? DESCRIPTION (provided by applicant): The essential micronutrient selenium (Se) is known to play a significant role in immune homeostasis and immune responses. Thus far, the majority of studies have focused on the effect of Se on either T cells or macrophages. In addition to these cells, B cells are well known for their involvement in immune homeostasis, yet the role of Se and selenoproteins in B cells has largely been understudied. There are evidence that Se may influence humoral responses in humans and animals. A few recent studies have noted the potential role of selenoproteins in B cell calcium signaling and protein folding. However, no studies to date have addressed the role of Se in B-cell receptor (BCR) signaling and its downstream effects such as B cell differentiation, proliferation, and immunoglobulin secretion. Redox status of B cells influences the B cell functions and differentiation. Given the central role of selenoproteins in regulating the redox status of cells, we hypothesized that selenoproteins influence B cell development and functions by regulating the redox status of cells. Preliminary studies indicated that BCR endocytosis and antigen trafficking to MHC class II compartments are significantly impaired in Se-deficient B cells. Defects in BCR endocytosis and antigen processing in Se-deficient B cells were associated with the higher levels of cellular ROS. Interestingly, BCR endocytosis and antigen degradation were accelerated in B cells isolated from Se-supplemented mice, suggesting that B cells functions could be enhanced by dietary Se-supplementation. The proposed study will be the first to establish the role of selenoproteins in B cell functions and development with the following specific aims: Specific Aim 1: Establish the role of selenoproteins in B cell antigen processing and presentation. To determine the contributions of selenoproteins to antigen processing and presentation, BCR endocytosis & signaling, antigen trafficking, degradation, and presentation will be measured in Se-deficient, Se-adequate and Se-supplemented B cells. Specific Aim 2: Examine the role of selenoproteins in B cell differentiation and development. Since we observed a significant reduction the frequency and number of B cells in the spleen of TrspB mice, B cell developmental stages in bone marrow and B cell subsets in peripheral tissues in TrspB mice will be compared with that of wild-type (WT) littermate controls. Specific Aim 3: Investigate the effect of Se in B cell-mediated immune responses. Immunoglobulin synthesis and secretion will be measured by in vitro assays using TrspB B cells. In addition, disease progression in models of acute tularemia and chronic bordetellosis, will be monitored in TrspB mice. The proposed studies will have a major impact on the field by addressing three critical questions: 1) What is the contribution of selenoproteins to the functions and development of B cells? 2) How do selenoproteins influence the memory response? 3) Does dietary Se supplementation lead to better humoral immune responses, which could have high translational value. The significance of the proposed studies is that they will lead to a better understanding of the contributions of Se and selenoproteins to B cell homeostasis.
|Effective start/end date||4/11/16 → 3/31/17|
- National Institute of Allergy and Infectious Diseases: $393,000.00