals with underlying arthritis. After 48 hours, the CIA group developed sepsis, whereas infected control mice remained resilient towards the insult. CIA promoted lymphopenia following infection and was characterized by an accumulation of immature neutrophils with impaired cytokine productions. Analysis of blood samples via single-cell transcriptomics provided in this context detailed insights into the pathobiological patterns of sepsis-specific cell populations. Furthermore, the bone marrow compartment was profoundly altered by sepsis, and stem cell groups were identified that were strongly associated with sepsis-mediated emergency hematopoiesis. Notably, CIA-induced hyperplasia of draining lymph nodes led to an accumulation of activated cells as early as the subclinical phase of infection, resulting in excessive production of inflammatory cytokines. CIA-specific immune cell infiltrates, associated with hyperactivated synovial fibroblasts in the paw joints, contributed to this cytokine storm in the early stages of infection. Remarkably, blocking inflammatory cytokines at this time point did not improve the clinical course of sepsis in CIA mice. Through this project, extensive insights into the pathophysiology of sepsis in the context of pre-existing rheumatic autoimmunity were obtained, forming a prospective basis for the development of urgently needed diagnostic tools for at-risk patients. Our results highlight the importance of effective therapeutic management of underlying rheumatic diseases, through which the risk of life-threatening infections can be significantly reduced.
Publications
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Interleukin-6 overexpression and elevated granulocyte-to-lymphocyte ratio indicate hepatic stress in experimental group a Streptococcus sepsis. Medical Microbiology and Immunology, 214(1).
Brunsch, Valerie; Bergmann-Ewert, Wendy; Müller-Hilke, Brigitte & Aleith, Johann
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Maximizing Insights, Minimizing Animal Testing: A Framework for Validating Multiparametric Single‐Cell Cytokine Analysis Panels. European Journal of Immunology, 55(3).
Aleith, Johann; Bergmann‐Ewert, Wendy & Müller‐Hilke, Brigitte
