Uncovering new aspects of a cellular danger system involved in inflammatory diseases



The complement system is a part of the immune system that detects and removes bloodborne pathogens by killing them directly. When the system is uncontrolled, it can turn against the body and drive a broad range of inflammatory and autoimmune diseases, including conditions affecting the joints and the heart. While the complement system is widely recognized as a potentially valuable target for medical interventions, despite decades of effort, currently only three complement-targeting medications are FDA-approved, and these are only useful in a handful of rare diseases.


The complement system was thought to function exclusively in the blood and outside of our cells, so drugs targeting it have traditionally been aimed at the bloodstream. However, IRP researchers led by Claudia Kemper, Ph.D., discovered that all cells in the body express their own complement system that functions within them. The research team named these in-cell systems the ‘complosome’ and showed that it controls central pathways that help cells generate and use energy. Importantly, the team showed that an over-active complosome is associated with inflammatory diseases such as arthritis, heart disease, and COVID-19, while an under-active complosome leads to recurrent infections. What’s more, the researchers found that they could tamp down the over-active complosome in cells from patients with arthritis or COVID-19 using drugs that can reach the complosome within cells.


This research may explain why treating disease by targeting the complement system in the blood or outside of cells has met with little success. The possibility of developing drugs that target the complosome within cells may provide an effective tool for reducing inflammatory and other diseases.


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Yan B, Freiwald T, Chauss D, Wang L, West E, Mirabelli C, Zhang CJ, Nichols EM, Malik N, Gregory R, Bantscheff M, Ghidelli-Disse S, Kolev M, Frum T, Spence JR, Sexton JZ, Alysandratos KD, Kotton DN, Pittaluga S, Bibby J, Niyonzima N, Olson MR, Kordasti S, Portilla D, Wobus CE, Laurence A, Lionakis MS, Kemper C, Afzali B, Kazemian M. (2021). SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation. Sci Immunol. Apr 7;6(58):eabg0833. doi: 10.1126/sciimmunol.abg0833.

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This page was last updated on Thursday, June 8, 2023