IgG4 Consortium Research

WP1: Biobank

IgG4 autoimmune diseases are very rare, which means that each one individually affects less than one in 2000 people in Europe.

However, there are many different types of IgG4 autoimmune diseases, such as MuSK myasthenia gravis, LGI1/Caspr2 autoimmune encephalitis, anti-IgLON5 disease or paranodopathies with antibodies against Caspr1, Neurofascin 155 or Contactin-1. Therefore, as a group, IgG4-AIDs affect about 1 in 900 people in Europe.

One major difficulty to study rare diseases in general is the collection of enough biosamples (e.g. blood samples) from patients, since it is essential to study large patient cohorts to obtain reliable data. Therefore, in work package 1, we are collecting patient biosamples from many European countries, and make these accessible to the scientists working in IgG4-TREAT via a web database. We already collected over 1000 biosamples from patients with IgG4 autoimmune diseases and provided these to the different research groups in work packages 2-4.

Further, it is a main aim to characterize the patient biosamples, and to collect and analyze clinical data, to learn more about the diseases, e.g. how specific immune cells and autoantibodies may be related to the disease severity, and to compare whether there are commonalities between the different diseases.

In summary, WP1 provides a database with information of well-characterized patient biosamples to all other scientists in IgG4-TREAT, and aims to identify commonalities in IgG4-AID.

WP2: 

Antibodies are small proteins made by the immune system to fight germs. One of the antibody types our body normally makes is IgG4. Research developed in WP2 aims to understand why some people make a harmful type of IgG4 antibody (pathogenic IgG4). In this project, we focus on IgG4-related autoimmune diseases, where these antibodies wrongly attack the body's own tissues.

We want to find the reasons why this response happens. First, we are looking at genes that may make some people more likely to produce pathogenic IgG4 antibodies. Some of these genes are linked to the immune system. Second, we are studying blood samples to search for biomarkers. Biomarkers are measurable signs in the blood that can help us detect disease or follow its activity. We are also investigating immune cells, especially B cells, which are the cells that make antibodies.

We are comparing patients with different IgG4-autoimmune diseases, such as MuSK myasthenia gravis and LGI1 autoimmune encephalitis, with healthy people. We are also studying blood and cell samples in the laboratory, using modern methods that can measure many proteins, genes, and cell features at the same time.

Our goal is to understand what drives the harmful IgG4 response. In the long term, this could help doctors identify patients earlier, follow disease activity more easily, and develop better treatments that target the right immune pathways.

WP3: Understanding the Pathogenic Mechanisms of IgG4 Antibodies 

Our research program is dedicated to advancing the understanding of the pathogenic mechanisms of IgG4 antibodies (IgG4 Abs). Although IgG4 antibodies are increasingly recognized as key contributors to a variety of autoimmune diseases, many of the biological and structural mechanisms that drive their pathogenic effects remain poorly understood. By combining expertise in neuroimmunology, we aim to uncover how specific properties of IgG4 antibodies contribute to disease development and progression.

Our work focuses on several complementary research objectives some examples are:

1. Cloning and analysis of patient-derived monoclonal antibodies

Patient-derived monoclonal antibodies (mAbs) provide a unique opportunity to study disease-relevant immune responses. By isolating and cloning these antibodies, we aim to identify molecular features associated with pathogenicity and better understand antibody-driven disease mechanisms.

2. Understanding the role of valency in novel humanized active immunization models

Antibody valency can strongly influence biological activity and disease outcomes. Using newly developed humanized active immunization models, we investigate how different antibody configurations affect immune responses and pathogenic potential.

3. Investigating IgG4 monoclonal antibody pathogenicity in experimental models

To translate molecular findings into biological understanding, we evaluate the pathogenic effects of IgG4 monoclonal antibodies in disease-relevant experimental models. These studies help us establish direct links between antibody characteristics and disease manifestations.

Together, these integrated approaches will provide a comprehensive understanding of the biology and pathogenic mechanisms of IgG4 antibodies, ultimately contributing to improved diagnostics, disease prediction, and the development of more targeted therapeutic strategies.

WP4: 

Currently, many IgG4 Autoimmune Disease (IgG4-AID) patients rely on therapies that are not very specific and may present with undesired side-effects. Therefore, one of the goals of our research efforts is to develop more targeted treatments for IgG4-AIDs. However, to achieve this we need a better understanding of the disease pathology. So our work in this project is also focused on creating a more accurate disease model that better reflects human physiology. Disease models are invaluable tools for modeling and studying autoimmune diseases from the basic understanding of the disease pathology to treatment development and testing.

Human IgG4 possesses a unique capability in which the two arms of one antibody molecule can recognize different proteins (antigens), therefore, resulting in a bispecific antibody. This process is known as "Fab-arm exchange" (FAE). FAE is a crucial process as the bispecific property of IgG4 contributes to their pathogenicity in IgG4-AIDs. However, mouse antibodies do not possess the capability to FAE and cannot replicate human IgG4 response in disease modeling. In WP4, we will develop a mouse model with antibodies similar to human IgG4 ("humanized"). This will better represent human IgG4 to model IgG4-AIDs and to test novel treatment strategies.

Furthermore, we will develop an apheresis approach based on the removal of the pathogenic IgG4 antibodies from the patient. Apheresis is a medical procedure that allows patient's blood to flow through a machine, which can remove specific components from the blood, before returning the remainder of the blood back to the body. In this case, we will develop a matrix capable of specifically capturing and removing IgG4 antibodies. We will utilize the aforementioned novel mouse model as a model to test the IgG4 apheresis strategy aimed as a novel therapy for all IgG4-AIDs.