Periodic Reporting for period 2 - AUTOCOMPLEMENT (The role of complement in the induction of autoimmunity against post-translationally modified proteins)
Reporting period: 2019-03-01 to 2020-08-31
The modified proteins, and their controls have now been used to study the interaction with complement. Importantly, we could replicate the preliminary data used in the proposal, that carbamylated proteins, one of the PTM, indeed bind complement proteins. In addition, we observed that this is occurring for more, but not all, of the modifications. We have now confirmed that not only complement proteins from human serum are binding PTM proteins but that also mouse complement proteins can do so in a similar way. This is highly encouraging as it indicates that the mouse is indeed an appropriate animal model to use for the proposed studies. First immunization experiments in mice with PTM proteins have now been performed yielding interesting insight into the break of tolerance and the specificity of the anti-PTM response. The first large set of sera have now been used for the detection of the presence of anti-PTM protein antibodies. We could indeed detect autoantibodies that target these PTMs. Some individuals could harbor antibodies against several of the PTM’s while others only display reactivity against one PTM. Interestingly, in a subset of patients suffering from Rheumatoid Arthritis we observed no reactivity against any of the PTMs, as was also the case for the healthy controls.
Now in this ERC project the main aim is to identify not just the clinical associations of the presence of the anti-PTM antibodies but the reason why antibodies against these PTM proteins are made.
Our first large sets of data based on Mass Spec and ELISA clearly indicate that complement proteins are binding very prominently. This binding is in the absence of binding of antibodies, indicating a direct interaction.
The notion that direct binding of complement to PTM protein endows the PTM proteins with an auto-adjuvant effect is the key element of the ERC grant. We expect to define this adjuvant effect at the molecular level in the human setting and experimentally in mice. We envisage that this knowledge can be used to inhibit unwanted immune responses against e.g. PTM proteins in autoimmunity, but may actually also be useful as an adjuvant for therapeutic vaccination protocols.