ReviewStructural and functional properties of membrane and secreted IgD
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 Cμ 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.
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Present address: INSERM E99-28, Angers University Hospital, France.