Resolve, revise, and relax: The 3 Rs of B cell repertoire adjustment

Abstract

Competition for limited, cell extrinsic survival factors is a general feature of peripheral selection checkpoints involved in B lymphocyte maturation and activation. Perhaps the best-characterized example involves BLyS (B lymphocyte stimulator), which modulates the size and composition of mature naïve B cell pools, but evidence for analogous competitive checkpoints is emerging for both germinal center B cells and plasma cells. Here we discuss how deliberate alteration of BLyS levels might be used to manipulate B cell repertoire selection in order to restore self-tolerance in autoimmunity, remodel the repertoire to accommodate neo-self antigens introduced through transplantation and gene therapy, or expand repertoire diversity to reveal novel, therapeutically useful specificities.

γδ T Cells Shape Preimmune Peripheral B Cell Populations

“…B cells can develop in the absence of IL-4 (10), but when it is present, this cytokine affects B cell development in bone marrow and periphery (11–13), and it enhances CD23 and MHCII expression (11, 14, 15), and suppresses CD5 expression by B cells (16). During B cell differentiation, B cell tolerance is established at several distinct checkpoints, including one in the bone marrow (central tolerance, BCR selection and editing) (17, 18), another during transition (more BCR selection and competition for BAFF) (17, 19), and a third during antigen activation in the germinal center, where B cells undergo somatic mutation as well as positive and negative selection (20, 21). …”

Rheumatoid Arthritis Clinical Benefits from Abatacept, Cytokine Blockers, and Rituximab Are All Linked to Modulation of Memory B Cell Responses

“…The TNF family member (TNFSF13) BAFF, also called B lymphocyte stimulator (BLyS), serves essential functions in B cell survival and maturation during early antigen-independent phases in the bone marrow or after transitional B cells traffic and differentiate into mature antigen-naive B cells in the periphery. BAFF also supports the end-differentiation of plasma blasts and plasma cells 25 . Notably, BAFF blockade has very different effects on the distribution of human B cell subsets in the bloodstream than other biologic agents, as described above, and these same patterns have been seen with the anti-BAFF antibody belimumab, as well as the more recently developed anti-BAFF antibody tabalumab, and the decoy receptor TACI-Ig (atacicept).…”

Chronic inflammation and aging: DNA damage tips the balance

“…Cancro et al have provided evidence for the hypothesis that central and peripheral selection checkpoints involved in B cell differentiation are governed by competition for limited cellular growth and survival factors, such as B Lymphocyte Stimulator (BLyS) [20,21]. If survival factors are no longer limiting, either owing to a decreased number of precursor cells or following increased production of these factors as a compensatory homeostatic mechanism, B cell development is biased toward survival and the generation of a more autoimmune repertoire [22]. A similar risk may apply to thymic function in old age, in particular under conditions of thymic stimulation.…”