Immunoglobulin D (IgD) - Definition, Properties, Structure and Functions

Immunoglobulin D (IgD) is a type of antibody present in the immune system. It is also called IgD and it is one of the five major classes of immunoglobulins. It was discovered in 1965 and it is present in very low amount in the blood.

IgD forms about 0.25% to 1% of the total serum immunoglobulins. It is a rare antibody in the bloodstream but it has important role in immune response. It is mainly associated with B-cells and mucosal defence.

Structurally, IgD is generally a Y-shaped or T-shaped molecule. It is made up of two delta heavy chains and two light chains. A special feature of IgD is its long and flexible hinge region. This hinge region helps the antigen binding arms to move freely and bind with antigens present at different distance.

In human body, IgD is found in two forms. These are membrane-bound IgD and secreted IgD. The membrane-bound form is present on the surface of mature B-lymphocytes along with Immunoglobulin M (IgM).

On the surface of B-cells, IgD acts as a receptor. It helps in the activation of B-cells when antigen is encountered. It also helps in maintaining immune tolerance, so that immune system does not attack its own body tissues.

The secreted form of IgD is mainly present in mucosal region. It is mostly found in upper respiratory tract such as nose, mouth, salivary glands, tear ducts, airways and tonsils. Thus, it has important role in mucosal immunity and respiratory defence.

IgD also connects adaptive immunity with innate immunity. Secreted IgD can bind with immune effector cells like basophils and mast cells. After antigen detection, these cells release antimicrobial substances, inflammatory mediators and cytokines such as Interleukin-4 (IL-4).

IgD is also involved in allergic reaction and hypersensitivity. It may help to block allergens and reduce excessive inflammation in respiratory tract. But all functions of IgD are not completely understood till now. It is considered as a specialised antibody for mucosal and respiratory immune protection.

History and Discovery of IgD

Immunoglobulin D (IgD) is an ancient antibody molecule. It is believed to evolved about 500 million years ago. It is as old as Immunoglobulin M (IgM) and it appeared with the first jawed vertebrates.
IgD was present from early vertebrate evolution. It was found in jawed vertebrates like cartilaginous fishes. This shows that IgD is not a newly developed immunoglobulin.

Earlier, scientists thought that IgD was a recently evolved antibody. They also believed that it was found only in primates and rodents. This idea was changed after IgD was identified in species like channel catfish.
IgD was officially discovered in human beings during 1964-1965. The discovery was done by Rowe and Fahey. It was first detected in human blood serum.
In the beginning, IgD was identified as a myeloma protein in human serum. Later studies showed that IgD is also present in normal healthy serum. Thus, it was accepted as a normal immunoglobulin class.

It was named Immunoglobulin D because its structure was different from other known immunoglobulin classes. At that time, only three main classes of immunoglobulins were known. So, the new distinct class was called IgD.
After its discovery in serum, IgD was also found on the surface of B-cells. This was identified in 1972. It showed that IgD is not only a serum antibody, but also a receptor molecule of B-lymphocytes.
For many years, the exact function of IgD was not clearly understood. It remained as a puzzling immunoglobulin in immunology. So, IgD was considered as an antibody with unclear biological role.

In recent studies, some functions of IgD became more clear. It is involved in B-cell activation, immune tolerance and mucosal immunity. It also has important role in respiratory immune defence.

Normal Serum Levels of IgD

Age group	Normal serum IgD level
General serum value	≤10 mg/dL
Adult reference value	≤10 mg/dL
Alternative adult lab range	<14.11 mg/dL
Newborn	Usually very low or almost absent
Children	Low level. It may slowly increase with age.

General Characteristics of IgD

Immunoglobulin D (IgD) is a type of immunoglobulin present in very low amount in the blood. It is a minor serum antibody and also present on the surface of mature B-cells. It is mainly related with B-cell function and mucosal defence.
IgD is generally present as a monomer. It is Y-shaped or T-shaped in structure. It is composed of two delta (δ) heavy chains and two light chains, either kappa (κ) or lambda (λ).

