B cell diversity and division of labor
B cells are known to play multiple effector and regulatory functions through diverse mechanisms of action[2]. Such mechanisms include the defining B cell function, namely antibody production after differentiation into plasmablasts (PB; proliferative, blasting antibody secreting cells typically of short life-span) and plasma cells (PC; mature, resting antibody secreting cells some of which may have very long life spans after homing either to the bone marrow or the spleen) [11]. Spontaneous antibody production may also be a function of specific B cell subsets, in particular B1 cells. In addition, B cells may produce both, proinflammatory cytokines (including L-6, TNF and INFγ) [12], and regulatory cytokines, prominently including IL-10 [13]. Mouse models have demonstrated the ability of B cells to influence T cell activation and polarization into different effector T helper subsets including TH1, TH2 and TH17, a function that in autoimmune disease is likely of pathogenic consequence [12] [14–16]. On the other hand, B cells have also been reported to either induce or inhibit the generation of regulatory T cells [2,17,18,16]. Importantly, several B cell subsets are capable of inhibiting pro-inflammatory responses in macrophages and dendritic cells and the activation of effector T cells, to a large extent through the generation of IL-10. These regulatory B cell functions have been ascribed to different B cell subsets which have been variously labeled B regulatory cells (Bregs) and B10 cells, and will be further discussed below in the context of SLE and other human autoimmune diseases [19–22].
Finally, B cells are powerful antigen presenting cells with the ability to activate antigen-specific T cells and influence the development and/or the maintenance of T cell memory [23]. While some studies have provided experimental evidence for antigen-specific Bregs, the full extent of this phenomenon and the coordinated participation of the APC and IL-10 production functions remain to be fully elucidated.
Given the multiple functions played by B cells and their opposing effects in autoimmunity, it remains essential to understand whether there exists strict division of labor among different B cell subsets or whether instead, there is significant functional plasticity among multiple B cell subsets which could be induced by extrinsic cues in a disease specific fashion. Under the former model, it should be possible to assign a specific, function-linked, surface or transcriptional phenotype to distinct B cell subsets, analyze their frequency in a given disease and in individual patients and design therapeutic approaches to target the population of interest accordingly (whether to eliminate, inhibit or expand such population). Moreover, this could be done in an individualized, patient-directed fashion. Under the latter model, it would be more effective to target the extrinsic milieu responsible for pathogenic alteration of B cell functions. Of course, these two approaches need not be mutually exclusive and thus, one could envision global or selective elimination of specific pathogenic B cell subsets combined with strategies to modify the immunological environment in order to promote B cell protective functions.
Thus, a precise understanding of the phenotype, function and developmental programs of different human B cell subsets is of the essence for a rational design of B cell targeted therapies. The current state of knowledge of human B cell diversity will be discussed in the next section.
Explanation:
