Immunoglobulin D

Immunoglobulin D (IgD) is an

The function of IgD has been a puzzle in immunology since its discovery in 1964. IgD is present in species from cartilaginous fish to humans (with the possible exception of birds).[2] 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

IgD has structural diversity throughout evolution of vertebrates because it is a structurally flexible locus to complement the function of IgM. One of the important features of IgD is that it can substitute for the function of IgM in the case of IgM defects.[7]^[8] B cells may express IgD by alternative RNA splicing and class switch recombination. Alternative splicing is promoted in all jawed vertebrates but class switch recombination occurs only in higher vertebrates and increases diversification of IgD.^[9] In jawed fishes, the structure of the constant region is highly diverse with amplifications of Cδ exons.^[10][8] Different splice variants exist due to alternative splicing. In humans and primates, IgD has three Cδ domains and a long H region with an amino-terminal region rich in alanine and threonine residues. C-terminal regions are rich in lysine, glutamate and arginine residues modified with O-glycosylation for binding a putative IgD receptor on the surface of activated T cells.^[11][12] Human IgD with its H region interacts with heparin and heparan sulphate proteglycans expressed in the basophils and mast cells.^[12] Mouse IgD has a shorter H region and different amino acid composition modified with N-glycosylation.

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.

A primary

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.^[13] 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.^[13] Enders et al. (2014)^[14] found in mice that null mutations in ZFP318 resulted in no IgD expression.

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^[3] or secreted IgD that binds to monocytes,^[15] mast cells,^[16] and basophils.^[6][17] Counter-intuitive to the contemporary dogmas that suggest these activated immune responses via IgD expression can potentiate autoimmune diseases and allergic inflammation, a 2010 study by Nguyen TG et al. has first demonstrated that treatments with a B-cell activating monoclonal anti-IgD antibody can attenuate disease severity in an animal model of collagen-induced arthritis.^[15] This novel therapeutic effect by anti-IgD antibody treatment was later confirmed in mouse models of epidermolysis bullosa acquisita^[18] and in chronic contact hypersensitivity.^[19] Studies have shown that levels of secreted lgD are usually elevated in patients with an autoimmune disease, and recently it has been demonstrated that IgD enhanced the activation of peripheral blood mononuclear cells in Rheumatoid Arthritis (RA) patients leading to the hypothesis that IgD could be an immunotherapeutic target for the management of RA.^[20] 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.^[21]

References