Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets

Abstract

B cells are critical players in the orchestration of properly regulated immune responses, providing protection against infectious agents without inflicting autoinflammatory damage. A balanced B cell compartment is also essential to create protective immunity in response to vaccines. This difficult compromise is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to powerfully modulate other components of the innate and adaptive immune system. For the most part, however, the necessary division of labor among different B cell populations is poorly understood. B cell dysfunction has been implicated in multiple autoimmune conditions. The physiological importance and complexity of B cell functions has been brought to the fore in recent years by the success of rituximab-based B cell depletion therapy (BCDT) in multiple autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS) which are conventionally viewed as T-cell mediated conditions. Given the widespread utilization of BCDT in malignant and autoimmune diseases and the key role of B cells in both protective immunity and pathogenic autoimmunity, a better understanding of B cell functions is of the essence and a focus of the research in our division. We are investigating these issues through a variety of approaches, including the study of the phenotype and function of human B cell populations in health, their perturbation in autoimmune disease states, the effects of targeted biologic therapies, and the study of relevant murine models.

Figures

Figure 1. Model of B cell effector and regulatory functions in health and disease

Immunologic homeostasis is dependent on the balance between protective (regulatory, anti-inflammatory) B cells and effector (pro-inflammatory) B cells and their corresponding cytokines. We postulate that physiologically, transitional cells predominantly produce IL10 which in a normal environment exerts anti-inflammatory actions, opposing IL12-mediated DC induction of Th1 cells, contributing to the induction of Treg cells, and suppressing autoreactive Th1 cells. This situation would be altered in SLE due to abnormal numbers or function of transitional cells and the cytokines they produce, as well as the type I interferon dominated milieu which primes proinflammatory functions of IL10. In addition, dysregulated effector memory B cells in SLE would produce an excess of pro-inflammatory cytokines (IFNγ, IL-12p40, TNF), shifting the scales toward a proinflammatory phenotype. Finally, we postulate that prolonged absence of B cells induced by BCDT has the potential to either restore physiological balance between protective and pathogenic B cell functions or even to create at least temporarily an environment dominated by transitional cells with anti-inflammatory and tolerogenic functions and Treg inducing activity

Figure 2. Timing and intensity of depletion and repopulation in two groups of SLE responses to BCDT

(A/B) Both groups depleted to