REGULATION OF IGA PRODUCTION AND TRANSPORT BY VITAMIN A

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Recent epidemiologic studies have shown that children with marginal vitamin A deficiency (VAD) are at increased risk of developing and dying from respiratory and enteric infections. The secretory IgA system plays an important role in protecting against such infections. VAD may increase susceptibility to mucosal infections by decreasing production of IgA or impairing its transport across epithelial surfaces. Such defects would be consistent both with vitamin A's well-characterized role in stimulating and maintaining the differentiation of mucosal epithelial cells and with its more recently identified role in regulating antibody production. For these reasons we propose to examine the effect of vitamin A on the secretory IgA response in BALB/c mice. Specific Aim 1 will determine if VAD affects the mucosal IgA response and serum IgG response to intranasal infection with influenza A virus or intranasal immunization with inactivated virus. The following experiments will be conducted: (A) The concentration of total and influenza A-specific IgA and IgG will be measured by ELISA in the (i) saliva, (ii) nasopharyngeal secretions, (iii) tracheal and bronchopulmonary secretions and (iv) serum of VAD and control mice. (B) The number of plasma cells producing influenza A-specific IgA and IgG will be enumerated by ELISPOT in the respiratory tract and spleen of VAD and control mice. (C) The effect of VAD on protection against reinfection will be determined by measuring virus replication (by plaque assay) in the upper and lower respiratory tract of previously infected or immunized VAD and control mice. Specific Aim 2 will determine if the transport of polymeric IgA (pIgA) via the polymeric immunoglobulin receptor (pIgR) is affected by vitamin A status. The following experiments will be conducted: (A) Hepatocyte-mediated transport of intravenously administered pIgA into the bile will be measured in VAD and control mice. (B) Hepatocyte pIgR protein levels will be measured by western immunoblot analysis and compared between VAD and control mice. (C) Tissue mRNA levels and the rate of transcription of the pIgR gene will be measured using the monoclonal-antibody solution-hybridization (MASH) assay and nuclear run-off assays, respectively, in VAD and control mice.