Preventing the Production of Autoreactive B Cells in Systemic Lupus Erythematosus
Abstract
Most patients with autoimmune diseases, which include type 1 diabetes (T1D), rheumatoid arthritis (RA), Sjögren s syndrome (SS), and multiple sclerosis (MS), fail to remove potentially harmful autoreactive B cells that develop in all people but are normally eliminated in healthy individuals. It has been recently suggested that these autoreactive B cells contribute to the development of autoimmune diseases because new treatments that kill all B cells slow down the appearance of T1D and improve the condition of other patients with autoimmune diseases such as RA and MS. However, the elimination of B cells only improved the condition of some patients with systemic lupus erythematosus (SLE), not all, potentially because this treatment does not affect the production of autoreactive antibodies. In addition, this treatment that eliminates B cells does not correct the origins of the faulty production of autoreactive B cells, which come back after a few months and seems to be responsible for the patient s relapse. Hence, there is a need for alternative strategies that would eliminate more specifically autoreactive B cells and prevent autoantibody production. Our research goal is to correct the impaired removal of autoreactive B cells in SLE patients. Since a gene variant called R263Q PTPN22 that produces nonfunctional PTPN22 enzymes protects against SLE and RA, blocking the enzymatic activity of PTPN22 with small molecules could represent a novel therapeutic approach to thwart autoimmunity. In line with this hypothesis, PTPN22 inhibition eliminated the production of autoreactive B cells in mice transplanted with human stem cells (HSCs) carrying another PTPN22 gene variant, which is often present in T1D, RA, and SLE patients. Hence, the generation of mice engrafted with HSCs isolated from the bone marrow of SLE patients will determine if this model may recapitulate the defective removal of autoreactive B cells potentially associated with SLE and will allow us to test whether the injections of PTPN22 inhibitor may prevent the production of autoreactive B cells. Inhibiting PTPN22 may therefore represent a novel and groundbreaking strategy to prevent the development of SLE if given early when subjects are either recently diagnosed or display a high risk to develop SLE due to the presence of predictive autoantibodies in their serum.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810408
Entities
People
- Eric Meffre
Organizations
- United States Army
- Yale University