B cell

Background

B cells are a type of white blood cell that plays a crucial role in adaptive immunity, which is the specific and long-lasting immune response mounted by the body against pathogens. B cells are derived from stem cells in the bone marrow and mature in the bone marrow as well as secondary lymphoid organs, such as the spleen and lymph nodes.

The key features of B cells include the expression of B cell receptors (BCRs) on their cell surface and their ability to produce and secrete antibodies, also known as immunoglobulins (Igs). BCRs are membrane-bound antibody molecules that recognize specific antigens, which are foreign substances or molecules that can elicit an immune response.

B-cell development and differentiation occur in the bone marrow and involve a series of complex steps. Here is an overview of the process:

Steps	Process
1. Stem Cell Commitment	B-cell development begins with the commitment of hematopoietic stem cells (HSCs) towards the lymphoid lineage. The HSCs undergo a series of differentiation steps to become common lymphoid progenitors (CLPs).
2. Progenitor Stage	CLPs migrate to the bone marrow, where they undergo further differentiation into early lymphoid progenitors (ELPs). ELPs express specific surface markers, including CD19, CD10, and CD34.
3. Pre-B Cell Stage	ELPs progress into the pre-B cell stage. At this stage, rearrangement of the immunoglobulin heavy chain (IgH) gene occurs. The IgH gene consists of multiple gene segments that rearrange to generate a functional heavy chain variable region. Successful rearrangement leads to the expression of a pre-B cell receptor (pre-BCR) on the cell surface.
4. Immature B Cell Stage	Pre-B cells that express a functional pre-BCR undergo clonal expansion and further maturation into immature B cells. Immature B cells express both the IgM and IgD forms of the B cell receptor. During this stage, the rearrangement of the immunoglobulin light chain (IgL) genes takes place.
5. Negative Selection and Tolerance	Immature B cells undergo a process called negative selection to eliminate self-reactive B cells that could potentially cause autoimmune responses. B cells that recognize and bind strongly to self-antigens undergo apoptosis or receptor editing, where secondary rearrangements of the IgL genes occur to modify the specificity of the BCR.
6. Maturation and Migration	Mature B cells that successfully pass negative selection and acquire self-tolerance leave the bone marrow and enter the secondary lymphoid organs, such as the spleen and lymph nodes. In these organs, they can encounter antigens and initiate immune responses.
7. Activation and Differentiation	Mature B cells become activated upon encountering specific antigens that match their B cell receptors. Activation triggers signaling pathways that lead to B cell proliferation and differentiation. Activated B cells can differentiate into two main cell types: a. Plasma Cells: Some activated B cells differentiate into plasma cells, which are specialized antibody-secreting cells. Plasma cells produce and secrete large quantities of antibodies specific to the encountered antigen. b. Memory B Cells: Another subset of activated B cells differentiates into memory B cells. Memory B cells have an extended lifespan and provide immunological memory. They can mount a rapid and robust immune response upon re-exposure to the same antigen.

The process of B-cell development and differentiation is tightly regulated to ensure the production of diverse B cell repertoires capable of recognizing a wide range of antigens. Any disruptions or abnormalities in this process can lead to immune deficiencies or dysregulation of immune responses.

Fig.1 B cell development and differentiation. (Schultheiß C, et al., 2022)

Functions of B Cells

Role of B Cells in Adaptive Immunity

• Antibody Production: B cells are responsible for the production and secretion of antibodies. When a B cell encounters an antigen that matches its BCR, it becomes activated and differentiates into plasma cells, which are antibody-producing factories. Plasma cells secrete large quantities of antibodies that can bind to the specific antigen, neutralize pathogens, and facilitate their elimination by other immune cells.
• Memory B Cells: After an infection or immunization, a subset of activated B cells differentiates into memory B cells. These cells have a longer lifespan than plasma cells and have the ability to "remember" specific antigens encountered during the initial immune response. Memory B cells allow for a faster and more robust immune response upon re-exposure to the same antigen, providing immunological memory.
• Antigen Presentation: B cells can act as professional antigen-presenting cells (APCs). They capture antigens through their BCRs, process them, and present antigenic peptides on their cell surface in association with major histocompatibility complex class II molecules (MHC II). This allows B cells to interact with T cells, specifically CD4+ helper T cells, and initiate coordinated immune responses.
• Antibody-Mediated Effector Functions: Antibodies produced by B cells participate in various effector functions. These include neutralization of pathogens by binding to their surface molecules, opsonization by coating pathogens and enhancing their uptake by phagocytes, activation of the complement system, and facilitating the killing of infected cells by antibody-dependent cellular cytotoxicity (ADCC).
• Regulation of Immune Responses: B cells also contribute to the regulation and modulation of immune responses. They can differentiate into regulatory B cells (Bregs) that secrete anti-inflammatory cytokines and suppress excessive immune activation. Bregs play a role in maintaining immune tolerance and preventing autoimmune reactions.

