Other Proteins Involved in Regulating B Cell Activation

Background

B cell activation is a fundamental process in the adaptive immune response, enabling B cells to recognize and respond to antigens. It involves a series of complex interactions and signaling events. Here's an introduction to B cell activation:

Steps	Details
1. B Cell Receptor (BCR) Recognition	B cell activation begins with the binding of antigens to the BCR on the surface of B cells. The BCR is composed of membrane-bound immunoglobulin (Ig) molecules, which act as antigen receptors. Each B cell expresses a unique BCR with specificity for a particular antigen.
2. BCR Crosslinking and Signal Initiation	When multiple BCRs on a B cell bind to their corresponding antigens, crosslinking occurs. Crosslinking leads to the aggregation of BCR complexes, initiating intracellular signaling cascades. The cytoplasmic tails of the Igα and Igβ proteins within the BCR complex contain immunoreceptor tyrosine-based activation motifs (ITAMs), which play a crucial role in signal transduction.
3. BCR Signaling Pathways	BCR signaling is mediated by various proteins and enzymes, including kinases, adaptor molecules, and transcription factors. The signaling pathways triggered by BCR activation include the Src family kinases (such as Lyn), Syk kinase, phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways. These pathways activate downstream effectors, leading to cellular responses such as proliferation, survival, and antibody production.
4. Co-stimulation and T Cell Help	B cell activation often requires co-stimulatory signals from other immune cells, particularly T cells. Co-stimulatory molecules on the B cell, such as CD40, interact with their ligands (CD40L) on T cells, providing additional activation signals. T cell help is essential for optimal B cell activation and differentiation.
5. Internalization and Antigen Processing	Upon BCR engagement, the antigen is internalized into the B cell through receptor-mediated endocytosis. Once inside the B cell, the antigen is processed into smaller peptide fragments. These antigen fragments are then presented on the surface of the B cell using major histocompatibility complex class II (MHC II) molecules.
6. Antigen Presentation and T-B Cell Interaction	MHC II-bound antigen fragments are displayed on the B cell surface, allowing interaction with antigen-specific T cells. T helper cells recognize the antigen-MHC II complex and provide co-stimulatory signals to the B cell. The interaction between the B cell and T cell is essential for full B cell activation and differentiation.
7. B Cell Activation and Proliferation	B cell activation triggers a series of cellular responses, including increased expression of co-stimulatory molecules, cytokine production, and cell cycle entry. These signaling events lead to B cell proliferation, causing the expansion of antigen-specific B cell clones.
8. Differentiation into Effector Cells	Activated B cells can differentiate into two main effector cell types: plasma cells and memory B cells. Plasma cells are specialized for antibody production and secrete large amounts of antibodies specific to the recognized antigen. Memory B cells are long-lived cells that retain the ability to recognize and respond rapidly to the same antigen upon re-exposure.

B cell activation is a tightly regulated process that ensures the generation of an effective immune response against antigens. It integrates signals from the BCR, co-stimulatory molecules, and T cell help, leading to B cell proliferation, differentiation, and the production of antibodies.

Molecules Involved in Regulating B Cell Activation

Several molecules play critical roles in regulating B cell activation. These proteins contribute to the signaling pathways, co-stimulation, and interactions necessary for efficient B cell activation. Here are some key proteins involved in the regulation of B cell activation:

Key proteins	Functions
CR1 (Complement Receptor 1)	CR1, also known as CD35, is a receptor for complement fragments, such as C3b and C4b. It is expressed on B cells and other immune cells. CR1 promotes B cell activation by facilitating the recognition and uptake of antigen-antibody complexes through complement-mediated mechanisms.
LAIR1 (Leukocyte-associated Immunoglobulin-like Receptor 1)	LAIR1 is an inhibitory receptor expressed on various immune cells, including B cells. It contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic domain. LAIR1 negatively regulates B cell activation by inhibiting signaling pathways triggered by activating receptors.
LILRA2 (Leukocyte Immunoglobulin-like Receptor Subfamily A Member 2)	LILRA2 is a member of the immunoglobulin-like receptor family. Its specific role in regulating B cell activation is not well characterized, but it is known to be expressed on B cells and other immune cells.
LILRA3 (Leukocyte Immunoglobulin-like Receptor Subfamily A Member 3)	LILRA3 is another member of the immunoglobulin-like receptor family. Its function in B cell activation is not extensively studied, and its expression on B cells is not well defined.
LILRB1 (Leukocyte Immunoglobulin-like Receptor Subfamily B Member 1)	LILRB1, also known as CD85j or ILT2, is an inhibitory receptor expressed on B cells, T cells, and other immune cells. It contains ITIMs in its cytoplasmic domain and negatively regulates B cell activation by inhibiting signaling pathways triggered by activating receptors.
ILT4 (Immunoglobulin-like Transcript 4)	ILT4, also known as LILRB2 or CD85d, is an inhibitory receptor expressed on B cells, T cells, and other immune cells. It interacts with specific ligands and regulates immune cell functions, including B cell activation and immune tolerance.
LILRB3 (Leukocyte Immunoglobulin-like Receptor Subfamily B Member 3)	LILRB3 is a member of the immunoglobulin-like receptor family. Its specific role in B cell activation is not well characterized, and its expression on B cells is not extensively studied.
LILRB4 (Leukocyte Immunoglobulin-like Receptor Subfamily B Member 4)	LILRB4, also known as ILT3 or CD85k, is an inhibitory receptor expressed on B cells, dendritic cells, and other immune cells. It interacts with specific ligands and modulates immune cell functions, including B cell activation and immune responses.
SLAMF7 (Signaling Lymphocytic Activation Molecule Family Member 7)	SLAMF7, also known as CD319 or CS1, is a cell surface receptor expressed on B cells, plasma cells, and other immune cells. It can transmit activating signals and contribute to B cell activation and differentiation.
VAV1 (Vav Guanine Nucleotide Exchange Factor 1)	VAV1 is a signaling protein involved in B cell receptor signaling and other immune cell signaling pathways. It acts as a guanine nucleotide exchange factor and plays a role in the activation of small GTPases, such as Rac1, which are involved in cytoskeletal rearrangements and signaling cascades during B cell activation.
B Cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL)	BAFF and APRIL are members of the tumor necrosis factor (TNF) superfamily. They bind to receptors (BAFF-R, TACI, and BCMA) on B cells, promoting B cell survival, proliferation, and antibody production. BAFF and APRIL play important roles in maintaining the B cell pool and regulating B cell activation.

