Richard Weltzin

M Cell-Mediated Antigen Transport and Monoclonal IgA Antibodies for Mucosal Immune Protection

The normal, healthy intestinal epithelium serves as a barrier to entry of most large macromolecules and particles, including microorganisms. An important component of this barrier is the presence on the mucosal surface of specific secretory IgAs against enteric pathogens. Paradoxically, the generation of a secretory immune response to protect against colonization and entry of microorganisms requires transport of microorganisms across the epithelial barrier and entry into organized lymphoid tissue, where presentation of antigen and stimulation of IgAcommitted lymphoblasts can occur. The major route of antigen transport across the intact epithelial barrier for stimulation of a secretory immune response is through transepithelial transport by intestinal M cells (for review see REF. 1). M cells are specialized epithelial cells present in the epithelium overlying lymphoid follicles. They can be identified morphologically by the lack of the well-organized brush border and thick glycocalyx which characterize adjacent enterocytes, and by the presence of a large basal invaginated pocket containing

Production and Use of Monoclonal IgA Antibodies Complexed with Recombinant Secretory Component for Passive Mucosal Protection

To respond to the constant challenge of their mucosal surfaces by pathogenic organisms, mammals have evolved non-immune protection mechanisms as well as a distinct mucosal immune system, the effector molecule of which is secretory IgA (S-IgA). Mucosal and glandular epithelial cells are able to transcytose dimeric and polymeric IgA by a specific receptor-mediated transepithelial transport mechanism. The polymeric immunoglobulin receptor (poly Ig R) is a member of the immunoglobulin supergene family2. The ectodomain of this integral membrane protein is composed of five domains, homologous to variable Ig domains1,3, the first of which is responsible for binding of the polymeric IgA4. Upon binding of IgA at the basolateral surface of epithelial cells, the receptor-IgA complex is endocytosed and during translocation across the cell the interaction of IgA with the receptor is further stabilized by the formation of a disulfide bridge between the poly Ig R fifth domain and one constant domain of the IgA dimer heavy chain5. Once at the apical surface of the epithelium, the receptor is cleaved and its entire ectodomain, also called secretory component (SC) remains bound to the IgA5. There is some evidence that SC protects IgA dimers against proteolytic degradation6. S-IgA antibodies are thus produced locally by a unique collaboration between plasma cells, present in the interstitium of mucosal and glandular tissues, and the overlying epithelial cells.

Identification and Use of Protective Monoclonal IgA Antibodies Against Viral and Bacterial Pathogens

Research in our laboratories is focused on the roles played by intestinal epithelial cells in the secretory immune response to enteric pathogens. One of our goals is to generate and characterize specific IgA antibodies that can prevent interaction of pathogens with epithelial surfaces. It is now generally recognized that microorganisms and macromolecules that can adhere to epithelial cells are most effective in eliciting specific secretory IgA antibodies1,2, presumably because adherent immunogens are most efficiently endocytosed and transported across the epithelium. Adherence to the M cells of follicle-associated epithelia is probably crucial in this regard, since transepithelial delivery of antigens by these cells may be a prerequisite for a mucosal immune response3–5.