Treatment of Autoimmune Diseases and Malignancies

• B cells are involved in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Therapeutic strategies aim to regulate B cells in these conditions. This can be achieved through targeted depletion of B cells using monoclonal antibodies against B cell-specific markers like CD20 (e.g., rituximab) or by inhibiting B cell activation and function using drugs like B cell receptor signaling inhibitors.
• In malignancies, B cells can give rise to certain types of lymphomas and leukemias. Treatments may involve targeting B cells with chemotherapy, radiation, or monoclonal antibodies specific to B cell markers, combined with other therapies depending on the specific malignancy.

Role of B Cells in Allergic Reactions and Vaccine Research

• B cells contribute to allergic reactions by producing IgE antibodies. IgE antibodies bind to allergens, leading to the release of inflammatory mediators that cause allergic symptoms. Therapeutic approaches targeting B cells, such as monoclonal antibodies against IgE (e.g., omalizumab), can alleviate symptoms in allergic individuals.
• In vaccine research, B cells are essential for the generation of protective immunity. Vaccines aim to induce B cells to produce specific antibodies and memory B cells. This can be achieved by exposing individuals to harmless forms of antigens or parts of pathogens, which stimulate B cell activation and subsequent antibody production. Memory B cells provide long-term protection, allowing for a faster and stronger response upon re-exposure to the pathogen.

Role of B Cells in Infectious Pathogens and Pathogen Clearance

B cells have a critical role in the immune response against infectious pathogens. They help clear pathogens through several mechanisms:

• Antibody-Mediated Clearance: Antibodies produced by B cells can bind to pathogens, neutralize them, and facilitate their clearance by other immune cells. Antibodies can also activate the complement system, leading to pathogen lysis and opsonization for phagocytosis.
• Antigen Presentation: B cells can present antigens to T cells, which triggers the activation of specific T cell responses. This collaboration between B cells and T cells enhances the immune response and promotes pathogen clearance.
• Cytotoxicity: Some B cells, called cytotoxic B cells or antibody-dependent cellular cytotoxicity (ADCC) cells, can directly kill infected cells by releasing cytotoxic molecules or engaging with other immune cells to eliminate pathogens.

In summary, B cells are crucial players in the immune system. Through their BCRs, they recognize antigens, interact with T cells, produce antibodies, generate memory responses, and contribute to the clearance of infectious pathogens. Understanding the functions and regulation of B cells is essential for developing therapies for autoimmune diseases, malignancies, allergies, and effective vaccines.

Fig.2 Summary of various B cell functions. (Selvaraj UM, et al., 2016)

Exploring Future Research Directions for B Cells in the Immune System

Future research directions for B cells in the immune system are vast and hold great potential for advancing our understanding of B cell biology and their roles in health and disease. Here are some promising research areas:

• B Cell Subsets and Heterogeneity: Investigating the diversity and functional heterogeneity of B cell subsets within the immune system is an important research avenue. Identifying distinct B cell subsets, their phenotypic markers, and functional properties can enhance our understanding of their unique roles in different immune responses and diseases.
• B Cell-T Cell Interactions: Further elucidating the intricate interactions between B cells and T cells is crucial. Understanding the mechanisms governing B cell and T cell collaboration in immune responses, such as antigen presentation, co-stimulation, and cytokine signaling, can provide insights into immune regulation and help develop targeted immunotherapies.
• B Cells in Tissue-Specific Immunity: Exploring the functions of B cells in various tissues and organs beyond secondary lymphoid organs is an emerging research area. Investigating tissue-resident B cells and their roles in local immune responses, such as in the gut, lung, and skin, can provide insights into tissue-specific immunity, autoimmune diseases, and host-microbiota interactions.
• B Cell Epigenetics and Gene Regulation: Studying epigenetic modifications and gene regulation in B cells can shed light on the mechanisms underlying B cell development, differentiation, and function. Epigenetic changes, such as DNA methylation and histone modifications, play critical roles in B cell development and are implicated in B cell-related disorders. Unraveling these regulatory mechanisms can lead to novel therapeutic approaches.
• B Cells in Autoimmunity and Immunodeficiency: Investigating the contributions of B cells to autoimmune diseases and immunodeficiencies is an ongoing research focus. Understanding the dysregulation of B cell responses in autoimmune conditions and identifying the underlying mechanisms can aid in the development of targeted therapies. Furthermore, studying B cell deficiencies and their impact on immunodeficiencies can provide insights into improving immune responses and developing novel treatment strategies.
• B Cells in Cancer Immunotherapy: Expanding our knowledge of B cells in cancer immunotherapy is an exciting area of research. Harnessing the potential of B cells in cancer treatment, such as using engineered B cells for targeted immunotherapies or exploiting their antibody production capabilities for tumor targeting, holds promise for novel therapeutic approaches.
• B Cells and Vaccination Strategies: Investigating the role of B cells in vaccine responses and designing more effective vaccination strategies is critical. Understanding how B cells contribute to the generation of protective immunity, optimizing antigen presentation, and enhancing B cell memory responses can lead to improved vaccine design and development against infectious diseases and emerging pathogens.