Role of Proteins that Regulate B Cell Activation in Disease Development

Autoimmune Diseases

• Rheumatoid Arthritis (RA): Dysregulation of CR1 and LILRB1 has been associated with increased risk and severity of RA by affecting complement activation and immune responses.

Cancer

• Multiple Myeloma: SLAMF7 is highly expressed on plasma cells and serves as a therapeutic target in multiple myeloma. Monoclonal antibodies targeting SLAMF7, such as elotuzumab, have shown efficacy in treating multiple myeloma.

Infectious Diseases

• HIV/AIDS: VAV1 plays a role in B-cell receptor signaling and activation. Dysregulation of VAV1 has been implicated in B-cell dysfunction and impaired immune responses in HIV/AIDS.

Immunodeficiency Disorders

• Primary Immunodeficiency Disorders: Dysregulation of LILRA2 and LILRA3, members of the ILT/LIR family, may contribute to the development of primary immunodeficiency disorders by affecting immune responses and regulation.

Miscellaneous Diseases

• Fibrosis: LAIR1 is involved in the regulation of collagen production and tissue fibrosis. Dysregulation of LAIR1 has been implicated in fibrotic diseases, such as liver fibrosis and pulmonary fibrosis.
• Transplant Rejection: ILT4 is an inhibitory receptor expressed on immune cells, including B cells. It plays a role in immune tolerance and has been implicated in regulating transplant rejection responses.
• Inflammatory Disorders: Dysregulation of LILRB3 and LILRB4, inhibitory receptors, has been associated with inflammatory disorders such as inflammatory bowel disease (IBD) and autoimmune thyroiditis.

It's important to note that the roles of these proteins can vary depending on the specific disease context, and further research is needed to fully understand their mechanisms and therapeutic implications in each disease.

Fig.2 Diverse uses of LILRB4 in autoimmune diseases. (Xiang Z, et al., 2024)

Case Study

Case 1: O'Connell P, Blake MK, Godbehere S, Amalfitano A, Aldhamen YA. SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity. J Neuroinflammation. 2022;19(1):241.

To evaluate how SLAMF7 intrinsically regulates B cell responses the authors cultured WT splenic B cells in vitro in the presence or absence of SLAMF7 receptor activation (via receptor cross-linking) and evaluated cell surface B cell activation markers via spectral cytometry. The authors found decreased autofluorescence (a proxy for lymphocyte activation) (D), MHC-II (E), GL7 (F), and PD-L1 expression (G) on SLAMF7-activated B cells compared to unstimulated B cells. Examination of soluble factors in supernatant of cultures of SLAMF7-stimulated B cells revealed decreased levels of Eotaxin (H), IL-17 (I), TNF⍺ (J), and CCL5 (K) in B cells with SLAMF7 activation compared to unstimulated cells, revealing an inhibitory role for SLAMF7 in B cells. While changes in some of these surface and soluble activation markers were minimal, together they suggest SLAMF7 signaling is capable of tempering B cell activation in a mild manner.

To determine what role SLAMF7 expression on B cells plays in regulating T cell responses, the authors set up an in vitro co-culture model consisting of T cells isolated from WT mice at peak EAE severity, combined with either WT or SLAMF7−/− B cells isolated from naïve mice, along with stimulation using MOG peptide. Using this model, the authors were able to assess the contribution of SLAMF7 expression on B cells to antigen-induced T cell proliferation and found that SLAMF7 expression on B cells restrains antigen-induced CD8+ T cell proliferation (L). Similarly, SLAMF7 expression on B cells also decreased antigen-induced PD-1 expression on CD8+ T cells (M) and CD69 expression on CD8+ T cells (N) (no significant changes found in CD4+ T cell phenotypes. Fittingly, the authors also found that SLAMF7−/− B cells express more CD80 compared to WT B cells (O).

Together, these results suggest that in the absence of SLAMF7, B cells are more prone to activation and preferentially induce CD8+ T cell activation, possibly via MHC-II, PD-L1, CD80, and/or direct SLAMF7 ligation mechanisms.

Fig.1 SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity.

References

• Xiang Z, Yin X, Wei L, Peng M, Zhu Q, Lu X, Guo J, Zhang J, Li X, Zou Y. LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets. Biomolecules. 2024; 14(2):187.
• Shlomchik MJ. Sites and Stages of Autoreactive B Cell Activation and Regulation. Immunity. 2008;28(1):18-28.
• Doherty DG, Melo AM, Moreno-Olivera A, Solomos AC. Activation and Regulation of B Cell Responses by Invariant Natural Killer T Cells. Front Immunol. 2018;9:1360.