Elsevier

Molecular Immunology

Volume 37, Issue 15, October 2000, Pages 871-887
Molecular Immunology

Review
Structural and functional properties of membrane and secreted IgD

https://doi.org/10.1016/S0161-5890(01)00006-2Get rights and content

Abstract

More than 35 years ago, study of an unknown immunoglobulin (Ig) in the serum from a myeloma patient led to the discovery of IgD. Subsequently, the finding that it also exists as a membrane-bound Ig stimulated a large number of studies during the 70s. Then, the interest on IgD shrank, largely because of the lack of known function of secretory IgD (secIgD) and of a stagnating knowledge of the functions of surface IgD. In the recent years, very significant advances followed the tremendous accumulation of data on the physiology of the B cell receptor, of which IgD is the major component, on the role of secIgD in normal and diseased individuals. This review, which is focused on human IgD but integrates data in the mouse and other species when needed, summarizes present data on the structure, synthesis and functions of both membrane and secIgD, IgD receptors and the involvement of IgD in various diseases, especially the hyperIgD syndrome.

Introduction

In 1965, the study of a novel immunoglobulin (Ig) in the serum from a myeloma patient led to the discovery IgD by Rowe and Fahey (1965). This finding stimulated a large number of studies and it became soon apparent that this (then) new class of Ig is expressed at the B lymphocyte membrane level in humans and mice (van Boxel et al., 1972, Rowe et al., 1973a, Rowe et al., 1973b, Finkelman et al., 1976). Hence, data on membrane IgD (mIgD) in normal and diseased individuals accumulated during the 70s, as summarized in an issue (volume 37) of Transplantation Reviews, which was devoted to IgD in 1977. Subsequently, the interest in IgD decreased for a number of reasons. Methodological reasons prevented major advances in the knowledge of the production, regulation and functional properties of mIgD and secIgD. IgD concentration in the normal human serum is very low (see below), no antibody (Ab) activity could be attributed to IgD until quite recently and IgD was found to be absent in mouse sera (demonstration of serum IgD in the latter species had to wait till 1979 (Finkelman et al., 1979)). Moreover, IgD is not present in every species and this does not relate to phylogeny and evolution. IgD is present in primates, dog, mouse and rat whereas it is undetectable in rabbit, guinea pig, swine, cattle, sheep and xenopus (Finkelman et al., 1976, Martin et al., 1976, Ruddick and Leslie, 1977, Finkelman et al., 1979, Chen et al., 1982, Mussmann et al., 1996, Naessens, 1997, Butler, 1998). More recently, an Ig similar to mammalian IgD by its sequence, gene location immediately downstream of the μ gene in the CH cluster, expression by alternative splicing and co-expression with IgM was identified in both cartilaginous (channel catfish, Wilson et al., 1997) and osseous (salmon and cod, Hordvik et al., 1999, Stenvik and Jorgensen, 2000) fishes. These data suggest that IgD might have served an as yet unidentified important function early in the evolution of the immune system (Wilson et al., 1997). Recently also, knowledge on the structure and sophisticated regulation and functions of the complex now known as the B cell receptor (BCR) tremendously increased, as well as those on the role of IgD in the regulation of the immune response and on its involvement in various diseases. IgD hence appears to be recovering lost ground in scientists' and physicians' interest and this seems to justify this short review, which is mainly devoted to human IgD.

Section snippets

The IgD molecule

As for the other Ig, mIgD and secIgD differ by the C-terminal part of the δ heavy (H) chain, namely an hydrophilic tail for secIgD and the short extracellular, hydrophobic transmembranous and intracytoplasmic regions specific of mIg. The intracytoplasmic tail of mIgD is especially short. It is identical to that of mIgM in humans and mice and it contains only three residues (Lys-Val-Lys). Human IgD is made up of two identical H and light (L) chains organized in variable (V) and constant (C)

IgD gene and synthesis

The CH gene encoding the human δ chain is located in the IgH cluster in position 14q32 on chromosome 14. It might be the result of a duplication of the gene during evolution (Magor et al., 1999). It spans about 10 kb and it is special by the presence of eight exons. In addition to the exons coding for each C domain, there are two exons for the hinge region, an exon δs that encodes the tail of secIgD (and is not found in the other Ig isotypes) and two exons δm1 and δm2 for the region specific

Functions of IgD

IgD is the major component of the mature B lymphocyte BCR and functions of mIgD were the subject of thousands of studies. Hence, trying to review this topic is largely beyond the scope of this paper. The only point we would like to discuss briefly is the respective role of mIgD and mIgM. Immature (IgD− IgM+) B lymphocytes respond to antigen concentrations that induce a response of mature B lymphocytes by anergy or apoptosis (Cambier et al., 1977, Carsetti et al., 1993), which suggests a major

IgD membrane receptors

Membrane receptors that bind IgD were first described in human (Sjöberg, 1980) then rediscovered in the mouse (Coico et al., 1985, Adachi and Ishizaka, 1986) and human again (Coico et al., 1990). This receptor binds secIgD and mIgD, dimeric and polymeric or complexed, including IgD bound to their specific antigen or to anti-δ Ab (Coico et al., 1988b). In both species, the receptor is induced by oligo- or polymeric IgD and downregulated by monomeric IgD (Coico et al., 1987a, Coico et al., 1988a,