The molecular weight of IgD is about 180 to 185 kDa. It is little heavier because it has a long hinge region. This hinge region is one of the important character of IgD.
The hinge region of IgD is very long and flexible. It allows the antigen binding arms to stretch and bind with antigens present at wide distance. Due to this long hinge region, it is also easily broken by proteolytic enzymes.
IgD is present in very small concentration in serum. It forms about 0.25% of total serum immunoglobulins. The normal serum level is about 30 microgram/ml.

Secreted IgD has a short half-life in blood. Its half-life is about 2.8 days. This is because the long hinge region makes the molecule unstable and rapidly degraded.
IgD occurs in two forms in the body. One is membrane-bound form and other is secreted form. Membrane-bound IgD is found on mature B-lymphocytes, while secreted IgD is found in blood and mucosal secretions.
Secreted IgD is present in tears, saliva and upper respiratory tract fluids. So, it is more important in mucosal region. It takes part in local defence of respiratory tract.

Membrane-bound IgD acts as antigen receptor of B-cells. It helps in activation of B-cells after antigen binding. It also helps in immune tolerance.
Secreted IgD binds with pathogens and helps in activating innate immune cells. It can arm basophils and mast cells. These cells then release antimicrobial and inflammatory factors.

Structure of IgD

Immunoglobulin D (IgD) is a richly glycosylated monomeric antibody. It is generally present as Y-shaped molecule, but due to high flexibility it may also show T-shaped form. This shape is mainly due to movement of its long hinge region.

IgD is made up of four polypeptide chains. These are two identical delta (δ) heavy chains and two identical light chains. The light chains may be either kappa (κ) or lambda (λ) type.
The molecular weight of whole IgD molecule is about 180 to 185 kDa. Each delta heavy chain has weight about 60 to 64 kDa, while each light chain has weight about 23 to 25 kDa.
The chains of IgD are arranged into different globular domains. These domains are formed by intrachain disulfide bonds. The light chain has two domains, one variable domain and one constant domain.

The delta heavy chain has four domains. These are one variable domain and three constant domains. The constant domains are called Cδ1, Cδ2 and Cδ3.
The heavy chain and light chain are joined by interchain disulfide bonds. These bonds are present near the carboxyl end of the light chain. This gives stability to the basic immunoglobulin structure.
In membrane bound IgD, the two delta heavy chains are joined with each other by only one disulfide bridge. Due to this, the molecule gets more conformational freedom. It can move more freely on the surface of B-cells.

The most important structural character of mammalian IgD is its very long and flexible hinge region. This hinge region is present between Cδ1 and Cδ2 domains of the heavy chain. It gives high mobility to the antigen binding arms.
The amino-terminal part of hinge region is rich in alanine and threonine residues. It also contains up to seven O-linked glycans. These carbohydrates make the molecule highly glycosylated.
The carboxy-terminal part of hinge region is rich in charged amino acids. These include lysine, glutamate and arginine residues. This part helps in giving special chemical nature to the hinge region.

The long hinge region of IgD is exposed outside. So, it is easily degraded by proteolytic enzymes like plasmin and bacterial proteases. This is one reason why secreted IgD has very short half-life in blood.
IgD has two antigen binding sites. So, its valency is 2. These sites are formed by variable regions of heavy and light chains, which together bind with specific antigen.
The flexible hinge region allows the two Fab regions to move and swivel. Thus, IgD can bind with antigens that are present at wide distance on pathogens. This is an important feature of IgD structure.

IgD is found in membrane-bound and secreted form. Membrane-bound IgD has extra amino acids at the C-terminal end, which helps to anchor it in the B-cell membrane.
Membrane-bound IgD is also associated with Ig-alpha (Igα) and Ig-beta (Igβ) chains. These chains help in signal transmission inside the B-cell after antigen binding.
Secreted IgD does not have the membrane anchoring segment. It is released as soluble antibody in blood and mucosal secretions. This form mainly takes part in mucosal immune defence.

