Immunoglobulin D

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Some antibodies form polymers that bind to multiple antigen molecules. Mono-und-Polymere.svg
Some antibodies form polymers that bind to multiple antigen molecules.

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. [1] Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

Contents

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 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 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. [3] Cδ knockout mice (mice that have been genetically altered so that they do not produce IgD) have no major B cell intrinsic defects. [4] [5] IgD may have some role in allergic reactions.[ citation needed ]

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. [6] 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.[ citation needed ]

Structural diversity

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 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. [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]

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

<span class="mw-page-title-main">Basophil</span> Type of white blood cell

Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte and how they work is not fully understood. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They also produce compounds that coordinate immune responses, including histamine and serotonin that induce inflammation, and heparin that prevents blood clotting, although there are less than that found in mast cell granules. Mast cells were once thought to be basophils that migrated from the blood into their resident tissues, but they are now known to be different types of cells.

<span class="mw-page-title-main">Immunoglobulin G</span> Antibody isotype

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

<span class="mw-page-title-main">Plasma cell</span> White blood cell that secretes large volumes of antibodies

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen, where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Immunoglobulin class switching</span> Biological mechanism

Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG. During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

<span class="mw-page-title-main">Isotype (immunology)</span>

In immunology, antibodies are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen . In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen . They appear at different stages of an immune response, differ in structural features, and in their location around the body.

<span class="mw-page-title-main">J chain</span> Protein-coding gene in the species Homo sapiens

The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion. The J chain is well conserved in the animal kingdom, but its specific functions are yet to be fully understood. It is a 137 residue polypeptide, encoded by the IGJ gene.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

<span class="mw-page-title-main">FCGR2B</span>

Fc fragment of IgG receptor IIb is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.

<span class="mw-page-title-main">FCAR</span> Mammalian protein found in Homo sapiens

Fc fragment of IgA receptor (FCAR) is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89. FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies. FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils, though it is notably absent from intestinal macrophages and does not appear on mast cells. FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound. Inside-out signaling primes FcαRI in order for it to bind its ligand, while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain.

Antibody structure is made up of two heavy-chains and two light-chains. These chains are held together by disulfide bonds. The arrangement or processes that put together different parts of this antibody molecule play important role in antibody diversity and production of different subclasses or classes of antibodies. The organization and processes take place during the development and differentiation of B cells. That is, the controlled gene expression during transcription and translation coupled with the rearrangements of immunoglobulin gene segments result in the generation of antibody repertoire during development and maturation of B cells.

Anti-immunoglobulin antibodies are defined as a protein that detects other antibodies from an organism. Specifically, anti-immunoglobulin antibodies are created by B-cells as antibodies to bind to other immunoglobulins. Immunoglobulins have two regions: the constant region and the variable region. The constant region is involved in effector function, while the variable region is involved in recognizing and binding to antigens. Anti-immunoglobulin antibodies may bind to either the variable or constant region of the immunoglobulin. Anti-immunoglobulin antibodies are a type of secondary antibody. They are able to detect primary antibodies through multiple methods such as a Western blot, immunohistochemistry, immunofluorescence staining, flow cytometry, and ELISA.

