All ETDs from UAB

Advisory Committee Chair

Louis B Justement

Advisory Committee Members

David D Chaplin

John F Kearney

Christopher A Klug

Phillip D Smith

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The marginal zone (MZ) in the spleen provides a critical defense against blood-borne pathogens. Specialized MZ macrophages (MZM) identified previously based on scavenger receptor (MARCO) or C-type lectin (SIGN-R1) expression, play an essential role in the capture of bacteria whereas MZ B lymphocytes are rapidly activated to produce protective antibodies. Contact between MZM and MZ B cells has been suggested, however the functional role of the interaction is not clear. The goal of this dissertation is to understand the development of the marginal zone and the functional importance of the interaction between MZ B cells and MZM. In the first study, we examined the role of CD19 in MZ development. In CD19-/- mice where MZ B cells are missing, SIGN-R1+ MZM are lost and CD11c DC distribute abnormally in the MZ. The lack of MZ B cells could be an intrinsic defect in B cells and/or a secondary defect in the extrinsic MZ microenvironment. Adoptively transferred B cells from normal mice are able to reconstitute MZ B cells in CD19-/- mice and further restore MZM distribution and MZ DC distribution. Thus, MZ B cells are required for generation of the normal MZ microenvironment, but the deficiency of MZ B cells in CD19-/- mice is caused by an intrinsic defect in B cell signaling. In the second study, we examined the cross-talk between MZ B cells and MZM. We found that SIGN-R1+ MZMs constitute a subset of the MARCO+ MZMs and that MARCO+ MZMs exist in mice lacking MZ B cells. Secondly, the continuous presence of MZ B cells is required to maintain SIGN-R1+ MZMs. Finally, MZ B cells obtain certain types of Ag exclusively through their interaction with SIGN-R1+ MZMs during the initial exposure to Ag. Therefore, MZ B cells regulate expression of molecules on macrophages involved in antigen transfer to B cells. Collectively these findings demonstrate that CD19 intrinsic signaling is required for the generation of MZ B cells, that MZ B cells are required for maintenance of a normal MZ environment and finally that MZ B cells and MZMs collaborate together during the initial host response to blood-borne pathogens.

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