Synthesis and Production of IgD

Early B-cell development occurs in the bone marrow. In this stage, immunoglobulin gene undergoes V(D)J recombination and a new variable region is formed. The B-cell at first transcribes only the nearest constant region gene Cμ, so IgM is produced first.
The immature B-cell then leaves the bone marrow. It migrates to peripheral lymphoid tissues like spleen and lymph nodes. Here the B-cell becomes mature and ready for expression of IgD also.
In mature B-cell, a long primary pre-mRNA is transcribed. This RNA contains the rearranged VDJ region and also the constant region exons of Cμ and Cδ. So the same long transcript has region for IgM and IgD.

A regulatory protein called Zinc-finger protein 318 (ZFP318) is formed in mature B-cells. It blocks the normal termination site PolyA 1 after Cμ region. Because of this, transcription does not stop after IgM part.
The transcription now continues beyond Cμ region. It reaches the downstream Cδ exons and stops at second polyadenylation site PolyA 2. This is the read-through transcription needed for IgD formation.
After this, alternative splicing occurs. The Cμ region is removed from the RNA as intron. The VDJ region is then joined directly with Cδ exons. Thus, delta (δ) mRNA is formed.

The delta mRNA is translated to form delta heavy chains. These heavy chains combine with light chains. The light chains may be kappa (κ) or lambda (λ). This forms the complete IgD molecule.
The formed IgD is mostly attached to B-cell membrane. It is called membrane-bound IgD (mIgD). It is expressed on mature B-cell surface together with IgM.
Some B-cells present in mucosal tissues can produce secreted IgD. These cells are mainly found in tissues like tonsils. Here unusual class-switch recombination takes place for IgD production.

This class-switching is mediated by Activation-induced cytidine deaminase (AID). The Cμ region is deleted from the gene. After this, the cell can use Cδ region directly for producing IgD.
These specialised B-cells change into plasma cells. They synthesize and release soluble IgD (sIgD). This secreted IgD is mainly released in mucosal membranes and takes part in local immune defence.

Distribution Process of IgD in the Body

Membrane-bound IgD (mIgD)

IgD is mainly present as membrane-bound antibody on mature naïve B-lymphocytes. It acts as antigen receptor on the surface of B-cells. It is generally co-expressed with IgM and forms about 1% of the plasma membrane proteins.

The B-cells carrying mIgD are present in secondary lymphoid organs. These are mainly spleen, lymph nodes, tonsils and some mucous membranes. Thus, this type of IgD distribution is mainly related with mature B-cell region.

Some mucosal B-cells express only IgD and not IgM. These cells are mostly found in nasopharyngeal lymphoid tissues. The important sites are tonsils and adenoids.

Secreted IgD in Blood

Secreted IgD (sIgD) is released into blood by plasma cells. But its amount is very low in serum. It forms only about 0.25% of total serum immunoglobulins.

The normal serum concentration of IgD is about 30 microgram/ml. This low level is due to short half-life of IgD. It is also easily degraded by proteolytic enzymes.

Secreted IgD in Mucosal Secretions

Secreted IgD is mainly distributed in mucosal areas. It is more important in upper respiratory tract. It works as a surveillance molecule in mucosal immunity.

It is found in nasal mucus, saliva, tears, airways, lungs, tonsils, salivary glands, mammary glands and middle ear. These are the main mucosal places where IgD is distributed.

IgD is very less in intestine and digestive tract. In these places, IgA is the main immunoglobulin. So, IgD distribution in digestive tract is negligible.

IgD Bound with Innate Immune Cells

After secretion, IgD may attach with innate immune effector cells. These cells include basophils, mast cells and monocytes. They are present in blood and also in mucosal tissues.

On basophils, IgD binds with receptor complex made of Galectin-9 and CD44. By this attachment, IgD remains on basophil membrane. It helps basophils to take part in immune activation.

