Estrogen Receptor Alpha Regulation of B-Cell Receptor Signaling, B-Cell Activation, and Peripheral B-Cell Tolerance
Abstract
Lupus is an autoimmune disease because it is caused when a patient’s own immune cells, which normally protect the body by fighting off infection from invaders such as viruses and bacteria, instead attack the patient’s own body. Normally, the cells of our immune system are prevented from attacking our own body, but when the processes for preventing self-attack do not function properly, lupus can develop. Symptoms of lupus often include fatigue, joint pain, fevers, and skin rashes. These symptoms have a major impact on the quality of life of lupus patients as well as their ability to work and care for their families. Lupus can also lead to serious, potentially life threatening diseases affecting vital organs such as the heart and kidneys. Approximately 90% of patients with lupus are women, and the disease is most commonly diagnosed in women of reproductive age. Both the age at which lupus usually develops and the dramatic female sex bias in lupus, are due, in part, to estrogens, one group of female sex hormones. Although we have known for decades that estrogens play a major role in lupus, relatively little is understood about how estrogens promote this disease or what effects estrogens exert on the type of immune cells involved in lupus. Estrogens exert their effects on cells by binding to cellular proteins, called estrogen receptors. We have shown that one type of estrogen receptor, estrogen receptor (ER) alpha, mediates the effects of estrogens in lupus. We have also shown that ER alpha influences the action some of the genes that control a person’s risk of developing lupus. In the absence of ER alpha, the effects of one of these genes, Sle1b, is eliminated or greatly reduced. In females, Sle1b promotes abnormal growth and development of B cells, one type of immune cell that contributes to lupus, and allows the B cells to bypass the normal processes that prevent lupus by stopping the development of B cells that attack our own body. Sle1b influences the action of the B cell receptor, a protein that controls virtually all aspects of B cell development, growth, and function. We found that ability of Sle1b to perturb normal B cell growth and development is strongly reduced when ER alpha function is disrupted. We have also found that ER alpha influences how B cells respond when the B cell receptor is activated. Others have shown that some of the cellular processes initiated by the B cell receptor influence the activity of ER alpha. Thus, not only does ER alpha impact Sle1b and the B cell receptor, but the converse is also likely to be true – Sleb and the B cell receptor impact ER alpha. The objective of this application is to determine how ER alpha and Sle1b work together to disrupt normal B cell development and contribute to lupus. First, we will determine on a deeper level how ER alpha influences the action of the B cell receptor and Sle1b and thereby regulates B cell growth and development Next, we will determine how the B cell receptor and Sle1b may in turn influence the action ER alpha and how this impacts B cell growth and development. This research will shed light on how estrogens, acting via ER alpha, promote lupus. Although we have known for decades that estrogens promote lupus, the basis for this effect is not well understood. Thus, this work will help us to gain insight into why most lupus patients are women. A deeper understanding of how estrogens promote lupus has the potential to lead to novel lupus therapies, and there is an urgent need for new lupus therapies that are safe and effective. The pharmaceutical industry has a long-standing interest in the development of drugs that bind to estrogen receptors and modify some of their actions. Such drugs are approved for the treatment of some diseases in which estrogens play a major role, including breast cancer and osteoporosis. These same drugs can be used to treat lupus in women after menopause, but because of concerns about effects on t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310599
Entities
People
- Karen Gould
Organizations
- United States Army
- University of Nebraska Medical Center