Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Regulatory Biology

Department

Biological, Geological and Environmental Sciences

First Advisor

Jorgensen, Trine

Subject Headings

Biomedical Research, Immunology, Molecular Biology

Abstract

Systemic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disorder predominantly (9:1) targeting females. Currently, there is no cure for SLE and also there is a lack of disease predicting biomarkers. The major aim of my research is to determine the cellular basis of the sex bias in SLE and subsequently facilitate the development of better therapeutics and biomarkers for the disease. In (NZBxNZW) F1 mice a similar female bias is observed as in humans and testosterone is shown to be protective against lupus-like disease development, but the mechanism is not well understood.

We found higher levels of Gr1hiCD11b+ myeloid cells in (NZBxNZW) F1 male mice as compared to females. Interestingly, Gr1hiCD11b+, as well as Gr1lowCD11b+, cells have been characterized as granulocytic and monocytic myeloid derived suppressor cells (MDSCs), respectively. Hence, we hypothesized that - Gr1hiCD11b+ cells suppress B cell activation and differentiation and protect against lupus-like disease.

We report here that Gr1hiCD11b+ cells from pre-pubertal male and female BWF1 significantly suppress in vitro cytokine-mediated B cell differentiation into plasma cells. In vivo depletion of Gr1+ cells leads to significantly elevated levels of ANA in male (NZBxNZW)F1 mice. Additionally, Gr1hiCD11b+ cells are regulated by male sex hormone.

Our findings also show that Gr1+ cells suppress antibody response to antigen challenge in (NZB x NZW) F1 male mice through inhibition of T follicular helper (TFH) cells and germinal center formation. The identification of testosterone dependent immune-suppressive cell population in lupus-prone mice can, in part, explain the protective role of testosterone in lupus-like disease development.

We also examined the hormone independent contribution of male versus female immune system in development of lupus like disease in (NZBxNZW)F1 mice. The results of these studies indicate that the intrinsic auto-immune capabilities of the female (NZBxNZW)F1 hematopoietic cells can override the protective effect of testosterone.

Further studies are required to identify the correlation between immune system development and sex hormones with specific emphasis on the identification of molecular targets that may better serve as therapeutic and preventive tools for management of SLE and provide a better quality of life for people suffering from this disease.

Download

Included in

Biology Commons

COinS