Proteolytic cleavage then releases Ig into the lumen (9). often misunderstood or underappreciated. In this short review, we will discuss J-chain in light of the various proposed models of its expression and regulation, with an added focus on the evolutionary significance of J-chain and its expression in different B cell lineages/differentiation states. == Joining Chain (J-chain) == Joining chain, or J-chain, is a small polypeptide that regulates the multimerization of IgM and IgA. It appeared with the emergence of adaptive MAPK13-IN-1 immunity in jawed vertebrates (1), and is an unusual molecule, in that it does not appear MAPK13-IN-1 to be a member of any characterized protein domain family (2). Mammalian J-chain is acidic and contains eight cysteine residues, six of which form intrachain disulfide bonds (C1C6, C4C5, and C7C8), while the remaining two form interchain disulfide bonds with cysteines in the IgM or IgA heavy-chain tails (2,3). When MAPK13-IN-1 associated with J-chain, mammalian IgM is secreted as a MAPK13-IN-1 pentamer and IgA as a dimer, the typical form in mucosal secretions (Table I). In the absence of J-chain IgA is secreted as a monomer (Table I), the form most common in the blood (4). This monomeric, J-chainIgA is secreted from different cells from those producing IgA dimers, and the two forms of IgA have distinctive functions, such as providing a barrier to commensal infections (dimeric IgA) and induction of inflammation (monomeric IgA) (5,6). The other mammalian isotypes IgG/E/D do not multimerize (Table I), although some plasma cells that express these isotypes also Rabbit polyclonal to AFF3 express J-chain. Due to differences in the secretory tail of the IgG/E/D heavy chains, J-chain does not associate with these isotypes (discussed below in the context of MAPK13-IN-1 all vertebrate Igs), hence their secretion as monomers regardless of J-chain expression (7). == Table I. == Summary of Ig isotypes with a focus on multimerized and mucosally secreted isotypes throughout evolution Some isotypes such as IgA in mammals and IgM in cartilaginous fish can be secreted in either multimeric or monomeric forms, with or without J-chain, respectively. While J-chain has been lost in teleost fish, it has been found in a lobed-fin fish, the lungfish, which is closely related to tetrapods. Although teleosts do not express J-chain, IgT has been shown to interact with the pIgR secretory component directly. The mechanism of mucosal transport without J-chain association in these cases is unclear. In addition to multimerization, J-chain is required for Ig transport across the mucosal epithelium in tetrapods (8). The C-terminal domain of J-chain is required for association with a portion of the poly-Ig receptor (pIgR) known as secretory component (SC) or secretory piece. While J-chain is associated with Ig in plasma cells, epithelial cells produce pIgR. Secreted J-chain+Igs bind to pIgR on the basolateral surface of mucosal epithelial cells, leading to endocytosis of the entire complex and transport by transcytosis to the cells apical surface. Proteolytic cleavage then releases Ig into the lumen (9). The SC remains with J-chain and IgM/A after transcytosis across the epithelium (10). Based on current understanding of J-chain transcriptional control, discussed in detail below, it is widely assumed thatallplasma cells express J-chain (1113), although there are inconsistencies in the documentation of J-chain protein levels in mammalian plasma cells, including the monomeric IgA-secreting cells (14). The connection between RNA expression and protein levels is not always clear, although they are often used interchangeably in the literature. Some of this confusion stems from technical difficulties in studying the molecule. Structural changes, or epitope masking of J-chain when it is associated with Ig, have made the detection of J-chain, and the production of high-quality antibodies that recognize native J-chain, challenging. These difficulties are exemplified by inconsistencies in J-chain detection in early studies. Whether or not a denaturant (e.g. urea) was used to unmask J-chain epitopes before immunohistochemical detection led to different interpretations of J-chain expression in plasma cells. Specifically, studies that did not utilize urea treatment before staining for J-chain inadvertently underestimated the number of J-chain+cells (5,15,16). The unique structure and biochemical behavior of J-chain, combined with its lack of association with monomeric Igs such as IgG, have relegated the J-chain to a lower echelon of immune molecules and it has been relatively overlooked for many years, since its heyday in the 1970s and 80s, especially in the lab of the esteemed Marian Koshland (17), and a short resurgence over a decade ago with the report of the J chain knockout mouse by Leandersons group. Several basic questions about J-chain gene regulation and expression remain unanswered, and there are key differences in the two central models of J-chain expression. In this.