The Germinal Center Reaction and Antibody Diversification Mechanisms in B Cell Neoplasia and Autoimmune Disease

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Background

The adaptive immune system is of key importance for the defense against invading pathogens. Its humoral component is responsible for memory B-cell and plasma cell formation which safeguards pathogen neutralization and long-lived protection upon re-challenge. The germinal center (GC) is a specialized micro-anatomical site within secondary lymphoid organs that is of central importance for the maturation of the antibody response triggered by antigen encounter. Affinity maturation by (i) immunoglobulin variable gene somatic hypermutations (SHM); (ii) antigen-dependent selection and (iii) class switch recombination (CSR) occur in the context of the GC reaction, resulting in the production of high affinity antibodies that efficiently trigger pathogen neutralization via diverse immune effector mechanisms.

Within the GC, antigen-activated B cells undergo multiple rounds of proliferation, activation-induced cytidine deaminase-dependent SHM, and are subject to selection by competing for co-stimulation by presenting antigen to T follicular helper cells (TFH) that has been captured from follicular dendritic cells (FDC). Thus, the GC represents an important site for the unique interplay between different cell types, leading to production of high-affinity memory B cells and plasma cells that are required for long-lived humoral immunity.

Conversely, the GC reaction has also been firmly implicated in the pathogenesis of B-cell malignancies and autoimmune diseases. The antibody diversification mechanisms that take place in GC B cells may result in chromosomal aberrations and mutations that drive lymphomagenesis. Furthermore, perturbations of the GC reaction may lead to the emergence of autoreactive B-cell clones that contribute to the development of autoimmune disease. Therefore, elucidating the cellular and molecular mechanisms that dictate the GC reaction is essential to understand the ontogeny and evolution of B cell neoplasia and autoimmune diseases such as rheumatoid arthritis (RA). Interestingly, several important disease characteristics are shared between B-cell neoplasia and RA, including a disturbed GC reaction and overlapping/similar B-cell receptor specificities. This indicates that both pathologies can originate from similar antigenic stimuli. Chronic B-cell activation by (auto)antigen, in combination with local inflammation and decreased immune surveillance, and checkpoint function is central to the development of B-cell neoplasia and RA. Also, RA-associated lymphoproliferation represents a risk factor for developing B cell neoplasia.

In recent years, novel experimental approaches, including mathematical modeling, have provided important insight into the cellular dynamics and the molecular aspects of cellular interactions within the GC and antibody diversification mechanisms and have provided means for close recapitulation of the GC reaction. It is evident that the ongoing efforts to characterize the GC reaction in health and disease will improve vaccination strategies, help to identify possible shared mechanisms that drive B-cell neoplasia and RA, and increase our understanding of other immune-related diseases.

In this Research Topic, we aim to gather a series of articles that discuss the role of the GC in the pathogenesis of B-cell neoplasia and RA with a particular emphasis on antibody diversification processes, the importance of the B-cell receptor (BCR) in these diseases, and modeling approaches to study molecular and cellular dynamics of the GC under normal and pathological conditions.

We seek Original Research, Review, Mini-Review, Hypothesis and Theory, Clinical Trial and Opinion articles that cover, but are not limited to, the following subjects:

1. The causes and consequences of GC perturbations in the context of B-cell neoplasia and RA pathogenesis.
2. The importance of antigen receptor (BCR and TCR) repertoire and immunogenetics in B-cell lymphomagenesis and autoimmune diseases.
3. Molecular aspects of antibody diversifications, selection, and affinity maturation in the GC, in relation to the emergence of genomic aberrations and autoreactive clones.
4. B cell tolerance and autoimmune germinal center development.
5. Gene regulatory networks and multiscale models of lymphocyte proliferation and differentiation in the GC, B-cell neoplasia and autoimmune diseases.
6. Pre-clinical models addressing the role of the GC in B-cell neoplasia and autoimmune diseases.
7. Clinical studies addressing the increased risk of B-cell neoplasia in RA patients.

Keywords: Germinal center, B-cell lymphoma, Rheumatoid arthritis, B-cell selection, Systems biology, Somatic hypermutation, Affinity maturation, Class switch recombination, B cell receptor

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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