Extrafollicular responses in humans and SLE

Abstract

Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long-standing autoreactive B-cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody-secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B-cell depletion. Long-lived, highly mutated antibodies are typically generated through T-cell-dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B-cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive-derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B-cell pathway, its relationship to other effector B-cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age-Associated B cells (ABCs), a TLR-7-driven B-cell population that mediates murine autoimmune and antiviral responses.

Keywords: ABC; B cells; DN2; SLE; extrafollicular; plasma cells.

Figure 1.

Pathways of B cell activation. Cartoon of three known pathways of B cell activation and effector differentiation. Differential features of T-I and T-D EF responses are summarized from animal studies and remained to be ascertained in human responses. Murine T-independent responses (left, purple) result in direct conversion of naïve B cells into Ab secreting cells within days of stimulation. T-dependent, EF responses (middle, blue) go through a series of stages before terminal differentiation, and show higher levels of clonal expansion, CSR, and memory formation than T-independent responses. The cartoon depicts the proposed cellular components of the human EF differentiation pathway driven by T-cell cytokines IL-21 and IFNγ in a TLR7-driven fashion (96). GC responses (right, red) result in the highest levels of affinity maturation, memory formation, and LLPC development, but are slower to develop.

Figure 2.

Comparative B cell phenotypes and T-bet expression in peripheral B cell subsets. Top left contour plots: Flow cytometry characterization of T-bet- and T-bet+ B cells within SLE. The vast majority of T-bet+ cells concentrate within the DN (IgD- CD27-), and naïve (IgD+ CD27-) populations. In turn, T-bet+ DN and naïve cells universally express a CXCR5- CD11chigh (CD21low; not shown), phenotype, characteristic of DN2 and activated naïve (aNAV). A small cell fraction of a similar T-bet+ CXCR5- CD11c+ (CD21low, not shown) phenotype can also be identified within the SWM compartment. Top right histograms: Comparative B cell subset histogram profiles utilizing resting naïve (rNAV) or DN2 B cells as references conclusively reveals that dominant T-bet expression resides in aNAV and DN2 B cell fractions. SWM- (CD27+ IgD- CXCR5- CD11c+) and to a lesser extent SWM+ (CD27+ IgD- CXCR5+ CD11c-) have higher T-bet expression than rNAV but much less than aNAV and DN2.