Research Projects

A fundamental component of our innate immune system is the complement system. The complement system consists of more than 50 plasma proteins and receptors that interact with pathogens, thereby providing an immediate line of defence against pathogenic intruders. The most abundant complement protein is C3. The activation of C3 must be tightly controlled, as binding of C3 to healthy cells can induce severe damage and can lead to autoimmunity. We have discovered that C3 forms a complex with MHC class II molecules (MHC II), expressed by Dendritic Cells. The C3 that is attached to MHC II is marked by the regulatory protein ubiquitin, a process called ubiquitination, which leads to internalization and degradation of MHC II-C3. This is a highly significant finding because formation of MHC II-C3 complexes may be a novel mechanism for capturing and eliminating potentially harmful C3.

In this project, we will investigate the molecular mechanisms behind the MHC II-C3 complex formation and the regulation of C3 levels through ubiquitination. We will unravel which pathways of complement activation are involved and characterize the MHC II carbohydrate structure that enables C3 binding through a variety of biochemical techniques, supplemented with immunological techniques including spectral flow cytometry, cell culture, and animal models. These findings may contribute to the development of therapeutic strategies for complement-mediated diseases by manipulating receptor ubiquitination.

Further reading:
P Schriek, ... and JA Villadangos. 2022. Marginal zone B cells acquire dendritic cell functions by trogocytosis. Science 375:eabf7470. PMID: 35143312.
Dimitrios C. Mastellos, George Hajishengallis & John D. Lambris. A guide to complement biology, pathology and therapeutic opportunity. Nature Reviews Immunology volume 24, pages118–141 (2024)

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