The role of IgD in the immune system is still relatively unknown. In an elaborate set of experiments, Chen et al. revealed some of IgD's secrets by showing that B cells in the upper respiratory mucosa actively undergo IgM to IgD class-switching, which results in the production of IgD antibodies that can bind to respiratory bacteria and some of their products. In addition, these IgD antibodies can also bind to basophils, resulting in the generation of antimicrobial and B cell activating factors. Dysregulation of these immune processes could play a role in the development of autoinflammatory diseases.
While today's basic immunology text books still consider the function of the immunoglobulin D molecule as unknown, researchers are making progress in elucidating its possible role in the immune system of humans and other species, its evolutionary history, and its role in the development of autoinflammatory diseases. In August's issue of Nature Immunology, Chen et al. showed that IgD is produced by a special subpopulation of upper respiratory mucosal B cells, and is able to release B cell activating and antimicrobial factors after binding to a calcium-mobilizing receptor on basophils1.
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During their development in the bone marrow, immature B cells will start to express membrane-bound IgM. When these cells leave the bone marrow and home to secondary lymphoid organs, they also start to express membrane-bound IgD. At this stage, they are called mature B cells. After antigen recognition, mature B cells lose their IgD expression and undergo somatic hypermutation and class-switch recombination (CSR), yielding IgA, IgG or IgE antibodies. During this process, different cytokines and costimulators direct which antibody isotype will be generated2. In some B cells there is also class-switching from IgM to IgD, indicating that IgD plays an active role in the immune system and possibly has some functional advantage over other antibody isotypes3. These IgD+IgM- plasma cells produce IgD antibodies that are released into the blood stream but are also present in respiratory, salivary, lacrimal, and mammary secretions4,5.
By using immunohistochemistry, light microscopy and flow cytomerty, Chen et al. showed that in contrast to splenic, bone marrow, hepatic, lymph node and intestinal tissue, upper respiratory mucosa tissue (tonsils and nasal mucosa) contains a high percentage of IgD-producing IgD+IgM- plasma cells. Within these anatomical sites, IgD+IgM- B cells have different topographical and morphological futures when compared to conventional IgD+IgM+ B cells. For example, IgD+IgM- B cells are present in germinal centers, while IgD+IgM+ B cells mainly occupy the follicular mantle, but not germinal centers. Furthermore, in spite of having a plasma cell-like appearance, IgD+IgM- B cells do not fully express all plasma cell markers. In addition, cell surface markers that are normally downregulated by terminally differentiated plasma cells, are retained on these cells. A small percentage of IgD+IgM- plasma cells was also found in peripheral blood. Taken together, these data raise the question where class-switching from IgM to IgD takes place.
By using PCR to detect small circular DNA fragments known as switch circles, which are generated during CSR, the authors found that IgM to IgD CSR occurs only in tonsillar B cells. No IgD-specific switch circles were found in other lymphoid tissues. This suggests that B cells that have migrated to the upper respiratory tract actively undergo IgM to IgD CSR in situ. This immediately raises another question, that is, which signals are necessary for IgM to IgD CSR?
It is well established that CSR takes place after engagement of CD40 on B cells by CD40L on T cells (T cell-dependent way), or by engagement of TACI on B cells by BAFF or APRIL from innate immune cells (T cell-independent way). During these interactions, different cytokines will direct which antibody class will be produced6. By incubating B cells with different combinations of cytokines in the presence or absence of CD40L, BAFF or APILL, the authors found that class-switching from IgM to IgD is induced by exposure to CD40L, BAFF or APRIL, in combination with either IL-15 and IL-21 or IL-2 and IL-21. Since it is known that these three cytokines are produced by dendritic cells and helper T cells1, it would be interesting to find out which type of antigens activate these cells to produce this combination of cytokines and therefore IgM to IgD class-switching. Although highly speculative, a number of observations suggest that viruses are able to induce IgD production. First, IL-2 and IL-15 show a great amount of redundancy in their activities, making IL-21 the critical switch factor. Indeed, other studies have shown the involvement of IL-21 as a B cell switch factor7,8,9. Second, IL-21 is produced by helper T cells after engagement of Toll-like receptor 310. Given that this receptor recognizes double-stranded viral RNA, it is conceivable that IgD is involved in the defense against viruses11. This view is also supported by the observation that mice undergoing an acute infection with lymphocytic chriomeningitis virus or vesicular stomatitis virus produce increased amounts of virus-specific IgD12. However, more direct experimental work is needed to find out which antigens are really responsible for the generation of IgD switch factors. In contrast to the results presented by Chen et al., some groups have shown spontaneous IgD secretion by tonsillar B cells, which increased after stimulation with anti-CD40 and IL-4 or IL-1013. Taken together, the authors have shown that class-switching to IgD can be induced in a T cell-dependent or T cell-independent way, and that IL-21 is a critical switch factor for IgD class-switching.
