Dr. Hui-Chen Hsu is Associate Professor of Medicine in the Division of Clinical Immunology and Rheumatology. Dr. Hsu collaborated with Drs. John D. Mountz, Hao Li, Jun Li, Yong Zhou, David Crossman, Janusz H. Kabarowski and several other leading investigators in the field and made the seminal discovery on a novel pathogenic role of type I interferon (IFN) in promoting systemic lupus erythematosus (SLE), a challenging autoimmune disease without a cure. The work stemmed from Dr. Hsu’s research which focuses on how elevated type I IFNs produced by plasmacytoid dendritic cells (pDCs) in the spleen marginal zone can induce follicular translocation of marginal zone (MZ) B cells.

Complementary to this, Dr. Mountz' laboratory focuses on determining the cellular and molecular mechanism underlying defective clearance of apoptotic cells by marginal zone macrophages (MZMs) in autoimmune BXD2 mice. Their work together shows that that these processes are interdependent, and an integrated understanding of these mechanisms now provides a novel framework to explain the key hallmarks of human SLE and mouse lupus including the presence of elevated type I IFNs and high titers of autoantibodies against apoptotic self-antigens. The work is now published in the July issue of the Journal of Clinical Investigation. The impact of the work goes beyond understanding the pathogenic role of type I IFN and the molecular mechanisms leading to MZM defects in lupus as it also suggests that therapeutic strategies that eliminate B cells non-specifically may exhibit the potential to enhance apoptotic cell clearance defects via indirect depletion of MZMs as MZMs heavily rely on MZ B cells for their survival and normal function in clearing apoptotic cells. The new paradigm is to design new SLE therapies that can maintain MZM integrity while at the same time eliminating autoreactive B cells.

The current work can be traced back to the discovery of a novel mouse model for autoimmunity, the BXD2 recombinant inbred strain of mouse, by Dr. Hsu’s group. This mouse has led to several novel insights into basic mechanisms at the cellular and molecular mechanism of autoimmunity over the past 12 years. Dr. Hsu was also the first investigator to describe a specific role for IL-17 to induced development of spontaneous autoreactive germinal centers in these mice, which was published in Nature Immunology in 2008. Dr. Hsu’s research is currently supported by an NIH R01 grant titled “Entry of antigen-presenting B cells into the follicle directed by IFN-α and IL-17.”

Dr. Hsu obtained both her MS and PhD at Rutgers University in New Brunswick, NJ. She became interested in autoimmune research while she studied molecular mechanisms related to cell cycle dysregulation in lupus prone mice for her PhD dissertation. Dr. Hsu was very inspired by Dr. Mountz’s work and thus joined UAB exactly 20 years ago in August 1995 to receive her post-doctoral training in Dr. Mountz laboratory. After 20 years, Dr. Hsu continues to enjoy her research at UAB and she is devoted to find the mechanisms and better therapies for SLE.

Abstract

Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is associated with increased circulating apoptotic cell autoantigens (AC-Ags) as well as increased type I IFN signaling. Here, we describe a pathogenic mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleens of BXD2 lupus mice disrupts marginal zone macrophages (MZMs), which normally clear AC debris and prevent follicular entry of AC-Ags. Phagocytosis of ACs by splenic MZMs required the megakaryoblastic leukemia 1 (MKL1) transcriptional coactivator–mediated mechanosensing pathway, which was maintained by MZ B cells through expression of membrane lymphotoxin-α1β2 (mLT). Specifically, type I IFN–induced follicular shuttling of mLT-expressing MZ B cells disengaged interactions between these MZ B cells and LTβ receptor–expressing MZMs, thereby downregulating MKL1 in MZMs. Loss of MKL1 expression in MZMs led to defective F-actin polymerization, inability to clear ACs, and, eventually, MZM dissipation. Aggregation of plasmacytoid DCs in the splenic perifollicular region, follicular translocation of MZ B cells, and loss of MKL1 and MZMs were also observed in an additional murine lupus model and in the spleens of patients with SLE. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signaling in the MZM barrier to prevent follicular entry of AC-Ags.

Full Manuscript