The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/2/747/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 4, February 15, 1999 747-752

Brief Definitive Reports

A Human Immunoglobulin (Ig)A C{alpha}3 Domain Motif Directs Polymeric Ig Receptor–mediated Secretion

J. Mark Hexham, Kendra D. White, Leonidas N. Carayannopoulos, Wlodeck Mandecki, Renee Brisette, Yih-Sheng Yang, and J. Donald Capra

From the Molecular Immunogenetics Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

Polymeric immunoglobulins provide immunological protection at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR). Using a panel of human IgA1/IgG1 constant region "domain swap" mutants, the binding site for the pIgR on dimeric IgA (dIgA) was localized to the C{alpha}3 domain. Selection of random peptides for pIgR binding and comparison with the IgA sequence suggested amino acids 402–410 (QEPSQGTTT), in a predicted exposed loop of the C{alpha}3 domain, as a potential binding site. Alanine substitution of two groups of amino acids in this area abrogated the binding of dIgA to pIgR, whereas adjacent substitutions in a β-strand immediately NH2-terminal to this loop had no effect. All pIgR binding IgA sequences contain a conserved three amino acid insertion, not present in IgG, at this position. These data localize the pIgR binding site on dimeric human IgA to this loop structure in the C{alpha}3 domain, which directs mucosal secretion of polymeric antibodies. We propose that it may be possible to use a pIgR binding motif to deliver antigen-specific dIgA and small-molecule drugs to mucosal epithelia for therapy.

Key Words: immunoglobulin A • secretory immunoglobulin A • polymeric immunoglobulin receptor • J chain • mucosal immunity

Address correspondence to J. Donald Capra, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104. Phone: 405-271-7210; Fax: 405-271-8237; E-mail: jdonald-capra{at}omrf.ouhsc.edu

Rabbit pIgR-expressing MDCK cells, untransfected MDCK cells and sheep anti-pIgR polyclonal antiserum were kind gifts from Keith Mostov, University of California at San Francisco, San Francisco, CA. The vector for baculovirus expression of the human pIgR was a kind gift from Jean-Pierre Kraehenbuhl, University of Lausanne, Lausanne, Switzerland. We also thank Shirley Hall for performing the DNA sequencing.

Present addresses are as follows: J.M. Hexham, Transplantation Research, Novartis Pharmaceuticals Corporation, 556 Morris Ave., Summit, NJ 07901; L.N. Carayannopoulos, Washington University Medical School, St. Louis, MO 87978; W. Mandecki and R. Brisette, DGI Biotechnologies LLC, PO Box 424, Edison, NJ 08818; and Y.-S. Yang, Department of Internal Medicine, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75235.


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