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In an attempt to gain some understanding of IgD function, the authors hypothesized that since IgD+IgM- cells are mainly present in the upper respiratory mucosa, IgD would possibly be able to bind to airborne pathogens like Moraxella catarrhalis and Haemophilus influenzae. In fact, other studies have already shown that IgD is capable of binding H. influenzae14. The authors found that IgD secreted by IgD+IgM- plasma cells binds to these respiratory bacteria and even some of their products like LPS, capsular polysaccharide, and the M. catarrhalis viruelence factor MID. However, it is questionable if IgD can compete with the large amounts of IgG, IgA, and IgM that are also produced at these sites,15,16. In order to understand more about the role of IgD in mucosal immunity, more research is needed to find out how IgD reaches the mucosa surface and the way it eliminates pathogens. Since IgD is a poor complement activator, some authors have suggested that IgD eliminates pathogens by means of immune exclusion4.
Although the results mentioned above give us a very new look on the role of IgD in the immune system, even more spectacular was the finding that IgD binds to circulating basophils both in vitro and in vivo, and that crosslinking of these IgD-armed basophils results in the generation of B cell activating (IL-4, IL-13 and BAFF) and antimicrobial factors (ß-defensin 3, cathelicidin, SPAG11, PTX3, CRP and the cathelicidin-derived peptide LL-37). This fascinating discovery suggests that IgD-armed basophils help the immune system to monitor for invasive pathogens and challenge them by secreting antimicriobial factors. At the same time this system is also capable of regulating humoral immune responses by releasing antibody-inducing factors. The finding that basophils release an essential B cell-survival molecule after IgD crosslinking, that is BAFF, could explain the observation that IgD knock-out mice have reduced numbers of peripheral B cells (30-50% less B cells in the spleen and lymph nodes)17. Knowing that IgD binds to basophils makes it also conceivable that IgD serum concentrations partially depend on the number of basophils and their IgD-binding receptors. Perhaps this explains IgD's very wide normal range in sera of healthy individuals,5. Although some have argued that this phenomenon is mainly due to differences in its rate of synthesis in different individuals16.
In doing their experiments, the authors probably also took into account the 200th anniversary of Charles Darwin´s birth and the 150th anniversary of the publication of On the origins of species, as they found that IgD-armed granular leukocytes are also present in channel catfish (Ictalurus puntatus), indicating that IgD and basophils provide an evolutionary conserved immune surveillance system. This result is supported by the finding that IgD is also expressed in frog (Xenopus tropicalis) and lizards (Anolis carolinensis), and that IgW, which is orthologous to IgD, is found in cartilaginous fish and long fish. This suggests that IgD/IgW, like IgM, was present in the common ancestor of all living jawed vertebrates19,20.
Finally, Chen et al. also tried to find a link between autoinflammatory disorders and dysregulation of IgD class-switched B cells and IgD-armed basophils. These autoinflammatory disorders can result from different genetic deffects, but are all characterized by a disturbed initiation and control of inflammatory reactions, which causes periodic attacks of fever and tissue damage. In addition, these disorders are associated with the release of increased amounts of IL-1ß and TNF and high IgD production4. It was found that autoinflammatory patients have higher circulating and mucosal IgD+IgM- plasma cells. In addition, these patients have fewer circulating, but more mucosal IgD-armed basophils. Furthermore, crosslinking of these IgD-armed basophils also resulted in the release of IL-1ß and TNF, two cytokines that trigger inflammatory reactions. Although not completely conclusive, these results suggest that dysregulation of IgD class-switched B cells and IgD-armed basophils could play a role in the development of autoinflammatory disorders.