Surface Expression of IgD on B Lymphocytes

Immature B-cells in bone marrow express only surface IgM. At this stage IgD is not expressed on the cell surface. When these B-cells leave bone marrow and reach peripheral lymphoid tissues, they start expressing membrane-bound IgD (mIgD) along with IgM.
mIgD is attached with B-cell membrane by extra amino acids present at its C-terminal end. This part helps the molecule to remain fixed on the B-cell surface. In some condition, IgD may also be present as glycosylphosphatidylinositol (GPI)-linked membrane molecule.
On B-cell surface, mIgD does not work alone. It combines with two signalling chains, CD79a (Ig-alpha) and CD79b (Ig-beta). Together they form the complete B-cell receptor (BCR) complex.

The heavy chains of mIgD are joined by only one disulfide bridge near the carboxy terminal region. Because of this less covalent joining, the molecule has high movement. Its antigen binding arms can move and bind with antigen more freely.
mIgD has a very long and flexible hinge region. Due to this structure, its signalling capacity is restricted. It mainly responds to repeated and multivalent antigens which can cross-link many IgD receptors on B-cell surface.
mIgD does not respond properly to soluble monovalent antigens. These antigens cannot cross-link the surface IgD receptors. So, no strong B-cell activation is produced by these small single antigens.

In mildly self-reactive B-cells, surface IgM is downregulated after contact with monovalent self-antigens. But mIgD remains present at high level. Since IgD does not respond to these monovalent self-antigens, the B-cell remains silent or anergic.
This anergic condition is important for immune tolerance. It prevents the B-cell from producing autoantibodies against self body tissues. Thus, surface IgD helps in preventing harmful autoimmune response.
When mIgD is cross-linked by multivalent foreign antigen, the B-cell becomes activated. The activated B-cell may move into germinal center. Then it can differentiate into memory B-cell or antibody secreting plasma cell.

Most mature B-cells express both IgM and IgD on their surface. But some special B-cells in nasopharyngeal mucosal tissues express only IgD. These cells are mainly found in tonsils and related mucosal lymphoid tissues.

Role of IgD as a B Cell Receptor (BCR)

BCR formation- Membrane-bound IgD (mIgD) pairs with two transmembrane signalling chains, CD79a (Ig-alpha) and CD79b (Ig-beta). This forms a functional B-cell receptor (BCR) complex on mature B-cells.
Signal transduction- When IgD-BCR binds with antigen, signal starts inside the B-cell. Src family tyrosine kinases are recruited and they phosphorylate ITAMs present on CD79a and CD79b tails.

Multivalent antigen response- IgD has long and flexible hinge region, so its signalling capacity is restricted. It responds mainly to repetitive multivalent antigens, which can cross-link many receptors on the B-cell surface, but it does not respond to soluble monovalent antigens.
Immune tolerance- In mildly self-reactive B-cells, monovalent self-antigens do not activate the IgD receptor. So the B-cell remains silent or anergic, and this prevents wrong production of autoantibodies against own body tissues.
B-cell survival- IgD-BCR gives survival signals to mature B-cells in peripheral immune system. It helps to keep broad and diverse B-cell population present in the body.

Protection from apoptosis- Strong stimulation of IgM receptor can cause receptor-mediated cell death or apoptosis. But strong stimulation of IgD receptor generally fails to induce apoptosis, so circulating B-cell pool is preserved.
Autoantibody control- IgD senses self-antigens less efficiently than IgM in the body. It is poor in making B-cells into short-lived plasma cells, so rapid and uncontrolled secretion of harmful autoantibodies is limited.
Germinal center entry- When IgD-BCR is cross-linked by multivalent foreign pathogen, enough activation signal is produced. The B-cell can migrate into germinal center and take part in T-dependent immune response and form protective antibody-secreting cells.

Co-receptor association- The activating co-receptor CD19 first remains associated with resting IgD clusters. After B-cell activation, it moves to IgM clusters, and this helps to adjust the total signalling output of the B-cell.

