Significance of immune system, cytokines and microbiota interplay for the development of chronic inflammation
There is a clear indication that rheumatic diseases, such as rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease, can be influenced by commensal microorganisms, but mechanistic aspects of microbiota contribution to the disease development, pathogenesis, and chronicity remain to be determined. We postulate that microbiota changes might modulate cytokines production and activation of the immune system in the development of chronic rheumatic diseases.
Proinflammatory cytokine production can be influenced by microbiota composition in rheumatic patients. We observed significant changes in microbiota composition in patients with rheumatic diseases, and enhanced capacity of such microbiota to induce Tumor Necrosis Factor (TNF) production from peripheral blood mononuclear cells. TNF blockade in patients leads to significant disease amelioration and tissue repair via poorly understood mechanisms. We have revealed that TNF blocks tissue repair via the downregulation of IL-22 biological activity both in mice and humans. In chronic autoimmune arthritis, we found that TNF is crucial for the regulation of blood monocyte homeostasis via control of T cell responses.
Since one of the mechanisms of immune-mediated control of microbiota composition is the production of microbiota-specific IgA antibodies by intestinal plasma B cells, we are currently dissecting the mechanisms of microbiota control by IgA and utilisation of these mechanisms for microbiota analysis and modulation. To this end, we have generated a set of microbiota-specific IgA antibodies specific to distinct microbiota species, and have identified several antibodies that bind immunologically relevant bacteria in the microbiota.
Altogether, our data reveal interplay between microbiota composition, cytokine production and rheumatic diseases manifestation, and provide potential novel strategies for treating rheumatic diseases by modulating intestinal microbiota.
Dr. rer. nat. Andrey Kruglov
Justus Ninnemann, PhD student
Katharina Kurz, PhD student
Julia Röchert, Master student
Sarah Khedhayir, Bachelor student
• Prof. Dr. Mathias Heikenwälder DKFZ, Heidelberg, Germany
• Dr. Anja Kühl Charite, Campus Benjamin Franklin, Berlin, Germany
• Prof. Dr. Stefan Kaufmann, MPIIB, Berlin, Germany
• Prof. Dr. Britta Siegmund, Charite, Campus Benjamin Franklin, Berlin, Germany
• Prof. Dr. Dennis Poddubny, Charite, Campus Benjamin Franklin, Berlin, Germany
• Prof. Dr. Paul Friedemann, Charite, Berlin, Germany
• Prof. Dr. Bastian Opitz, Charite, Campus Benjamin Franklin, Berlin, Germany
• Prof. Dr. Ivaylo Ivanov, Columbia University, New York, USA
• Prof. Dr. Sergei Grivennikov, Fox Chase Cancer Center, Philadelphia, USA
• Prof. Dr. Harald Prüß, Charite, Berlin, Germany
• Prof. Dr. Thomas Kammertoens, MDC, Berlin, Germany
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