3.3.2. Breakdown of B Cells Tolerance

Under physiological condition, B cells originate in the bone marrow from haematopoietic stem cells and during their development undergo several stages of selection because of a large portion of self-reactive and polyreactive B cell are normally generated [132]. The first checkpoint removes the polyreactive B cells in the bone marrow (central tolerance checkpoint), the second in the periphery ensures that only a small amount of self-reactive, and polyreactive mature naïve B cells survive. Finally, a third tolerance checkpoint called pre-germinal centre checkpoint, excludes self-reactive naïve B cells from entering B cell follicles [133].

A recent study has revealed the existence of deficiencies in both early and late B cell tolerance checkpoints in patients with SS. Indeed, the accumulation of circulating autoreactive naïve B cells in SS suggests an impairment of the autoreactive B cell clearance during the early peripheral tolerance checkpoints and an increased frequency of autoreactive unswitched and switched memory B cells reveals a possible impairment also in pre- and/or post-germinal centre tolerance checkpoints [134]. These observations have also been made in patients with SLE, RA and type 1 diabetes [135,136]. B cell depletion using anti-CD20 antibodies in Id3 knockout mice model leads to a significant histological improvement associated with a recovery of saliva secretory function and corroborate the hypothesis that B cells could play an important role in SS disease [137].

B cell hyperactivity is an important hallmark of SS. Two cytokines have been shown to be fundamental in B cell survival and proliferation: B cell Activating Factor of the TNF Family (BAFF) and APRIL (A proliferating ligand) [138]. Once SG tissue infiltration is established, a large number of cells such as dendritic cells, monocytes and macrophages but also SGEC and T lymphocytes can secrete BAFF. BAFF overexpression has indeed been documented in SS as well as in other systemic autoimmune diseases and has been correlated with autoantibodies [139].