Step by Step Detail Mechanism of Action of IgD

Mechanism of Membrane-bound IgD (mIgD)

Antigen surveillance- Membrane-bound IgD (mIgD) is present on mature B-cells as surface receptor. It scans the surrounding area for antigens. Due to its long flexible hinge region, it mainly responds to repetitive multivalent antigens and ignores soluble monovalent antigens.
Valency discrimination- IgD-BCR can differentiate between foreign multivalent antigen and self monovalent antigen. Multivalent antigens are generally present on pathogens and can cross-link the receptors. Monovalent self-antigens cannot cross-link IgD properly, so activation signal is not formed.

Anergy formation- When mildly self-reactive B-cells bind with monovalent self-antigens, the surface IgM receptors are triggered and then downregulated. But mIgD remains on the B-cell surface and does not give activation signal. Thus, the B-cell becomes silent or anergic.
Immune tolerance- The anergic B-cell remains dormant and unresponsive. It does not form plasma cell and does not secrete autoantibody. This mechanism prevents autoimmune attack against own body tissues.
Pathogen cross-linking- When mIgD meets multivalent foreign pathogen, many IgD molecules are pulled together on B-cell surface. This causes physical cross-linking of IgD-BCR. This is the starting step for B-cell activation.

Signal initiation- After cross-linking, intracellular signal starts inside the B-cell. Src family tyrosine kinases are recruited near the receptor complex. These kinases phosphorylate ITAMs present on CD79a and CD79b chains.
B-cell activation- Phosphorylation of ITAMs starts further signalling pathway inside the cell. The B-cell becomes activated. It can now proliferate and take part in immune response against the foreign antigen.
Germinal center entry- The activated B-cell moves into germinal center. Here it divides and differentiates. It may form antibody-secreting plasma cells or memory B-cells for later immune protection.

Mechanism of Secreted IgD (sIgD)

Innate cell arming- Secreted IgD (sIgD) is released in blood and mucosal membrane. It attaches on innate immune effector cells like basophils and mast cells. Thus, IgD connects adaptive immunity with innate immunity.
Basophil attachment- On basophils, sIgD binds with a receptor complex made of Galectin-9 and CD44. By this binding, IgD remains fixed on basophil surface. This makes basophil ready for antigen detection.
Antigen binding- When foreign antigen like respiratory microbe or food-derived antigen comes, it binds with variable region of basophil-bound IgD. The antigen joins more than one IgD molecule. This causes receptor cross-linking.

Calcium flux- Cross-linking of Galectin-9/CD44 complex starts signal inside the basophil. Intracellular calcium flux occurs. This rapidly activates the basophil.
Mediator secretion- Activated basophil releases many immune factors. These include antimicrobial peptides such as cathelicidin, pentraxin-3 and beta-defensin. It also releases BAFF, APRIL and cytokines like IL-3, IL-4, IL-5 and IL-13.
Th2 response- The released IL-4 recruits and differentiates CD4+ helper T-cells into Tfh2 cells. These Tfh2 cells help nearby B-cells. The B-cells then undergo class-switch recombination and produce more IgG and IgE antibodies.

Immune amplification- Through these mediator release, sIgD increases local immune response. It helps in mucosal defence, especially against respiratory microbes and mucosal antigens. This makes the immune reaction stronger at local site.
Allergy control- When sIgD is engaged together with IgE on same basophil, it gives anti-inflammatory effect. It suppresses IgE-induced basophil degranulation and histamine release. Thus, excessive allergic inflammation and hypersensitivity in mucosal tissues is reduced.

Role of IgD in B Cell Activation and Maturation

Maturation marker- IgD appears on the surface of B-cells when immature B-cells come out from bone marrow. These cells go to peripheral lymphoid tissues and become mature naïve B-cells. At this stage IgD is present with IgM on the same cell.

