Spontaneous germinal centers and autoimmunity

Abstract

Germinal centers (GCs) are dynamic microenvironments that form in the secondary lymphoid organs and generate somatically mutated high-affinity antibodies necessary to establish an effective humoral immune response. Tight regulation of GC responses is critical for maintaining self-tolerance. GCs can arise in the absence of purposeful immunization or overt infection (called spontaneous GCs, Spt-GCs). In autoimmune-prone mice and patients with autoimmune disease, aberrant regulation of Spt-GCs is thought to promote the development of somatically mutated pathogenic autoantibodies and the subsequent development of autoimmunity. The mechanisms that control the formation of Spt-GCs and promote systemic autoimmune diseases remain an open question and the focus of ongoing studies. Here, we discuss the most current studies on the role of Spt-GCs in autoimmunity.

Keywords: Autoimmunity; ectopic germinal centers; self-tolerance; spontaneous germinal centers.

Figure 1. Schematic of the Germinal Center (GC) Reaction

(1.) Naive B cells initiate a response to antigen and obtain CD4⁺ T cell help at the B cell:T cell border. (2.) GC B cells rapidly proliferate as centroblasts and interact with Reticular Cells that secrete CXCL12 within the dark zone of the GC. Centroblasts differentiate into centrocytes and follow a CXCL13 gradient that is produced by follicular dendritic cells (FDCs) in the light zone. (3.) Centrocytes compete for limiting antigen within immune complexes that are trapped on the surface of FDCs. (4). Centrocytes with high-affinity BCRs process and present antigen via MHCII to limiting cognate Tfh. In turn, Tfh provide survival signals for the conjugated GC B cell to undego several different fates. (5). GC B cells can remain within the GC and undergo another round of mutation and class switching or (6.) leave the GC and mature to (7.) long-lived plasma cells or (8.) memory B cells that can persist in the periphery for extended periods of time. (9.) Centrocytes that fail to be selected will undergo apoptosis and will be readily cleared from the GC by tingible body macrophages to prevent the buildup of self-antigen.

Figure 2. Signaling Pathways that modulate B Cell Receptor (BCR) signaling in Spt-GCs

Several signaling pathways have been shown to either promote or inhibit BCR signaling in the GC. BCR signaling in the GCs is triggered by BCR interaction with antigen complexes that are captured on the surface of FDCs (Fig 1). Lyn and FcgRIIb (shown in red) have been shown to limit BCR signaling and limit Spt-GC formation. However, TLRs (shown in yellow), Btk (in green), WASp (in green) and CD20 (blue) have been shown to promote BCR signaling pathways and enhance Spt-GC formation. Cytokine signals from FDCs (BAFF) and pDCs (type 1 interferon) also promote BCR signaling as well as GC B cell survival.

Figure 3. Signaling Pathways that regulate GC B cell and Tfh selection in Spt-GCs

After acquiring antigen, B cells present antigen via MHC II to T cells with cognate T cell receptors (TCRs). Several co-stimulatory molecules are involved in B cell activation that leads to GC formation or in the maintenance of GC B cells. Most of the receptors and co-stimulatory molecules that are involved in Spt-GC formation regulate B cell survival, proliferation, and class switching (CD40, CD80/86, IL4R, IL21R, IFNγR, BAFFR, TLRs), but IL-17R controls the migration of Tfh and GC B cells and SLAM family molecules have co-stimulatory functions.