B cell modulation in transplantation.

Abstract

B cells are cells of the lymphoid lineage characterized by the surface expression of antibody/immunoglobulin (Ig) as the B cell receptor (BCR). B cells are the precursors of antibody-forming plasma cells. It has recently been appreciated that subpopulations of B cells may also act as immunoregulatory cells. These ‘regulatory’ B cells were first described in the mouse and subsequently in humans 1,2, and mediate immunoregulation via the production of interleukin (IL)-10 and IL-35 3. B cells bind antigen via their BCR, and the outcome of this interaction depends upon the affinity of the BCR for the antigen and the environmental context. For example, B cell activation can be facilitated by the presence of complement components (C3b and C3d binding to CD21/CR2). B cells may also receive proactivation and survival signals via cytokines, including BAFF (B cell-activating factor belonging to the tumour necrosis factor family, also known as BLyS). Over-expression of BAFF is sufficient to drive abnormal B cell survival, hypergammaglobulinaemia and a lupus-like autoimmune disease in mice independent of T cell help 4. If the BCR aggregation is sufficient to induce signalling, the B cell internalizes bound antigen, processes it and presents in the context of major histocompatibility complex (MHC) class II. At the border between the B cell follicle and T cell zone of secondary lymphoid organs, the B cell MHC–peptide complex may be recognized by a cognate T cell. Following this T–B interaction, B cells return to the follicle to form the germinal centre, where they undergo somatic hypermutation and class-switch recombination. Here, B cells with a higher affinity for antigen are positively selected and differentiate into either memory B cells or plasma cells. A subset of CD4 T cells located within B cell follicles and characterized by expression of the transcription repressor Bcl-6 [known as T follicular helper (Tfh) cells] are essential for the development of germinal centre B cells 5. A small proportion of plasma cells arising from the germinal centre become established as long-lived plasma cells in the bone marrow. Given the potent and widespread effects of B cell activation, it is critical that there are also stringent control measures to prevent inappropriate B cell responses. To this end, the B cell expresses a number of inhibitory receptors, for example FcγRIIB, CD22, CD72 and PIR-B 6. In recent years, there has been increasing interest in how B cells, plasma cells and their associated antibody respond to allografts 7. Sensitized patients with preformed human leucocyte antigen (HLA) antibodies have an increased risk of acute and chronic antibody-mediated rejection (AMR), which significantly impacts allograft longevity 8. Furthermore, it is now well established that the appearance of de-novo donor-specific antibodies (DSAs) is associated with AMR and chronic allograft attrition 9. Outside their remit of antibody production, there is an appreciation that B cells may play a role in acute cellular rejection, also known as T cell-mediated rejection (TCMR). In contrast to these negative effects of B cells and antibody on the allograft, there is a growing body of evidence that B cells may be beneficial for long-term graft survival; a number of studies have shown a B cell transcriptomic signature in tolerant transplant recipients 10,11 and an up-regulation of B cell biomarkers in rejection-free transplant recipients 12 that may be due to the effects of ‘regulatory’ B cells. Possible strategies to target B cells in transplantation include: (i) B cell depletion; (ii) modulation of B cell activation; (iii) increase B cell inhibition; and (iv) enhancing the generation of regulatory B cells.