References

  1. ↑ Rogentine GN, Rowe DS, Bradley J, Waldmann TA, Fahey JL (1966). "Metabolism of human immunoglobulin D (IgD)". J. Clin. Invest. 45 (9): 1467–78. doi:10.1172/JCI105454. PMC   292826 . PMID   5919348.
  2. ↑ Ohta, Yuko; Martin Flajnik (2006-07-11). "IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates". Proceedings of the National Academy of Sciences. 103 (28): 10723–10728. Bibcode:2006PNAS..10310723O. doi: 10.1073/pnas.0601407103 . PMC   1636022 . PMID   16818885.
  3. 1 2 Übelhart, R; Hug, E; Bach, MP; Wossning, T; Dühren-von Minden, M; Horn, AH; Tsiantoulas, D; Kometani, K; Kurosaki, T; Binder, CJ; Sticht, H; Nitschke, L; Reth, M; Jumaa, H (2015). "Responsiveness of B cells is regulated by the hinge region of IgD". Nat Immunol. 16 (5): 534–43. doi:10.1038/ni.3141. PMID   25848865. S2CID   205369181.
  4. ↑ Edholm ES, Bengten E, Wilson M (2011). "Insights into the function of IgD". Dev. Comp. Immunol. 35 (12): 1309–16. doi:10.1016/j.dci.2011.03.002. PMID   21414345.
  5. ↑ Nitschke L, Kosco MH, Köhler G, Lamers MC (1993). "Immunoglobulin D-deficient mice can mount normal immune responses to thymus-independent and -dependent antigens". Proc. Natl. Acad. Sci. U.S.A. 90 (5): 1887–91. Bibcode:1993PNAS...90.1887N. doi: 10.1073/pnas.90.5.1887 . PMC   45985 . PMID   8446604.
  6. 1 2 Chen, Kang; Xu, Weifeng; Wilson, Melanie; He, Bing; Miller, Norman W; Bengtén, Eva; Edholm, Eva-Stina; Santini, Paul A; et al. (2009). "Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell–stimulating programs in basophils". Nature Immunology. 10 (8): 889–898. doi:10.1038/ni.1748. PMC   2785232 . PMID   19561614.
  7. ↑ Bengtén, Eva; Quiniou, Sylvie M.-A.; Stuge, Tor B.; Katagiri, Takayuki; Miller, Norman W.; Clem, L. William; Warr, Gregory W.; Wilson, Melanie (2002-09-01). "The IgH Locus of the Channel Catfish, Ictalurus punctatus, Contains Multiple Constant Region Gene Sequences: Different Genes Encode Heavy Chains of Membrane and Secreted IgD". The Journal of Immunology. 169 (5): 2488–2497. doi: 10.4049/jimmunol.169.5.2488 . ISSN   0022-1767. PMID   12193718.
  8. 1 2 Preud'homme, Jean-Louis; Petit, Isabelle; Barra, Anne; Morel, Jean-Claude Lecron, Franck; Lelièvre, Eric (October 2000). "Structural and functional properties of membrane and secreted IgD". Molecular Immunology. 37 (15): 871–887. doi:10.1016/s0161-5890(01)00006-2. ISSN   0161-5890. PMID   11282392.
  9. ↑ Ohta, Y.; Flajnik, M. (2006-07-03). "IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates". Proceedings of the National Academy of Sciences. 103 (28): 10723–10728. Bibcode:2006PNAS..10310723O. doi: 10.1073/pnas.0601407103 . ISSN   0027-8424. PMC   1636022 . PMID   16818885.
  10. ↑ Chen, Kang; Cerutti, Andrea (2010-08-19). "New insights into the enigma of immunoglobulin D". Immunological Reviews. 237 (1): 160–179. doi:10.1111/j.1600-065x.2010.00929.x. ISSN   0105-2896. PMC   3048779 . PMID   20727035.
  11. ↑ Iwase, H.; Tanaka, A.; Hiki, Y.; Kokubo, T.; Ishii-Karakasa, I.; Kobayashi, Y.; Hotta, K. (1996-07-01). "Abundance of Gal 1,3GalNAc in O-Linked Oligosaccharide on Hinge Region of Polymerized IgA1 and Heat-Aggregated IgA1 from Normal Human Serum". Journal of Biochemistry. 120 (1): 92–97. doi:10.1093/oxfordjournals.jbchem.a021398. ISSN   0021-924X. PMID   8864849.
