Germinal center versus extrafollicular responses in systemic autoimmunity: Who turns the blade on self?

Abstract

Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity.

Keywords: Autoantibodies; Autoimmunity; Extrafollicular; Lupus; Spontaneous germinal centers; TLR7.

Figure 1. Germinal center and extrafollicular pathways in plasma cell differentiation.

a. Germinal center (GC) response. GC response incorporates B cell clonal expansion, somatic hypermutation (SHM) and selection, and is the source of affinity matured memory B cells and plasma cells. GC selection is regulated by the balance of two T cell subsets: T follicular helper (T_FH) cells that promote GC responses and T follicular regulatory (T_FR) cells that inhibit the response. Self-reactive cells accidentally generated in the GC are safely confined in GC and are either cleared by apoptosis, or undergo new rounds of SHM and selection, thus eliminating self-affinity while increasing affinity towards foreign antigens if present. b. Extrafollicular (EF) response. Blimp-1 antagonizes the pro-GC signaling of Bcl-6 and promotes the development of short-lived PCs in EF sites (Shaffer et al., 2002). A subset of EF B cells known as age-associated B cells (ABCs or DN2 (IgD- CD27-) B cells are expanded in autoimmunity, the frequency of which correlates with autoantibodies and disease severity. The development of ABCs requires signals through the B cell receptor (BCR), TLR7, and cytokines such as IFN-γ and IL-21. ABCs differentiate readily into plasma cells and are considered a major source of autoantibodies.