2016 — 2017 |
Holodick, Nichol Elizabeth |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
B1a Cell Function in Sickle Cell Disease @ Western Michigan Univ School of Medicine
? DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is the most common hemoglobin disorder with 300,000 infants born affected each year globally. Streptococcus pneumoniae is the most common cause of pneumonia. Sickle cell (SS) patients are 600 times more susceptible to S. pneumoniae infections than the general population. This increased risk of pneumococcal infection is attributed mainly to lack of a functional spleen in SS patients. However, SS patients are still more susceptible than persons lacking a functional spleen for reasons other than SCD. Interventions such as antibiotics, vaccination, and hydroxyurea treatment have helped counteract this increased risk; yet, pneumococcal infection still poses a great risk for SS patients. Poor infection control in SS patients is mainly due to antibiotic resistance and the emergence of non-vaccine serotypes of S. pneumoniae. Recently, it has been demonstrated the SS environment itself leads to increased virulent strains of S. pneumoniae as well as differences in vaccine efficacy. Therefore, the long-term goal of this study is to gain a greater comprehension of the immune system in SCD, which will enable development of new preventative strategies and/or treatment of S. pneumoniae infection in SS patients. Specifically, the immediate goal of this proposal is to determine whether SCD and/or treatments given to sickle cell patients long-term have an affect on a specific subset of B cells, which provide the essential immediate protection from S. pneumoniae infection. Murine B-1a cells arise mainly during fetal development. These cells are essential for immediate protection and therefore survival from S. pneumoniae infection. The unique ability of fetal derived B-1a cells to provide protection against S. pneumoniae is attributed to their spontaneously secreted non-immune (natural) IgM, which is germline-like due to minimal insertion of N-region additions and little somatic hypermutation. It has been shown that the number of splenic B-1a cells is significantly reduced in a mouse model of SCD. We hypothesize that the level of natural IgM protection changes in SCD as a result of functional and/or repertoire associated alterations to the B-1a cell pool in response to the SS environment alone and/or commonly used therapies in SCD. To test this hypothesis and determine whether the SS environment and/or common treatments for this disease leads to a change in protective natural IgM we will perform the following aims: 1) Determine whether the function of the B-1a cell pool changes in sickle cell disease; and, 2) Evaluate the ability of natural IgM in sickle cell disease to protect against S. pneumoniae infection. This project will determine the effect SCD and/or treatments for this disease has on the ability of B-1a cells to provide immediate protection from S. pneumoniae infection. This further understanding of the SS immune system will provide new information that will likely lead to strategies and/or treatments of S. pneumoniae infection in SS patients.
|
0.909 |
2021 |
Holodick, Nichol Elizabeth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sex Determines Age-Related Changes in the Repertoire and Function of Natural Antibodies Protective Against Streptococcus Pneumoniae With Increasing Age @ Western Michigan Univ School of Medicine
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.
|
0.909 |