Understanding and targeting pathogenic IgG4 responses

The predominant autoantibody (sub)class is an important determinant in the pathophysiology of autoimmune diseases (AID).

Autoantibodies can be pro-inflammatory, such as IgG1, causing disease by complement-mediated or immune cell-mediated tissue damage.

In 2015 I was the first to describe a second group of AID where IgG4 autoantibodies, which are largely unable to activate the immune system, cause disease. Till date at least 29 different diseases classify as IgG4-predominated AID (IgG4-AID).

Why certain AID are predominated by IgG4 autoantibodies is not known, but this is confirmed to be critical for precipitation, mechanism and treatment of the disease. In fact selective permissive determinants for class switching to IgG4 in general are not known.

Recently, I realized that in contrast to IgG1 autoantigens, IgG4 autoantigens are single pass transmembrane proteins which are continuously shed from the cell.

I therefore hypothesize that a key element of the aetiology of IgG4-AID is IgG4-AID antigen shedding resulting in chronic, systemic antigen stimulation in the absence of ‘danger’ signals like bacterial antigens, viral antigens or cellular damage.

The goal of this project is therefore to unravel the antigenic and environmental cues that initiate and drive IgG4 (autoreactive) responses following this innovative paradigm, and to find strategies to specifically reduce pathogenic IgG4 responses.I will study this hypothesis using the archetypical IgG4-AID MuSK myasthenia gravis as a model.

The combination of state-of-the-art antibody technologies including human lymphoid organoids and AI-based antigen-antibody modelling, with my IgG4 autoimmunity expertise and our set of patient-derived monoclonal antibodies, puts me in an unique position to address the goal of this project.

I furthermore aim to provide a first proof of concept for specifically targeting IgG4+ B cells in vitro to pave the way for new therapeutic strategies for IgG4-AID and other IgG4-associated diseases