Project Summary/Abstract
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.