Activation marker- Serum IgD is regarded as an early marker of B-cell activation. Its presence in blood is related with activation stage of B-cells. It shows that B-cell response has started.
Antigen receptor- Membrane IgD acts as B-cell receptor (BCR). It remains on B-cell surface and detects antigen. It helps the B-cell to know whether the antigen will activate the cell or not.
Selective activation- IgD has long flexible hinge region. So it mainly acts when repeated multivalent antigen binds on it. These antigens cross-link many IgD receptors and then activation signal is formed.

T-cell presentation- After binding with antigen, the B-cell takes the antigen inside. The antigen is processed and shown to helper T-cells. Then helper T-cells stimulate the B-cell for rapid division and plasma cell formation.
Immune tolerance- IgD is less sensitive to soluble monovalent self-antigens than IgM. So mildly self-reactive B-cells are not fully activated. These cells remain silent or anergic and autoimmune attack is prevented.
Germinal center entry- When foreign pathogen cross-links IgD, strong signal is produced inside the B-cell. The activated B-cell then moves into germinal center. Here the cell undergoes further maturation and immune response.

Plasma cell control- IgD controls the fate of B-cells. During chronic endogenous antigen exposure, it does not allow rapid formation of short-lived plasma cells (SLPCs). The response is shifted more toward germinal center pathway.
B-cell survival- IgD signalling gives survival support to mature B-cells in peripheral immune system. It keeps the B-cell population alive. It also helps to maintain many different types of B-cells.
Memory formation- IgD is also involved in long-term B-cell memory. It helps in generation and maintenance of memory B-cells. These cells are useful during future antigen exposure.

Regulation of IgD Production

Alternative splicing- In most B-cells, IgD production is controlled at RNA level. A long pre-mRNA is formed which has both Cμ and Cδ region. The cell then selects the polyadenylation and splicing pattern, so either IgM or IgD mRNA is formed.
ZFP318 control- Zinc-finger protein 318 (ZFP318) is the main regulator of IgD production. It blocks the normal stopping site PolyA 1 after IgM gene. So transcription continues forward and reaches the IgD (Cδ) exons.
Read-through transcription- When ZFP318 blocks early termination, the RNA machinery does not stop after Cμ region. It reads through the downstream part and transcribes Cδ region. This helps in formation of delta mRNA.

B-cell stage- IgD production depends on the stage of B-cell development. In immature bone marrow B-cells, ZFP318 is almost absent and IgD is not produced. It becomes moderate in transitional B-cells and high in mature follicular and marginal zone B-cells.
Mature B-cell expression- When B-cells become mature, ZFP318 is highly upregulated. Then IgD starts to appear on the surface with IgM. This is a normal character of mature naïve B-cells.
Non-canonical CSR- In mucosal tissues like tonsils and adenoids, IgD production is controlled at DNA level. Here unusual class-switch recombination (CSR) occurs. It is different from common class switching.

AID function- Activation-induced cytidine deaminase (AID) mediates this special switching. It helps to delete the IgM (Cμ) gene region permanently. After this, the B-cell becomes able to produce only IgD.
IgD-only B-cells- After non-canonical switching, special B-cells are formed which express only IgD. These cells are mainly present in mucosal lymphoid tissues. They can later produce and secrete secreted IgD (sIgD).
Cytokine effect- Some cytokines can regulate IgD expression on B-cells. Interleukin-27 (IL-27) is one cytokine which partly controls surface expression of IgD. Thus, cytokine environment also affects IgD production.

Inflammation effect- In mucosal and respiratory areas, active inflammation can increase switching toward IgD. Chronic inflammatory condition and autoinflammatory syndromes may show more IgD-only B-cells and more secreted IgD production.

Factors Affecting IgD Levels

Factors causing high IgD levels

Genetic disorder- Hyper-IgD syndrome (HIDS) is a rare genetic disorder. It is also called Mevalonate kinase deficiency (MKD). In this condition, serum IgD level remains high and generally more than 100 units/L.
Cancer- Some blood and immune system cancers can increase IgD level. Lymphoma and IgD multiple myeloma are important examples. In IgD multiple myeloma, monoclonal IgD is produced in very high amount.