  12. 1 2 Swenson, Christina D.; Patel, Thakor; Parekh, Raj B.; Tamma, S. M. Lakshmi; Coico, Richard F.; Thorbecke, G. Jeanette; Amin, Ashok R. (August 1998). "Human T cell IgD receptors react with O-glycans on both human IgD and IgA1". European Journal of Immunology. 28 (8): 2366–2372. doi: 10.1002/(sici)1521-4141(199808)28:08<2366::aid-immu2366>3.0.co;2-d . ISSN   0014-2980. PMID   9710214. S2CID   36783085.
  13. 1 2 Murphy, K; Weaver, C (2016). Janeway's Immunobiology. New York, NY: Garland Science/Taylor and Francis. p. 195. ISBN   978-0-8153-4505-3.
  14. ↑ Enders, A.; Short, A.; Miosge, L.; Bergmann, H.; Sontani, Y.; Bertram, E.; Whittle, B.; Balakishnan, B.; Yoshida, K.; Sjollema, G.; Field, M.; Andrews, T.; Hagiwara, H.; Goodnow, C. (2014). "Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes". Proceedings of the National Academy of Sciences. 111 (12): 4513–4518. Bibcode:2014PNAS..111.4513E. doi: 10.1073/pnas.1402739111 . PMC   3970522 . PMID   24616512.
  15. 1 2 Nguyen, Tue G.; Little, Christopher B.; Yenson, Vanessa M.; Jackson, Christopher J.; McCracken, Sharon A.; Warning, Julia; Stevens, Veronica; Gallery, Eileen G.; Morris, Jonathan M. (2010). "Anti-IgD antibody attenuates collagen-induced arthritis by selectively depleting mature B-cells and promoting immune tolerance". Journal of Autoimmunity. 35 (1): 86–97. doi:10.1016/j.jaut.2010.03.003. ISSN   0896-8411. PMID   20456921.
  16. ↑ Zhai, Guan-Ting; Wang, Hai; Li, Jing-Xian; Cao, Ping-Ping; Jiang, Wen-Xiu; Song, Jia; Yao, Yin; Wang, Zhi-Chao; Wang, Zhe-Zheng (2018). "IgD-activated mast cells induce IgE synthesis in B cells in nasal polyps". Journal of Allergy and Clinical Immunology. 142 (5): 1489–1499.e23. doi: 10.1016/j.jaci.2018.07.025 . ISSN   0091-6749. PMID   30102935.
  17. ↑ Shan, Meimei; Carrillo, Jorge; Yeste, Ada; Gutzeit, Cindy; Segura-Garzón, Daniel; Walland, A. Cooper; Pybus, Marc; Grasset, Emilie K.; Yeiser, John R. (2018). "Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44". Immunity. 49 (4): 709–724.e8. doi:10.1016/j.immuni.2018.08.013. ISSN   1074-7613. PMC   6366614 . PMID   30291028.
  18. ↑ Kulkarni, Upasana; Karsten, Christian M.; Kohler, Thomas; Hammerschmidt, Sven; Bommert, Kurt; Tiburzy, Benjamin; Meng, Lingzhang; Thieme, Lara; Recke, Andreas (2016). "IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration". Journal of Allergy and Clinical Immunology. 137 (5): 1487–1497.e6. doi: 10.1016/j.jaci.2015.10.018 . ISSN   0091-6749. PMID   26653800.
  19. ↑ Nguyen, Tue G. (2018). "Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite a Th2-favoured humoral response". Immunology Letters. 203: 29–39. doi:10.1016/j.imlet.2018.09.008. ISSN   0165-2478. PMID   30218740. S2CID   52282444.
  20. ↑ Wu, Yujing (2016). "The Elevated Secreted Immunoglobulin D Enhanced the Activation of Peripheral Blood Mononuclear Cells in Rheumatoid Arthritis". PLOS ONE. 24 (1): 544–551. doi: 10.1080/16078454.2019.1642553 . PMID   31315540.
  21. ↑ Nguyen, Tue Gia (2021-01-07). "The therapeutic implications of activated immune responses via the enigmatic immunoglobulin D". International Reviews of Immunology. 41 (2): 107–122. doi:10.1080/08830185.2020.1861265. ISSN   0883-0185. PMID   33410368. S2CID   230821031.
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