All ETDs from UAB

Advisory Committee Chair

John D Mountz

Advisory Committee Members

David D Chaplin

Chander Raman

Etty Benveniste

Hubert M Tse

Janusz H Kabarowski

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Systemic lupus erythematosus (SLE) is characterized by elevation of type I interferon (IFN) signature genes and production of autoantibodies against apoptotic self-antigens. The complex nature of SLE, however, suggests that multiple immune dysregulations must integrate to initiate the disease. Here, we provided evidence that lupus can be initiated via type I IFNs-induced follicular translocation of membrane lymphotoxin (mLT)-expressing marginal zone (MZ) B cells in the spleen of lupus prone BXD2 mice. The mislocation of mLT+ MZ B cells induces two important pathogenic effects including deteriorations of marginal zone macrophages (MZMs) in the MZ, leading to defective clearance of apoptotic debris, and activation of follicular dendritic cells (FDCs), leading to the formation of germinal centers (GCs). These abnormal features are abrogated in BXD2-Ifnαr-/- mice. Thus, apoptotic antigens, loss of MZMs and activation of FDCs are ultimately connected via type I IFNs-induced invasion of innate B cells to initiate lupus.

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