Sepsis and Septic Arthritis in the Presence of Rheumatic Autoimmunity: Immunomonitoring and Immunomodulatory Intervention Strategies

• Applicant: Dr. Johann Aleith
• Subject Area: Rheumatology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504491062

Sepsis is a life-threatening disorder with high morbidity and mortality characterized by a disproportionate immune activation that ultimately leads to end organ damage. Epidemiological studies pointed towards rheumatoid arthritis as an important risk factor for sepsis and septic arthritis (SA). SA is a complication of sepsis, which is triggered by an infection of the joint that in turn induces an excessive inflammation and causes the destruction of bone and cartilage. In our preliminary work, we have demonstrated that preceeding rheumatic autoimmunity was indeed associated with an impaired immune response to an infection with Group A Streptococcus (GAS) in mice. Hence, bacteria disseminated unopposedly within the host, which caused exacerbated sepsis characterized by an exhaustive derailment of the immune reaction. Additionally, rheumatic autoimmunity facilitated GAS-induced joint damage and therefore aggravated SA. In our study, we inted to utilize our novel model of combined rheumatic autoimmunity and GAS-induced sepsis in order to characterize the cellular immune response and to identify the causative agents of the immune malfunction. To this end, we want to establish modern analytical methods that enable us to monitor the impact of the infectious disease within the blood, liver, spleen, joints and bone marrow. Therefore, we want to identify immune cell populations that contribute to the immune derailment by the excessive production of inflammatory cytokines. Furthermore, we will analyze disturbances in medullary stem cell homeostasis. Our goal is to better unterstand the interplay between pre-existing rheumatic autoimmunity and infection in order to link biomarkers to life-threateting disease courses. By exploitation of these biomarkers we intend to develope immunomodulatory strategies that are capable of antagonizing the dramatic consequences of sepsis. Alternatively, we will utilize the biological inactivation of inflammatory cytokines. In this context we want to understand how these treatments impact on the immune response and which strategy has the highest therapeutic potential.

• DFG Programme: Research Grants