Immunoglobulin D (IgD):

Abstract:

Immunoglobulin D is an ancient biological molecule which evolved and may cooperate functionally with Immunoglobulin M. It is expressed on B-lymphocytes and is secreted into the blood stream. It is produced as a monomeric antibody similar to Immunoglobulin G, and has a half-life of less than 3 days. IgD is involved in various immune related functions including as a “replacement” in certain instances for IgM or IgA in individuals that may have deficiencies in one of these antibody classes.

Introduction

Immunoglobulin D (IgD or gamma D) was discovered in the early 1960’s. The antibody has a molecular weight of 185 kDa and represents about 0.25% of the total amount of all immunoglobulins in the human serum. IgD is thought to have a distant evolutionary history as it is associated with species that possess adaptive immune responses. The oldest of these are the certain species of cartilaginous fish which were present 500 million years ago. This is at a juncture in evolutionary history when some of the first jawed vertebrates are thought to have appeared. The theory is that IgD has remained as is structurally and probably functionally since. IgD is expressed on B-lymphocytes as they leave the bone marrow as immature cells. As B-lymphocytes reach maturity, they will express both IgM and IgD. IgD may have a role in allergic reactions as it may bind to both basophils and mast cells. These cell types have a common origin in the bone marrow but differentiate along slightly different pathways. All these observations lead to the conclusion that IgD is at least partially a form of surveillance which is ancient in origin as it is positioned at sites of antigen entry into the mucosa.

Function

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 expression

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 mRNA transcript will contain the transcribed V-D-J cassette, and the Cμ and Cδ genes, with introns in between them.

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 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. Counter-intuitive to the conventional paradigm that activation of the immune system may potentiate autoimmune diseases and allergic inflammation, a study in 2010 by Nguyen TG et al. has first demonstrated that treatments with a monoclonal anti-IgD antibody can attenuate disease severity in an animal model of collagen-induced arthritis. This novel therapeutic effect by anti-IgD antibody treatment was later confirmed in mouse models of epidermolysis bullosa acquisition and in chronic contact hypersensitivity. 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. 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.

Immunoglobulin D Deficiency