IgD in human diseases

Not surprisingly, early studies were devoted to mIgD in immunoproliferative (Preud'homme et al., 1974) and immunodeficiency diseases (see Preud'homme et al., 1977 for review) and trying to discuss the innumerable studies performed during the last 35 years would require a book. Most results merely correspond to the characterization of proliferating or defective B cells in terms of maturation stage and mIg density. In addition to their medical and nosological impact, these data had the major

Conclusion

This short review hopefully makes it clear that the physiological function of IgD, in the BCR, in B–T cell interactions and even possibly as secreted Ab, is more important than thought some years ago. This also holds true for the implication of IgD in various human diseases. However, a number of both physiological and physiopathological questions remain largely open, which presently stimulates numerous studies.

References (241)

  • R.W. Griffiths et al.

    Proteolytic degradation of IgD and its relation to molecular conformation

    J. Biol. Chem.

    (1972)
  • M.L. Hibbs et al.

    Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease

    Cell

    (1995)
  • S.H. Josephs et al.

    Serum IgD concentrations in normal infants, children, and adults and in patients with elevated IgE

    J. Pediatr.

    (1980)
  • M. Adachi et al.

    IgD-binding factors from mouse T lymphocytes

    Proc. Natl. Acad. Sci. USA

    (1986)
  • T. Adachi et al.

    The specificity of association of the IgD molecule with the accessory proteins BAP31/BAP29 lies in the IgD transmembrane sequence

    EMBO J.

    (1996)
  • A.R. Amin et al.

    Release of IgD-binding factor by T cells under the influence of interleukin 2, interleukin 4, or cross-linked IgD

    Proc. Natl. Acad. Sci. USA

    (1988)
  • A.R. Amin et al.

    Specificity of the murine IgD receptor on T cells is for N-linked glycans on IgD molecules

    Proc. Natl. Acad. Sci. USA

    (1991)
  • A.R. Amin et al.

    The immunoaugmenting properties of murine IgD reside in its C delta 1 and C delta 3 regions: potentiel role for IgD-associated glycans

    Int. Immunol.

    (1993)
  • J. Arai et al.

    Non-X-linked hyper-IgM syndrome with systemic lupus erythematosus

    Clin. Exp. Rheumatol.

    (1998)
  • C. Arpin et al.

    The normal counterpart of IgD myeloma cells in germinal center displays extensively mutated IgVH gene, Cmu-Cdelta switch, and lambda light chain expression

    J. Exp. Med.

    (1998)
  • R. Ashfield et al.

    MAZ-dependent termination between closely spaced human complement genes

    EMBO J.

    (1994)
  • P. Aucouturier et al.

    Jacalin: a new laboratory tool in immunochemistry and cellular immunology

    J. Clin. Lab. Anal.

    (1989)
  • O.M. Avrech et al.

    Efficacy of the placental barrier for immunoglobulins: correlations between maternal, paternal and fetal immunoglobulin levels

    Int. Arch. Allergy Immunol.

    (1994)
  • E. Azuma et al.

    Hyperimmunoglobulinemia D following cancer chemotherapy

    Oncology

    (1991)
  • S.L. Bahna et al.

    Sequential changes of the five immunoglobulin classes and other responses in infectious mononucleosis

    Int. Arch. Allergy Apply Immunol.

    (1984)
  • S.L. Bahna et al.

    Changes in serum IgD in cigarette smokers

    Clin. Exp. Immunol.

    (1983)
  • S.L. Bahna et al.

    Elevated IgD antibodies to wheat in celiac disease

    Ann. Allergy

    (1980)
  • K. Bjerke et al.

    Distribution of immunoglobulin producing cells is different in normal human appendix and colon mucosa

    Gut.

    (1986)
  • J. Blade et al.

    Immunoglobulin D multiple myeloma: presenting features, response to therapy, and survival in a series of 53 cases

    J. Clin. Oncol.

    (1994)
  • E. Blasco et al.

    Proliferative response of human CD4+ T lymphocytes stimulated by the lectin jacalin

    Eur. J. Immunol.

    (1995)
  • P. Brandtzaeg

    Overview of the mucosal immune system

    Curr. Top. Microbiol. Immunol.

    (1989)
  • P. Brandtzaeg et al.

    Significance of different J chain profiles in human tissues: generation of IgA and IgM with binding site for secretory component is related to the J chain expressing capacity of the total local immunocyte population, including IgG and IgD producing cells, and depends on the clinical state of the tissue

    Clin. Exp. Immunol.

    (1984)
  • P. Brandtzaeg et al.

    Production and secretion of immunoglobulins in the gastrointestinal tract

    Ann. Allergy

    (1987)
  • P. Brandtzaeg et al.

    The human secretory immune system shows striking heterogeneity with regard to involvement of J chain-positive IgD immunocytes

    J. Immunol.

    (1979)
  • P. Brandtzaeg et al.

    The clinical condition of IgA-deficient patients is related to the proportion of IgD- and IgM-producing cells in their nasal mucosa

    Clin. Exp. Immunol.

