Autoimmunity, Antibody mediated effector functions and mechanisms of humoral tolerance
Understanding the cellular and molecular basis for autoimmune disease
An immune response and the cell types involved in such a response are controlled by a variety of activating and inhibitory signals, which set a threshold for cell activation. Small changes in this threshold can cause deregulated immune responses, resulting in either insufficient or overwhelming immune reactions, which are not able to clear viral or bacterial infections or cause excessive inflammation leading to destruction of healthy tissues and in the worst case to the induction of autoimmune diseases. In both cases antibodies of the IgG isotype play a critical role as they are an essential part of the adaptive immune system to fight invading pathogens but are also involved in destruction of healthy tissues during autoimmune diseases. Therefore several checkpoints are in place to ensure that the generation of novel antibodies by B cells does not result in production of self-reactive autoantibodies (Figure 1).
An important factor deciding whether a B cells becomes fully activated and differentiates into an antibody producing plasma cell is the regulation of activating signals transduced by the B cell receptor. A variety of negative regulators of B cell receptor signaling have been identified that are important for maintenance of humoral tolerance. In our previous studies we were able to show that the inhibitory FcgRIIB is essential to prevent the expansion of autoreactive B cells and their differentiation into autoantibody producing plasma cells. Further studies with human patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) support our data obtained in mouse model systems and suggest that FcgRIIB is a crucial checkpoint for humoral tolerance. Currently we are studying the role of FcgRIIB for tolerance in the human immune system in greater detail in novel humanized mouse models.
Understanding mechanisms for IgG activity in mice and humans
In our previous studies we were able to show that the different IgG subclasses have a varying capacity to destroy healthy tissues during autoimmune diseases or to kill tumor cells during antibody based tumor immunotherapy. We could demonstrate that cellular Fcg-receptors (FcgRs) expressed on a variety of cell types of the innate and adaptive immune system are crucial for the activity of the different IgG subclasses. Moreover, we were able to identify a novel mouse activating FcgR, called FcgRIV, which seems to be the orthologous receptor to human CD16A. In a variety of in vivo model systems of IgG dependent destruction of tumor cells or IgG dependent models of autoimmune disease we could demonstrate that FcgRIV alone or in combination with other receptors is essential for IgG mediated effector functions. Based on these results we are currently trying to identify which cell populations responsible for IgG dependent effects (Figure 2).
Another focus is to understand the function of IgG glycosylation variants. In human serum more than 30 different IgG glycosylation variants can be identified and it is unclear why such diversity exists and what the function of the different IgG glycovariants is. In our previous studies we could show that some of the glycovariants have a dramatically increased pro-inflammatory activity, whereas others acquire an active anti-inflammatory activity. Indeed, preparations of pooled IgG from the serum of thousands of donors, is known to be able to suppress the activity of IgG autoantibodies if infused at high doses into patients (IVIg therapy). One potential explanation for the high dose requirement to achieve anti-inflammatory activity might be the essential role of rare IgG glycosylation variants. Several projects in the laboratory try to understand the molecular and cellular players involved in this anti-inflammatory pathway.