These research directions have the potential to advance our understanding of B cell biology and pave the way for the development of innovative therapeutic interventions, personalized medicine approaches, and improved vaccination strategies to combat immune-related disorders and infectious diseases.

Fig.3 Potential roles of B cells in the pathogenesis of autoimmune hepatitis. (Schultheiß C, et al., 2022)

Case Study

Case 1: Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, Fallon PG. PD-L1hi B cells are critical regulators of humoral immunity. Nat Commun. 2015;6:5997.

Having established that PD-L1hi B cells can directly suppress T-cell responses the authors sought to address how this process occurred. CD4+ T cells and B220+ B cells were isolated from WT mice and stimulated with the bacterial superantigen Staphylococcus enterotoxin B (SEB) for 5 days. After co-culture, a proportion of CD4+ T cells became CXCR5+PD-1+ and expressed the transcription factor Bcl-6 (a). Given the propensity of PD-L1hi B cells to suppress T-cell responses, we investigated how this occurs following PD-1 ligation. The effects of PD-L1hi B cells on T-cell differentiation through PD-1 ligation were studied with respect to phosphorylation of Akt (pAkt), Stat3 (pStat3) and Stat5 (pStat5) following T-cell activation in vitro. CD4+ T cells, co-cultured with PD-L1hi B cells, exhibited significantly increased expression of pStat5 with a concomitant decrease in pAkt and pStat3 (b). Conversely, T cell co-cultures with PD-L1lo or PD-L1int B cells expressed elevated pAkt and pStat3 with lower expression of pStat5 .Suppression of TFH-cell differentiation was dependent on PD-L1hi B cells.

Fig.1 PD-L1^hi B cells restrict T-cell differentiation.

Case 2: Paris S, Chapat L, Martin-Cagnon N, et al. β-Glucan as Trained Immunity-Based Adjuvants for Rabies Vaccines in Dogs. Front Immunol. 2020;11:564497.

In this study, the authors used a model of anti-rabies vaccination to characterize the effect of β-glucan to impact the immune response of vaccinated dogs. The authors used a set of 14 well-characterized immune parameters specific to rabies antigen.

Serological parameters, i.e., VNA titers, total IgG and IgG1 concentrations, and avidity indexes were analyzed 28 days after Rabisin® vaccination adjuvanted or not with β-glucan injection. All dogs showed a seroconversion above the protection threshold at 0.5 IU/ml (A, B). No significant differences in the titers could be highlighted between the four different groups. The results observed for group A were very similar to the ones in groups C and D. Dogs from group B showed a significant increase of total IgG concentrations compared to group A (C). No differences between groups were seen for avidity indexes on D28 (E). Rabies-specific IgG-secreting cells were quantified at day 7 by ELIspot assay (F).

Overall, B-cell responses, which is the main correlate of protection against rabies, display similar profiles between groups A (standard Rabisin® vaccination) and D (double injection of β-glucan). Groups B and C, injected once with β-glucan, 1 month prior or at the same time as Rabisin® vaccination respectively, show a wider dispersion of their response toward an increase of all parameters. However, only total IgG and IgG1 isotype concentrations are able to show a significant difference between groups A and B; all other parameters fail to meet the statistical threshold.

Fig.2 Group comparison of rabies-specific B-cell immune parameters of vaccinated dogs (A–F).

References

• Chekol Abebe E, Asmamaw Dejenie T, Mengie Ayele T, Dagnew Baye N, Agegnehu Teshome A, Tilahun Muche Z. The Role of Regulatory B Cells in Health and Diseases: A Systemic Review. J Inflamm Res. 2021;14:75-84.
• Akkaya M, Kwak K, Pierce SK. B cell memory: building two walls of protection against pathogens. Nat Rev Immunol. 2020;20(4):229-238.
• Schultheiß C, Steinmann S, Lohse AW, Binder M. B cells in autoimmune hepatitis: bystanders or central players?. Semin Immunopathol. 2022;44(4):411-427.
• Selvaraj UM, Poinsatte K, Torres V, Ortega SB, Stowe AM. Heterogeneity of B cell functions in stroke-related risk, prevention, injury, and repair. Neurotherapeutics. 2016;13(4):729-747.