    (1987)
  • R. Brink et al.

    IgD expression on B cells is more efficient than IgM but both receptors are functionally equivalent in up-regulation CD80/CD86 co-stimulatory molecules

    Eur. J. Immunol.

    (1995)
  • R. Brink et al.

    Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen

    J. Exp. Med.

    (1992)
  • J.E. Butler

    Immunoglobulin diversity, B-cell and antibody repertoire development in large farm animals

    Rev. Sci. Techn.

    (1998)
  • J.C. Cambier et al.

    B-cell tolerance. III. Effect of papain-mediated cleavage of cell surface IgD on tolerance susceptibility of murine B cells

    J. Exp. Med.

    (1977)
  • K.S. Campbell et al.

    Alpha-chains of IgM and IgD antigen receptor complexes are differentially N-glycosylated MB-1-related molecules

    J. Immunol.

    (1991)
  • R. Carsetti et al.

    A role for immunoglobulin D: interference with tolerance induction

    Eur. J. Immunol.

    (1993)
  • L.L. Cederqvist et al.

    IgD and the fetal immune response

    Scand. J. Immunol.

    (1977)
  • C.L. Chen et al.

    Evidence for an IgD homologue on chicken lymphocytes

    J. Immunol.

    (1982)
  • Q. Chess et al.

    Serum immunoglobulin elevations in the acquired immunodeficiency syndrome (AIDS): IgG, IgA, IgM and IgD

    Diagn. Immunol.

    (1984)
  • S. Cho et al.

    A new multivalent B cell activation model — anti-IgD bound to Fc gamma RI: properties and comparison with CD40L-mediated activation

    Int. Immunol.

    (1997)
  • R.F. Coico et al.

    Physiology of IgD. VII. Induction of receptors for IgD on cloned T cells by IgD and interleukin 2

    J. Immunol.

    (1987)
  • R.F. Coico et al.

    Exposure to crosslinked IgD induces receptors for IgD on T cells in vivo and in vitro

    Proc. Natl. Acad. Sci. USA

    (1988)
  • R.F. Coico et al.

    Physiology of IgD. VIII. Age-related decline in the capacity to generate T cells with receptors for IgD and partial reversal of the defect with IL2

    J. Immunol.

    (1987)
  • R.F. Coico et al.

    Role of IgD and T delta cells in the regulation of the humoral immune response

    Immunol. Rev.

    (1988)
  • R.F. Coico et al.

    IgD-receptor positive human T lymphocytes. I. Modulation of receptor expression by oligomeric IgD and lymphokines

    J. Immunol.

    (1990)
  • Cited by (80)

    • IgD promotes pannus formation by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in FLS of CIA rats and the regulation of IgD-Fc-Ig fusion protein

      2021, International Immunopharmacology
      Citation Excerpt :

      Therefore, exploring new specific therapeutic targets is of great significance to further explore the pathogenesis of RA. Immunoglobulin D (IgD) is an immunoglobulin discovered in 1965 [13], comprising secreted IgD (sIgD) and membrane IgD (mIgD). Although IgD is extremely low in vivo, it plays a crucial role in autoimmune diseases [14].

    • Mechanism and regulation of class switch recombination by IgH transcriptional control elements

      2020, Advances in Immunology
      Citation Excerpt :

      IgD is co-expressed with IgM on the surface of normal naïve mature B cells. Expression of the Cδ gene results essentially from alternative splicing of a long primary transcript encompassing Cμ and Cδ exons (Chen & Cerutti, 2010; Preud'homme et al., 2000). CSR to IgD is generally considered as a rare event and has been mostly studied in humans where B cells that switch to IgD are relatively abundant in the upper aerodigestive mucosa-associated lymphoid tissues (Chen & Cerutti, 2010).

    • Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance

      2018, Current Opinion in Immunology
      Citation Excerpt :

      Notably, BCR signaling in response to all types of antigens requires Syk kinase, but responses to monvalent antigens uniquely require Src family kinases (SFKs) [25–27]. IgD has a longer and more flexible hinge than IgM [28], and this renders IgD unresponsive to monovalent model antigens while maintaining responsiveness towards multivalent antigens [20••]. However, the degree of this unresponsiveness is contested; a subsequent study showed that IgD can respond to soluble monovalent antigen in vitro and in vivo [29••].

    • IgD-activated mast cells induce IgE synthesis in B cells in nasal polyps

      2018, Journal of Allergy and Clinical Immunology
    • Immunoglobulin genes in Primates

      2018, Molecular Immunology
      Citation Excerpt :

      In humans, the gene has three CH domains that correspond to the CH1–CH7–CH8 domains of reptiles (Gambón-Deza and Espinel, 2008). Some mammalian species have lost this gene entirely and others, such as the murids (Muridae), have only two CH (Preud’homme et al., 2000) domains. Immunoglobulin E (IgE) and G (IgG) evolved from the duplication of an immunoglobulin called Y (IgY) that is currently found in birds and reptiles.

    View all citing articles on Scopus
    1

    Present address: INSERM E99-28, Angers University Hospital, France.

    View full text