Infection- Chronic infections may increase serum IgD level. Some respiratory pathogens also stimulate IgD production. Rubella infection and Mycobacterium tuberculosis exposure are related with increased IgD.
Autoimmune disease- Some autoimmune diseases can increase IgD level. Systemic sclerosis is one example. Here chronic inflammation causes more antibody activity and IgD level may become high.
Smoking- Cigarette smoking is also a factor for high IgD level. It may stimulate mucosal immune system. So, serum IgD level can increase in smokers.

Compensatory production- When other immunoglobulins are deficient, IgD production may increase. In IgA deficiency or IgM deficiency, IgD may act as substitute antibody. Patients with IgA deficiency and chronic upper respiratory infection often show more IgD-producing plasma cells.

Factors causing low IgD levels

Selective IgD deficiency- This is mostly a genetic condition where IgD level becomes abnormally low. Other antibodies remain normal. It usually does not cause symptoms and generally does not increase infection risk.
Hypogammaglobulinemia- Hypogammaglobulinemia is a condition where all types of antibodies are low. In this condition, IgD also becomes low. It is related with broad immune antibody deficiency.

Functions of IgD

B-cell receptor- IgD acts as antigen receptor on mature naïve B-cells. It remains on the B-cell surface and detects specific foreign antigen. After binding with pathogen, it gives activation signal and the B-cell starts proliferation and plasma cell formation.
B-cell activation- When IgD binds with proper foreign antigen, the B-cell becomes activated. The cell divides and differentiates into antibody secreting plasma cells. Thus, IgD helps to start humoral immune response.
Immune tolerance- IgD helps to prevent autoimmune reaction. It is less responsive to monovalent self-antigens of the body. So mildly self-reactive B-cells do not become plasma cells and harmful autoantibodies are not produced.

Mucosal immunity- Secreted IgD is important in mucosal defence. It is mainly found in upper respiratory tract, nasal passage, salivary gland and oral cavity. It protects these surfaces from microbes which enter through air and mucosal route.
Respiratory defence- IgD can bind with respiratory microbes, viruses and encapsulated bacteria. It helps to block their entry into host cells. It also marks them for destruction by immune cells.
Innate cell arming- Soluble IgD attaches with innate immune cells like basophils, mast cells and monocytes. When pathogen binds with this attached IgD, these cells become activated. They release antimicrobial factors, inflammatory mediators and cytokines like IL-4.

Immune amplification- Through activation of basophils and mast cells, IgD increases local immune response. The released cytokines and mediators attract other immune cells. Thus, mucosal defence becomes stronger at the infected site.
Allergy regulation- IgD has role in allergic reaction and hypersensitivity. When IgD is co-engaged with IgE on basophils, it reduces excessive degranulation. It also decreases histamine release and helps to limit allergic inflammation.
Substitute antibody- IgD may act as compensatory antibody when other immunoglobulins are deficient. In IgA or IgM deficiency, IgD production may increase. It can take part in protective function in such condition.

B-cell memory- IgD is also related with long-term B-cell memory. It helps in generation and maintenance of memory B-cells. These memory cells help during later exposure to same antigen.
T-cell interaction- After surface IgD binds antigen, the B-cell can take the antigen inside. The antigen is processed and presented to helper T-cells. Then helper T-cells further stimulate and direct the immune response.

Diseases Associated with Elevated or Abnormal IgD Levels

Hyper-IgD syndrome- Hyper-IgD syndrome (HIDS) is a rare inherited autoinflammatory disease. It is also called Mevalonate kinase deficiency (MKD). It is caused by mutation in MVK gene and serum IgD level remains very high, usually more than 100 IU/ml or units/L.

