Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.
The function of IgD has been a puzzle in immunology since its discovery in 1964. IgD is present in species from cartilaginous fish to human (with the possible exception of birds). This nearly ubiquitous appearance in species with an adaptive immune system demonstrates that IgD may be as ancient as IgM and suggests that IgD has important immunological functions.
In B cells, the function of IgD is to signal the B cells to be activated. By being activated, B cells are ready to take part in the defense of the body as part of the immune system. During B cell differentiation, IgM is the exclusive isotype expressed by immature B cells. IgD starts to be expressed when the B cell exits the bone marrow to populate peripheral lymphoid tissues. When a B cell reaches its mature state, it co-expresses both IgM and IgD. A 2016 study by Übelhart and colleagues found that IgD signaling is only triggered by repetitive multivalent immunogens, while IgM can be triggered either by soluble monomeric or by multivalent immunogens. Cδ knockout mice (mice that have been genetically altered so that they do not produce IgD) have no major B cell intrinsic defects. IgD may have some role in allergic reactions.
Recently, IgD was found to bind to basophils and mast cells and activate these cells to produce antimicrobial factors to participate in respiratory immune defense in humans. It also stimulates basophils to release B cell homeostatic factors. This is consistent with the reduction in the number of peripheral B cells, reduced serum IgE level and defective primary IgG1 response in IgD knockout mice.
Method of coexpression
In the human Heavy-Chain Locus, 3' of the V-D-J cassette is a series of C (for constant) genes, each conferring an Ig isotype. The Cμ (IgM) gene is 3' and closest to the V-D-J cassette, with the Cδ gene appearing 3' to Cμ.
Alternative splicing can then occur, causing a selection of either Cμ or Cδ to appear on the functional mRNA (μ mRNA and δ mRNA respectively). Alternative splicing is thought to be possible due to two polyadenylation sites, one appearing between the Cμ and Cδ, and the other 3' of Cδ (polyadenylation in the latter site would cause Cμ to be spliced away along with the intron). The precise mechanism of how the polyadenylation site is chosen remains unclear.
The resulting functional mRNA will have the V-D-J and C regions contiguous, and its translation will generate either a μ heavy chain or δ heavy chain. The heavy chains then couple with either κ or λ light chains to create the final IgM or IgD antibody.
Zinc finger protein 318 (ZNF318) has a role in the promotion of IgD expression and controlling the alternative splicing of the long pre-mRNA. In immature B cells that mainly express the μ transcript, there is no ZFP318 expression, but in mature B cells with dual IgM and IgD expression, both δ and μ transcript is made and ZFP318 is expressed. Enders et al. (2014) found in mice that null mutations in ZFP318 resulted in no IgD expression.
Activation of immune responses via IgD
Adaptive and innate Immune responses can be activated via membrane-anchored IgD that functions as a part of B-cell receptor (BCR) complexes or secreted-form IgD that bounds to monocytes, mast cells, or basophil.  Counter-intuitive to the current dogma that activation of the immune responses via IgD may potentially exacerbate autoimmune diseases and allergic skin inflammation, Nguyen TG et al. have first demonstrated that treatments with a monoclonal or polyclonal anti-IgD antibody have been shown to attenuate disease severity in mouse models of collagen-induce arthritis. This novel therapeutic effects by anti-IgD treatment were later confirmed by another group in a mouse model of epidermolysis bullosa acquisita, and in chronic contact hypersensitivity.
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