The Carboxyl-terminal Domains of IgA and IgM Direct Isotype-specific Polymerization and Interaction with the Polymeric Immunoglobulin Receptor

Abstract

Mucosal surfaces are protected by polymeric immunoglobulins that are transported across the epithelium by the polymeric immunoglobulin receptor (pIgR). Only polymeric IgA and IgM containing a small polypeptide called the "joining" (J) chain can bind to the pIgR. J chain-positive IgA consists of dimers, and some larger polymers, whereas only IgM pentamers incorporate the J chain. We made domain swap chimeras between human IgA1 and IgM and found that the COOH-terminal domains of the heavy chains (C␣3 and C4, respectively) dictated the size of the polymers formed and also which polymers incorporated the J chain. We also showed that chimeric IgM molecules engineered to contain C␣3 were able to bind the rabbit pIgR. Since the rabbit pIgR normally does not bind IgM, these results suggest that the COOH-terminal domain of the polymeric immunoglobulins is primarily responsible for interaction with the pIgR. Finally, we made a novel chimeric IgA immunoglobulin, containing the terminal domain from IgM. This recombinant molecule formed J chain-containing pentamers that could, like IgA, efficiently form covalent complexes with the human pIgR ectodomain, known as secretory component.

The Strength of B Cell Interaction with Antigen Determines the Degree of IgM Polymerization

“…The C-terminal focus of IgM polymerization and glycosylation diversity in mice (40), its recognition by pIgR (41), as well as the mediation of other functions, such as mannose binding lectin recognition (42), could indicate a structural or functional nexus centering around the C-terminal disulfide (Cys 578) and proximal N-linked glycosylation site (Asn 573) in trout as well as mammals. However, more intriguing is the possibility that modulation of this structural/functional nexus by the strength of Ag recognition may occur in other vertebrates as in trout.…”

The IgA system: a comparison of structure and function in different species

“…In dimeric IgA, two monomer units are arranged in an endto-end configuration stabilised by disulphide bridges and incorporation of the J (joining) chain, a 15 kDa polypeptide. Polymerisation is regulated by incorporation of the J chain since its presence stimulates polymerisation [42] and is directed by the COOH-terminal domains of the heavy chains [13]. The J chain is synthesised along with IgA in plasma cells and its incorporation is an early event in IgA polymerisation.…”

“…In humans, the binding of pIgA is initiated by non-covalent interaction at D1, further noncovalent interactions with D2 and/or D3 allow stable binding, after which this complex is stabilised by covalent interactions with D5 by means of disulfide bonds [72]. Both the J chain [42] and the COOH-terminal domain of the heavy chains [13] are essential for binding of pIgA to the pIgR.…”

Synergistic interaction of two independent genetic loci causes extreme elevation of serum IgA in mice

“…16 The observed lack of serum IgM elevation might result out of the fact that J-chain incorporation is an early event in dimeric IgA assembly, whereas this happens relatively late during the assembly of IgM pentamers. 3 However, there exist conflicting results regarding IgA and IgM expression of a published knockout mouse model by Lycke et al They describe just a two-fold (heterozygous) and four-fold (homozygous) increase in serum IgA levels and dramatically reduced serum IgM levels both in IgJ þ /À and IgJÀ/À mice, respectively. 4 It has been speculated that conflicting results could be due to a different genetic 129J substrain background.…”

“…2 Whereas J-chain incorporation is an early event in dimeric IgA-assembly, this happens relatively late during the assembly of IgM pentamers. 3 J-chain knockout mice with either homozygous or heterozygous deletion of the J-chain exhibit elevated IgA serum levels. 4 In contrast to wild-type mice, mucosal and glandular secretions of J-chain knockout mice contain monomeric IgA, which is not bound to the secretory component.…”