HIDS symptoms- Symptoms of HIDS usually starts in first year of life. The patient gets repeated attacks of high fever, chills, severe abdominal pain, swollen lymph nodes, joint pain and skin rashes. In many cases IgA level is also increased with IgD.
IgD myeloma- IgD multiple myeloma is a rare and aggressive blood cancer. It is a neoplastic plasma cell disease and forms only about 1% to 2% of all multiple myeloma cases. In this disease, abnormal plasma cells produce monoclonal IgD paraprotein.
Myeloma features- In IgD multiple myeloma, patients may have severe bone lesions, anaemia, high calcium level and acute kidney failure. The kidney damage is often due to cast nephropathy. This myeloma mostly shows lambda (λ) light chain restriction in about 90% cases.

Autoimmune disease- IgD level may be increased in systemic autoimmune diseases. In Rheumatoid arthritis (RA), increased secreted IgD can activate peripheral blood mononuclear cells. So, abnormal IgD is related with inflammatory activity in autoimmune condition.
Autoinflammatory condition- In different autoinflammatory syndromes, mucosal IgD-only B-cells may increase. IgD-armed basophils are also increased. These changes show that IgD takes part in abnormal inflammatory immune response.
Chronic infection- Some chronic infections can increase serum IgD level. Infections like rubella and Mycobacterium tuberculosis are related with abnormal rise of IgD. Respiratory pathogens may also stimulate IgD production in mucosal region.
Antibody deficiency- In some selective antibody deficiencies, IgD may increase as a compensatory antibody. When IgM or IgA is deficient, the body may produce more IgD. It works like a substitute protective antibody.
IgA deficiency- In IgA-deficient patients with chronic upper respiratory infection, IgD-secreting plasma cells may increase in nasal mucosa. This shows that IgD can increase when normal mucosal antibody defence is weak.

Laboratory Detection and Measurement of IgD

Serum level- Normal IgD level in serum is very low. It is about 30 microgram/ml. Due to this low amount, routine detection of IgD is difficult than other common antibodies.
Immunonephelometry- Total IgD level in blood can be measured by immunonephelometry. In this method, specific analyzer system is used. It gives quantitative value of serum IgD.
SPE test- Serum protein electrophoresis (SPE) or capillary zone electrophoresis (CZE) may fail to detect abnormal IgD. Because IgD is low in amount and rapidly degraded, it often does not show clear M-spike.
SPE pattern- In many cases of abnormal IgD, the electrophoresis pattern may look normal. Sometimes only mild polyclonal increase is seen. So, normal SPE does not exclude IgD related disease.
Standard IFE- In usual immunofixation electrophoresis (IFE), antisera are used against IgG, IgA, IgM, kappa and lambda. This usual panel does not include IgD heavy chain. So, IgD myeloma may be missed.
Misdiagnosis- If IgD heavy chain is not tested, abnormal IgD disease may look like light-chain-only disease. This can happen in IgD multiple myeloma. Therefore only routine IFE panel is not enough in suspected case.
Secondary IFE- For proper identification of IgD, a second targeted IFE is required. This test uses specific anti-IgD heavy chain antisera. Sometimes anti-IgE antisera is also used to exclude other rare heavy chain type.
Immunosubtraction- Immunosubtraction technique is used to confirm complete IgD molecule. Patient serum is treated with anti-kappa or anti-lambda antisera. If the IgD band disappears on IFE gel, it shows that light chain is attached with IgD heavy chain.
2D gel method- Two-dimensional gel electrophoresis is a more advanced method. With special silver staining, it gives better sensitivity and resolution. It can detect and isolate IgD paraproteins better than routine electrophoresis.
Urine electrophoresis- Urine protein electrophoresis of 24-hour urine sample is useful in IgD multiple myeloma. It detects Bence Jones proteins, which are free lambda or kappa light chains. This test may detect disease better than serum test alone.
HIDS testing- In Hyper-IgD syndrome (HIDS), serum IgD is persistently high. The level is usually more than 100 IU/ml or units/L. This increase should be confirmed two times, at least one month apart.

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Immunoglobulin D (IgD) – Definition, Properties, Structure and Functions