B-cell activation is triggered by the binding of a ligand (referred to as antigen) to the B-cell receptor (BCR), which initiates a cascade of intracellular signalling leading to the internalization of antigen for processing and presentation to T cells. For BCR activation, multivalent antigens or anti-BCR antibodies are required.
Structure of the BCR
Mature B cells express two BCR isotypes, IgM and IgD, both having identical antigen specificity. The BCR is composed of membrane immunoglobulin (mIg); a structure of four (in the case of IgD) or five (IgM) immunoglobulin domains in the heavy chain linked by a hinge, and a short intracellular domain consisting of just three amino acids: lysine, valine, lysine (KVK).
Fig.1 Schematic diagram of the monomeric BCR and the conformation-induced oligomerization model. (Treanor, 2012)
CXCR4 Signals Are Processed Through CD19 and the IgD-BCR
To understand how signals through CXCR4 are integrated via the IgD-BCR, scientists analyzed the activation of different signaling pathways, which are shared by both receptors. In B cells, the PI3K pathway is strongly regulated by CD19, which is localized in the vicinity of the IgD-BCR and IgM-BCR on resting and activated B cells, respectively. The expression of the IgD-BCR is required for the efficient phosphorylation of the PI3K downstream elements Akt and Foxo and Erk upon stimulation of B cells with either CXCL12 or Lat-A, suggesting that the cross-talk between CXCR4 and CD19 is BCR class dependent. The increased phosphorylation of Y182 of Igα also required IgD-BCR expression. These findings suggest that extensive actin depolymerization may represent a negative regulatory signal for the BCR.
Fig.2 CD19 is the linchpin between CXCR4, the BCR, and the actin cytoskeleton. (Becker, 2017)
The BCR of Class IgD Induces a Stronger and More Prolonged Protein Tyrosine Phosphorylation
Scientists have analyzed B cell lines expressing IgM or IgD antigen receptors with the same antigen specificity. Cross-linking of these receptors with either antigen or class-specific antibodies, results in the activation of protein tyrosine kinases and the phosphorylation of the same substrate proteins. The kinetic and the intensity of phosphorylation, however, was quite different between the two receptors when they were cross-linked by antigen. In the membrane IgD-expressing cells, the substrate phosphorylation increased further over time and persisted longer than 240 minutes after exposure to antigen. As a result, the intensity of protein tyrosine phosphorylation induced by cross-linking of membrane IgD was stronger than that induced by membrane IgM.
Activation of Immune System via IgD
Innate and adaptive Immune responses can be activated via membrane-anchored IgD that functions as a part of B-cell receptor (BCR) complexes or secreted-form of IgD that bounds to monocytes, mast cells, and basophil, respectively. Scientists have first demonstrated that treatments with a monoclonal anti-IgD antibody can attenuate disease severity in an animal model of collagen-induced arthritis. Activated immune responses via IgD-BCR and secreted IgD may exert suppressive effects on autoimmune diseases and allergic inflammations, suggesting a potential immune regulatory function of IgD.
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References
- Treanor B. B-cell receptor: from resting state to activate. Immunology. 2012, 136(1): 21-27.
- Becker, M.; et al. CXCR4 signaling and function require the expression of the IgD-class B-cell antigen receptor. Proceedings of the National Academy of Sciences. 2017, 114(20): 5231-5236.
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