B1a Cell Function in Sickle Cell Disease

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 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.