Streptococcus pneumoniae is the most common cause of pneumonia, leading to death in individuals over the age of 65 eight times more frequently than those aged 5-49, despite the long-standing availability of a vaccine for this age group (approved in 1983). In both murine and human systems, there is a greater incidence of, and susceptibility to, pneumococcal infection in males; nevertheless, the factors contributing to this difference between males and females is unknown. Therefore, the long-term goal of this study is to gain a greater understanding of the aging immune system in the context of sex, which will enable development of new preventative and/or treatment strategies of S. pneumoniae infection. Specifically, the goal of this proposal is to determine whether estrogen has an effect on a specific subset of B cells, B1a cells, which provide essential protection and therefore survival from S. pneumoniae infection through production of natural antibodies. Antibodies provide defense against infection by binding the pathogen and preventing infection of host cells. Natural antibodies are present in the absence of infection or intentional immunization. The unique ability of B1a cells to provide protection against S. pneumoniae is attributed to their production of natural antibodies, which have unique structural characteristics resulting from the fetal development of B1a cells. In addition to fetal development, B1 cell progenitors in adult bone marrow can also contribute to the B1a cell pool; however, the characteristics of fetal B1a cell derived natural antibodies are lost in these adult B1a cell derived natural antibodies. We have demonstrated natural serum IgM from aged male mice does not provide protection against S. pneumoniae infection. Unexpectedly, our preliminary results reveal differences in natural antibodies obtained from aged male and female B1a cells, in that age-related changes experienced by male B1a cell antibodies do not seem to occur in females. Yet, we do not know the role sex plays during the aging process to affect B1a cells over time resulting in a non-effective B1a cell derived natural antibody in aged males. We hypothesize estrogen affects the pool of natural antibodies capable of providing protection against S. pneumoniae in the aged. To test this hypothesis and determine if sex-related factors such as estrogen affect the ability of B1a cells to maintain protective natural IgM with age, we will perform the following aims: 1) Elucidate the role of estrogen in the production of natural IgM protective against S. pneumoniae infection in aged males and females, 2) Determine the role of estrogen in the development and selection of B1a cells with increasing age, and 3) Examine the effects of sex and estrogen exposure upon human B1 cell numbers and repertoire in young, middle aged, and aged donors. This project will determine the effect estrogen has on the ability of B1a cells to provide immediate protection from S. pneumoniae infection with increasing age. This further understanding of the aged immune system in the context of sex will likely suggest new prevention and/or treatments strategies of S. pneumoniae infection in both male and female elderly populations.
In both murine and human systems, reports demonstrate a greater incidence and susceptibility to Streptococcus pneumoniae infection in males, which claims the lives of people over the age of 65 eight times more frequently than those aged 5-49. B1a cells provide immediate and essential protection from S. pneumoniae through production of natural antibody; however, our previous results demonstrate natural serum antibody from aged male mice does not provide protection against S. pneumoniae infection. This project will determine the role of sex during the aging process in affecting the ability of natural antibodies to provide protection from S. pneumoniae infection.
