COSMIC Research programme

Overall Aim

Considering the close relationship between B-cell lymphoma (BCL) and rheumatoid arthritis (RA), and their link to the germinal center (GC) reaction, COSMIC facilitates a unique cross-fertilisation of RA auto-immunity and B-cell oncology research and clinical questions. We aim at providing novel insights into the underlying GC-related, possibly shared, molecular and cellular mechanism(s) of these two diseases. This is expected to lead to the identification of markers that can be exploited for preventive, diagnostic, and/or (personalised) therapeutic purposes to achieve best outcome and leverage the cost-effectiveness of treatment.

 

Background

Immune-related diseases such as BCL and RA 

  1. An incomplete understanding of the underlying molecular/cellular mechanisms;
  2. Uncertain diagnosis/prognosis
  3. Variable treatment efficacies of existing drugs.

This results in suboptimal patient management and a huge cost burden on healthcare systems, and prompts for personalized medicine. COSMIC addresses these challenges by pursuing a systems medicine approach focussing on the role of the germinal centre in B-cell lymphoma and rheumatoid arthritis

 

Germinal Center

The adaptive immune system is a key component of our defence against pathogens and comprises highly specialised cells and processes. Its humoral component is responsible for memory B-cell formation and high-affinity antibody production resulting from affinity maturation in germinal centres (GC), specialised anatomical sites typically found in secondary lymphoid tissues such as lymph nodes or spleen. B-cell clones express a unique B-cell receptor (BCR) consisting of an immunoglobulin (IG) whose variable domain is encoded by a rearrangement of the IG (V(D)J) genes. During affinity maturation, GC B cells undergo multiple rounds of proliferation, activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM), and selection to improve their BCR affinity for the antigen. Higher affinity cells have increased probability to be positively selected for further rounds of proliferation and SHM to further diversify, or to differentiate to memory and plasma cells, hallmarks of the adaptive immunity. B cells with increased antigen-affinity are selected due to their improved capability to capture antigen from the surface of follicular dendritic cells (FDC) and to present it to a limiting number of T follicular helper cells (Tfh). Within the GC, B cells also undergo IG class switch recombination (CSR) that leads to an exchange of the constant region of the BCR (different isotype), which influences the effector function of the B cells.

Perturbations of the germinal centre reaction (GCR) contribute to the emergence of clones expressing autoreactive antibodies or showing a transformed/malignant behaviour. Elucidating the cellular and molecular mechanisms of the GCR is essential to understand the ontogeny and evolution of BCL and RA.

 

Shared disease characteristics

Several important disease characteristics are shared between BCL and RA, such as the involvement of a disturbed GCR. In some cases similar/identical BCR specificities of the malignant B cells in BCL and autoreactive B cells in RA are found, indicating that BCL and RA can originate from similar antigenic stimuli. Chronic B-cell activation by (auto)antigen, in combination with local inflammation and decreased immune surveillance/immune checkpoints is central in the development of BCL and RA, while RA-associated lymphoproliferation represents a risk factor for developing BCL.

 

 Experimental and computational approaches

Despite recent progress, a precise understanding of the dynamics of the GCR and its role in BCL and RA pathogenesis has yet to emerge. The complexity of the GCR prompts for the development, application and integration of experimental approaches that go beyond state-of-the-art such as:

  1. Single cell transcriptomics of GC B cells;
  2. Quantitative analysis of the dynamic transcriptome and its regulation by signalling pathways;
  3. Next Generation Sequencing (NGS) analysis of the BCR repertoire to assess the clonal composition and its dynamics during the GCR;
  4. In-depth analysis of the (3-dimensional) BCR protein structures;

In addition, we need beyond state-of-the-art computational models that address specific questions related to GCR disturbances in BCL and RA, and multiscale models that integrate models at the cellular level with models at the molecular level to study how disturbed molecular pathways impact on the spatiotemporal dynamics of the GC cells.

COSMIC uses, develops, and synergistically integrates experimental and computational approaches to leverage our understanding of the role of the germinal center reaction in B-cell lymphoma and rheumatoid arthritis.


 

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