B cells and immunological tolerance

Abstract

Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B-cell depletion therapy may be, to a large extent, determined by the functional balance between different B-cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B-cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we first discuss current knowledge of B-cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B-cell gain-of-pathogenic function (or a B-cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B-cell pathogenic and protective functions.

Figure 1. Checkpoints and mechanisms of B cell tolerance with emphasis on human models

Schematic representation of the multiple checkpoints, mechanisms and determinants of tolerance during early and late B cell development. By and large, the information summarized is derived from transgenic mouse models. The two main human experimental models of B cell tolerance are depicted superimposed on the figure (checkpoints for 9G4 cells are shown with blue signs and ANA reactivity is shown in red; +: positive selection; ×: negative selection). This figure ignores the B1 compartment since no clear and unequivocal definition or even definitive proof of its existence is available for humans. The model also tries to incorporate existing questions regarding the identity of human recirculating MZ cells and the nature of the MZ precursor population (either transitional or follicular naïve B cells). For the purpose of this review, peripheral blood IgD+ (unswitched) CD27+ memory cells are considered a circulating MZ equivalent and represent the IgM+ memory population studied in terms of ANA autoreactivity. Such autoreactivity has been shown to decrease significantly when either the transitional or naïve follicular compartment is compared with unswitched memory cells. Accordingly, a red negative selection sign has been assigned to these potential checkpoints. T: transitional cells; PC: plasma cells; F_TH: follicular T helper cells. A table summarizing the CD antigens that permit classification of human B cell populations is also included in the figure (112). In addition to these subsets, germinal center B cells are characterized as IgD−, CD38++, CD10+ and generally CD27+ (54). Spleen marginal zone B cells are typically CD27+, CD21++, CD23+/−, CD1c+ and IgD− (although an outer marginal zone population is also observed in human spleen) (112). Peripheral blood unswitched CD27+ memory B cells may represent a recirculating marginal zone population also bearing the CD1c marker (113). Finally, long-lived plasma cells found in human bone marrow as well as spleen and tonsils express CD138 in addition to high levels of CD38 (114).

Figure 2. A broader view of B cell tolerance. Additional late checkpoints

Conventional late checkpoints are viewed as preventing the generation of autoreactive long-lived memory B cells and plasma cells in order to avoid autoantibody accumulation. Additional checkpoint could be envisioned that block the generation of autoreactive effector B cells (B_E) from either newly recruited GC cells or pre-existing central memory cells (B_CM) (85, 86). Such hypothetical checkpoints are indicated in this figure (Whether effector B cells may represent a distinct subset of memory B cells and whether they can also generate plasma cells remains to be elucidated.

Figure 3. The dual nature of B cells in autoimmunity

B cells are endowed with a Janus-like quality that enables them to perform functions that either promote or suppress autoimmunity. While division of labor is likely to exist between different B cell populations it is also possible that the function of a given B cell subset could be induced or modulated by the dominant cytokine environment characteristic of different autoimmune diseases.

Figure 4. Functional balance between protective and pathogenic B cell functions

This figure is predicated on the notion that pro-inflammatory pathogenic functions may be concentrated on memory B cells whereas transitional and possibly naïve B cells might provide protection at least in part by the secretion of cytokines such as IL-10 and TGFβ. Consequently, the relative balance achieved between these two opposing populations/activities would determine disease course and response to treatment.