%0 Journal Article
%T Missing Links in Antibody Assembly Control
%A Tiziana Anelli
%A Eelco van Anken
%J International Journal of Cell Biology
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/606703
%X Fidelity of the humoral immune response requires that quiescent B lymphocytes display membrane bound immunoglobulin M (IgM) on B lymphocytes surface as part of the B cell receptor, whose function is to recognize an antigen. At the same time B lymphocytes should not secrete IgM until recognition of the antigen has occurred. The heavy chains of the secretory IgM have a C-terminal tail with a cysteine instead of a membrane anchor, which serves to covalently link the IgM subunits by disulfide bonds to form ¡°pentamers¡± or ¡°hexamers.¡± By virtue of the same cysteine, unassembled secretory IgM subunits are recognized and retained (via mixed disulfide bonds) by members of the protein disulfide isomerase family, in particular ERp44. This so-called ¡°thiol-mediated retention¡± bars assembly intermediates from prematurely leaving the cell and thereby exerts quality control on the humoral immune response. In this essay we discuss recent findings on how ERp44 governs such assembly control in a pH-dependent manner, shuttling between the cisGolgi and endoplasmic reticulum, and finally on how pERp1/MZB1, possibly as a co-chaperone of GRP94, may help to overrule the thiol-mediated retention in the activated B cell to give way to antibody secretion. 1. Introduction In the arms race between pathogens and hosts, vertebrates developed a long-range weapon of high precision: the antibody. Antibodies are produced by activated B lymphocytes. Once they are secreted, the antibodies spread throughout the organism to recognize and bind to specific epitopes on pathogens. As such, the pathogens are stigmatized as a target for complement or phagocyte mediated attack and (if all is well) elimination. All weaponry is hazardous, because of the risk that it may ¡°go off¡± at the wrong moment and aim at the wrong target. Thus, it comes as no surprise that the immune system is reined in by a wealth of safety measures (unfortunately, they are not always fail-proof as the prevalence of autoimmune diseases illustrates). Safety dictates that B lymphocytes should not secrete antibodies, unless there is a confirmed sighting of an antigen, that is, when there is a good match between the antigen and the particular antibody which the B lymphocyte happens to express on its surface. At that moment, the B lymphocyte commits to become a plasma cell, which arguably is one of the most prolific secretory cells in the metazoan kingdom as it releases in bulk the antibody that specifically targets that very antigen. How can it be that the same cell that first obstinately prevents antibodies from leaking out makes
%U http://www.hindawi.com/journals/ijcb/2013/606703/