Departments & Organizations
Rheumatic Diseases Research Core
Yale Combined Program in the Biological and Biomedical Sciences (BBS): Immunology: Consequences of an Immune Response; Lymphocyte Development; Regulating the Immune Response
My work focuses on the etiology of autoimmune diseases affecting millions of individuals in the world by identifying molecules and pathways involved in the establishment of B-cell tolerance through the investigation of rare patients with primary immunodeficiency (PID), enrolled at Yale and through an international network.
Patients with PID provide opportunities to study the impact of specific gene defects on the regulation of B-cell tolerance and the removal of developing autoreactive B cells in humans. Using a RT-PCR based strategy that allows us to assess the frequency of autoreactive B cells, we found that alterations in B-cell receptor (BCR) signaling in patients lacking functional BTK or CD19, or mutations in molecules mediating TLR signaling such as TACI, IRAK4, MyD88 as well as in adenosine deaminase (ADA) and activation-induced cytidine deaminase (AID) all result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. Interestingly, successful gene therapy in ADA-deficient patients results in the restoration of early B-cell tolerance checkpoints, revealing that appropriate regiments could correct B-cell selection impairments characteristic of many patients with autoimmune conditions. Our investigations also revealed that central B-cell tolerance defects are primary to many autoimmune diseases including rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus and can result from genetic polymorphisms such as the R620W PTPN22 risk allele associated with all these diseases and that was reported to alter BCR signaling important for the regulation of this checkpoint.
In contrast, most patients with multiple sclerosis only suffer from specific defects of their peripheral B-cell tolerance checkpoint that likely result from abnormal regulatory T cells, which normally control this second B-cell selection step in the periphery. Regardless of which early B-cell tolerance checkpoint is defective in patients with autoimmune diseases, all these patients are characterized by the accumulation of autoreactive clones in their mature naïve B cell compartment, which may contribute to the development of autoimmunity by increasing the frequency of B cells presenting self-antigens. Understanding the etiology of autoimmunity is the first step toward effective treatment, therapy and ultimately, cure.
Education & Training
|PhD||University of Aix-Marseille, France (1996)|
|MS||University of Paris (1989)|
|BS||University of Paris (1988)|