Patients with primary immunodeficiencies provide rare opportunities to study the impact of specific defective genes on the regulation of B-cell tolerance and the removal of developing autoreactive B cells in humans. In addition, impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications. Alterations in B cell receptor (BCR) signaling pathways in patients lacking functional BTK, CD19, or molecules mediating TLR signaling such as IRAK4, MyD88, ADA and TACI result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells. Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms due to increase receptor signaling thresholds in all these patients' B cells and autoreactive B cells leaks from the bone marrow into the periphery. Our investigations revealed that central B-cell tolerance defects are primary to many autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) and result from genetic factors segregating with autoimmunity and which encode variants such as the C1858T PTPN22 risk allele. However, we found that patients with multiple sclerosis (MS) only displayed peripheral B-cell tolerance checkpoint defects whereas central B-cell tolerance was often established normally. Similar observations were observed in CD40L-, MHC class II- and DOCK8-deficient patients, who pointed to a potential role for regulatory T (Treg) cells in the removal of developing autoreactive B cells in the periphery. Specific peripheral B-cell tolerance checkpoint defects were also identified in IPEX patients carrying a FOXP3 mutation, which prevents the generation of functional Tregs. Interestingly, Treg cell functions have been reported to be defective in MS patients as well as in patients with RA. Hence, Tregs may play an essential role in preventing the accumulation of autoreactive B cells in subject's blood, thereby controlling the establishment and the maintenance of B-cell tolerance in the periphery.
Disclosure of Interest None declared