IgA antibodies are a prominent feature of immune responses in mucosal tissue. Since these sites are subject to constant challenge from environmental pathogens, it is likely that complexes of IgA and antigen are continually being formed and eliminated in various ways. It is well documented that phagocytic cells, in particular monocytes and macrophages, express IgA receptors (FcaR) through which IgA coated microorganisms may be internalized. Macrophages are also involved in presenting antigens to T-cells, producing specific immunity. These experiments will utilize chimeric human IgA of known binding specificity to produce defined IgA-Tetanus toxoid (TT) complexes that will be used to study FcaR-directed internalization, processing and presentation of antigen. The applicant's results suggest that antigen uptake via this route results in enhanced antigen presentation and that IgG antibody does not enhance to the same extent. The investigator will study the catabolism of complexes of IgA or IgG and Tetanus toxoid containing different numbers of antibody molecules to determine whether complexing to IgA alters antigen breakdown, perhaps contributing to better antigen presentation. Complementary experiments will examine the localization of TT antigen or TT complexed to IgA or IgG into various subcellular compartments and the co-localization of antigen with class II MHC to establish whether complexing to IgA alters the intracellular routing and MHC association of antigen. Preliminary results suggest that interaction of monocytes with a multivalent IgA complex may upregulate their expression of the B7-2 costimulatory molecule. The investigator will continue to study the modulation of costimulatory molecules following crosslinking of FcaR, the mechanism involved and the subsequent effects on antigen presentation. In parallel with these studies, the production of cytokines characteristic of Th1 and Th2 responses after interaction of T-cells with IgA or IgG complex treated monocytes will be investigated. The investigator's recent findings indicate that the FcaR ligand-binding chain associates with other membrane protein, in particular FceRI g chain, to form a multi-chain receptor complex. These interactions appear to be essential for linking receptor binding to cellular function. The role of different regions of the FcaR molecule in promoting this interaction will be analyzed by examination of mutant recombinant FcaR. The ability of different mutants to form appropriate mullet-chain receptor complexes will be correlated with endocytosis of IgA-TT complexes and subsequent antigen presentation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022816-14
Application #
6169823
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Ash-Shaheed, Belinda
Project Start
1996-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2002-08-31
Support Year
14
Fiscal Year
2000
Total Cost
$332,087
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755