While once some scientists thought that IgD might have no function at all21, Chen et al. now showed that IgD plays an active role in the immune system of both humans and other species, and that it was probably doing this for the last 500 million years. Hopefully, this piece of work will stimulate other researchers to reveal more secrets about this mysterious antibody that has puzzled immunologists since its discovery, more than 40 years ago.
- Chen et al. Immunoglobulin D enhances immune surveillance by activating, antimicrobial, proinflammatory, and B cell stimulating programs in basophils. Nature Immunolgy 10, 889-898 (2009).
- Abbas, A. K. et al. Cellular and molecular immunology. 6th edition (2006).
- Arpin, C. et al. The normal counterpart if IgD myeloma cells in germinal center displays extensively mutated IgVH gene, cu-cd switch, and l light chain expression. J. Exp. Med. 187, 1169-1178 (1998).
- Preud´Homme, J. L. et al. Structural and functional properties of membrane and secreted IgD. Mol. Immunol. 37, 871-887 (2000).
- Vladutia, A.O. Immunoglobulin D: properties, measurement, and clinical relevance. Clin. Diagn. Lab. Immunol. 7, 131-140 (2000).
- Cerutti, A. The regulation of IgA class switching. Nat. Rev. Immunol. 8, 421-434 (2008).
- Lin, J, X. et al. The role of shared receptor motifs and commin Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13 and IL-15. Immunity. 2, 331-9 (1995).
- Pistoia, V. et al. IL-21: a new player in the control of isotype switch in Peyer´s patches. Journal of Leukocyte Biol. 85, 739-743 (2009).
- Pene, J. et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. The Journal of Immunology. 181, 1767-1779 (2008).
- Holm, C. K. et al. TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells. J. immunol. 183, 4422-31 (2009).
- Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor. Nature 413, 732-8 (2001).
- Moskophidis, D. et al. Virus-specific IgD in acute viral infection of mice. J. Immunol. 158, 1254-1261 (1997).
- Levan-Petit, I. et al. Th2 cytkine dependence of IgD production by normal serum human B cells. Int. Immunol. 11, 1819-1828 (1999).
- Forsgren, A. et al. Many bacterial species bind human IgD. J. Immunol. 122, 1468-1472 (1979).
- Gyeney, L. Immunoglobulin levels of tonsillar cells. European Archives of Oto-Rhino-Laryngology. 222, 221-227 (1979).
- Rogentine, G. N. et al. Metabolism of human immunoglobulin D. J. Clin. Investig. 45, 1467-1478.
- Nitschke, L. et al. IgD-deficient mice van mount normal immune responses to thymus-independent and -dependent antigens. Proc. Natl. Acad. Sci. USA 90, 1887-1891 (1993).
- Tateno, K. et al. IgD radioimmunoassay sensitive to 10 ng/mL. J. Allergy Clin. Immunol. 57, 243-244.
- Otha, Y. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc. Natl. Acad. Sci. USA 28, 10723-10728 (2006).
- Wei, Z. Expression of IgM, IgD, and IgY in a reptile, Anolis carolinensis. J. Immunol. 183, 3858-3864.
- Blattner, F. et al. The molecular biology of immunoglobulin D. Nature 307, 417-422.
- Up to 20-25% of tonsillar antibody-producing plasma cells have a IgD+IgM- plasma cell phenotype.
- The rate of sysnthesis of IgD is approximately 10 times lower than that of IgG, IgA, IgM. IgD also has a higher turnover rate than these antibody isotypes16.
- In a study that measured the IgD concentration in sera of 200 individuals, IgD showed a 4 log wide normal range, which is much wider than the normal range of other antibody isotypes5,18.
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