Understanding Plasma Cell Differentiation in SLE
Abstract
Rationale, Objective and Aims Our immune system functions to eradicate pathogens from our body. One arm of this defense is through antibodies that facilitate pathogen clearance. However, if antibodies target our own body, autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), can arise. Most SLE patients have anti-nuclear antibodies (ANA). These antibodies recognize an array of molecules that normally reside in the nucleus of cells. However, when an injury or infection occurs, these molecules can be released from the nucleus of dying cells, thereby becoming accessible to binding by ANA, which usually results in an inflammatory response. Plasma cells are the immune cells that produce antibodies, and they can arise from B cells through different pathways. Our previous results have shown that the differentiation of most ANA+ B cells to plasma cells is prevented in healthy individuals, a process we call tolerance. In SLE, this tolerance process is unsuccessful, thereby leading to secretion of ANA and to subsequent inflammatory reactions throughout the body. Our previous research has shown that SLE patients can be separated in two groups based on their pattern of ANA+ plasma cells. In the proposed project, we aim to study the pathways that lead to the emergence of ANA+ plasma cells in SLE. Included among ANA+ PCs are cells making anti-DNA and anti-Sm antibodies, both of which are known to contribute to disease in SLE. We will compare the two groups of patients; we hypothesize that each group has a distinct pathway for the development of ANA+ plasma cells. Moreover, we will determine how to cause the differentiation of a naive or memory ANA+ cells to PCs to provide insights into prevention. Relationship to Focus Areas This proposal will address the focus area “Understanding lupus disease heterogeneity.” Since we observed that SLE patients cluster in two groups based on the pattern of ANA+ plasma cells, we aim to develop this strategy to subtype patients, and to further increase our understanding of how different disease mechanisms may be reflected by this method. Ultimate Applicability These studies will help to understand autoimmune disease mechanisms, in particular those that lead to production of ANA. Since the vast majority of SLE patients have these antibodies in their blood, this research will be applicable to most of them. Because normal plasma cells have such an important role in fighting infections, this research will help to develop more specific therapeutics that can target ANA+ plasma cells. Such therapies need to target the specific pathway that is malfunctioning in each individual patient. The results of our studies can be used to develop novel therapeutics that specifically block ANA+ plasma cells in the two groups of patients. Although developing novel drugs will take longer, our research may provide insight into targets for which drugs already exist and have been proven to be safe, for example when used in other diseases. In this case, the results of this study could be used within 3 to 5 years to study the effect of drugs in SLE patients. Some drugs may have already been tested in SLE patients, and using the results of this study, we may be able to cluster patients based on our strategy and look back at the success of those drugs in SLE patients. Finally, we will be able to use our methodology to subset patients in ongoing clinical trials to determine if we can identify in advance a patient subset that will or will not respond to a particular therapeutic intervention. Our research will therefore provide a better understanding of the disease mechanisms of SLE and may provide us with ways to develop drugs to target the disease differently in the two groups of patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010575
Entities
People
- Betty Diamond
Organizations
- The Feinstein Institute for Medical Research
- United States Army