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Years in Review: Discussions in B Cell Biology
The biosphere in the B station landscape is extremely large. It encompasses the emergence, development, and fate of B cells as they differentiate from progenitor B cells into individual subsets characterized by selective functions and anatomical locations (1). B cells can act directly on the surrounding environment (2) or remotely through the immunoglobulins they produce. The process of creating immunoglobulins changes the germline DNA sequence, first by cutting and joining segments of the VDJ gene in variable domains and then by involving in the process of hypersomatic mutation that can drastically change the biological properties of the affected immunoglobulins (3). Dysregulation of B-cell function and tolerance can lead to a wide range of diseases, including autoimmune (4) and lymphoproliferative (5) disorders. This research topic aims to stimulate discussion on topics beyond classical approaches to B-cell biology, thus offering an opportunity to broaden our perspectives.
Wang and Dr.report the first case of monoclonal IgM elevated nodal marginal zone lymphoma (NMZL) complicated by atypical non-traumatic chylothorax. This is an example of a non-immune complication arising from the anatomic location of a malignant B-cell tumor. Marginal zone lymphoma (MZL) is a group of B-cell lymphomas that originate in the marginal zone of the lymph node and can occur in the spleen, lymph nodes and mucosal lymphoid tissue, accounting for approximately 10% of all non-Hodgkin's lymphomas (NHL). The thoracic duct is the largest lymphatic vessel in the human body. About three-quarters of the lymph, or chyle, from the entire body passes through the thoracic duct and enters the systemic (venous) blood at the junction of the left subclavian and left internal jugular veins. Chylothorax is an accumulation of lymph in the pleural space. The patient had generalized lymphadenopathy with particular enlargement of the right hilar mediastinal nodes. The thoracic duct crosses the mediastinum from right to left at the level of the fifth thoracic vertebra. Obstruction, as in this case, of the thoracic duct above this level often results in a left-sided chylothorax. Treatment with anti-B cells led to resolution of the lymphadenopathy and thus the chylothorax.
Amendt and Tybulewiczreport possible interactions between antidepressants, such as mirtazapine, and liver-resident B cells affected by autoimmune liver disease (AILD). Innate B cells can damage the liver by producing autoantibodies, presenting self-antigens to T cells, or releasing pro-inflammatory cytokines. In the liver, both the anatomical position and function of existing B cells can lead to organ dysfunction. Of particular importance is the role that existing B1 B cells play in enhancing the disease-promoting effect of B2 cells. B1 B cells produce natural antibodies that can bind and neutralize harmful self-molecules such as oxidized lipids (eg oxLDL) or pro-inflammatory cytokines such as TNFα or IL1-β. Mirtazapine can "wash out" more migrating B2 B cells while retaining slower migrating B1 B cells by increasing hepatic sinusoidal blood flow. Enrichment of B1 B cells appears to limit liver inflammation and prevent liver damage either by increasing hepatic production of natural IgM through its anti-inflammatory effects or by directly altering patterns of cytokine production or both. This is a classic example of drug repurposing, where a drug originally developed to treat a disease in one organ system is discovered by chance to affect a completely different disease process in another organ system, opening up a new armamentarium for disease treatment.
Sequence comparisons of the immunoglobulin variable domain first revealed that the primary structure of each V domain contains four regions of relative sequence stability, called framework regions (FR), and three regions of high sequence variability, called complementarity-determining regions (CDR) (3). Subsequent crystallographic studies revealed that the CDRs are located on top of the variable domains and are aligned to create the antigen binding site, as classically defined. FRs thus serve as the scaffold upon which this antigen binding site rests. The main purpose of the scaffold is to establish the relationship between the heavy and light V domains (VHand VL).Rhodes and Dr.show that mutations in FR can affect the V angleH- VLinterface and thus affects the flexibility of the antigen binding site, allowing it to sample a wider range of epitope surfaces and structures than would be available to static VH- VLinterface. These findings have implications for the design of therapeutic monoclonal antibodies, which may be beneficial in some cases, but in others their clinical utility may be reduced by variations in the surface area of antigen binding sites. This work serves as a roadmap for future research in the development of monoclonal antibodies.
Finally, the process of affinity maturation by somatic hypermutation in the germinal center is extremely complex.Garg i on.report on the development of a computer model for assessing germinal center reaction. Using this tool, they find that the magnitude of selection stringency dictates clonal dominance. Limited antigen availability on follicular dendritic cells has been shown to accelerate the loss of B cell diversity as germinal centers mature. Their model predicts that a significant number of T follicular helper cells is required to balance affinity maturation with clonal diversity, as a low number of T follicular helper cells prevents affinity maturation and also narrows the space for a diverse B cell response.
In this year's review, these four reports illustrate the wide range of topics in health and disease that can be addressed through the study of B-cell biology. These works whet the appetite for what will be discovered in the coming years.
The author confirms that he is the sole contributor to this work and that he has authorized its publication.
This work was supported in part by NIH AI63555.
Conflict of interest
The author declares that the study was conducted in the absence of commercial or financial circumstances that could be interpreted as a potential conflict of interest.
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1. Hardy RR, Hayakawa K. Pathways of B cell development.Ann Rev Immunol(2001) 19:595-621.
2. Getahun A, Cambier JC. Functions of non-antibody-secreting B cells and their contribution to autoimmune diseases.Annu Rev Cell Dev Biol(2019) 35:337-56.
3. Schroeder HW Jr., Cavacini L. Structure and function of immunoglobulins.J Allergy Clin Immunol(2010) 125: S41-52.
4. Barnas JL, Looney RJ, Anolik JH. B-cell-directed therapies in autoimmune diseases.Curr Opin Immunol(2019) 61:92–9.
5. Mastio J, Saeed MB, Wurzer H, Krecke M, Westerberg LS, Thomas C. Higher incidence of B-cell malignancies in primary immunodeficiencies: a combination of intrinsic genomic instability and exocytosis defects at the immune synapse.Front Immunol(2020) 11:581119. doi:10.3389/fimmu.2020.581119
Keyword:autoimmune liver diseases, B1 B cells, chylothorax - central venous occlusive disease, computational biology of B cells, germinal center B cells, immunoglobulin structure, marginal zone lymphoma
Quote:Schroeder HW Jr. (2023) Editorial: Years in review: discussions of B-cell biology.Ispred. Immunol.14:1214494. to: 10.3389/fimmu.2023.1214494
Received:29. april 2023;Accepted:15. maj 2023;
Published:24. maj 2023
Edited and reviewed by:
Pablo Engel, University of Barcelona, Spain
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* Correspondence:Harry W. Schroeder ml.,firstname.lastname@example.org