Cytokine regulation of B-cell migratory behavior favors formation of germinal centers in autoimmune disease

Abstract

Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-alpha (IFN-alpha) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFN-alpha produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P(1) chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells.

Figure 1

Anatomic structure of a spontaneous germinal center (GC) in the spleen of a representative BXD2 mouse. Confocal image of a representative BXD2 spleen section stained with anti-IgM (red), anti-CD35 (white), and anti-CD4 (yellow) antibodies, and peanut agglutinin (PNA) (blue). Anti-CD35 antibodies are used to stain follicular dendritic cells (FDCs) that express CD35 (DZ: dark zone; FDCs: follicular dendritic cells; GC: germinal center; LZ: light zone; PNA: peanut agglutinin).

Figure 2

Marginal zone precursor B cells are near CD4 T cells in the vicinity of germinal center (GC) light zone end in the spleen of BXD2 mice. Confocal images of a representative BXD2 spleen section stained with anti-IgM (red), anti-CD23 (green), and anti-CD4 (white) antibodies, and peanut agglutinin (PNA) (blue). CD23^hiIgM^lo follicular (FO) B cells are green-colored; CD23^loIgM^hi marginal zone (MZ) B cells are red-colored; CD23^hiIgM^hi marginal zone precursor (MZP) B cells are yellow-colored; and PNA⁺ GC B cells are blue-colored. Bottom row displays higher magnifications of boxed areas in top row (FO: follicular B cells; GC: germinal center; MZ: marginal zone B cells; MZP: marginal zone precursor B cells; PNA: peanut agglutinin).

Figure 3

Migration of marginal zone precursor B cells regulated by type I interferon (IFN) and IL-17. This figure depicts our current view on the migration and migration arrest of CD86^hi antigen-bearing marginal zone precursor B cells. Our results suggest that type I IFN produced by plasmacytoid dendritic cells (pDCs) in the marginal zone (MZ) provides a signal to upregulate CD69. This downregulates S1P₁ and the S1P chemotactic response to favor the CXCL13-induced follicular entry of marginal zone precursor B cells. A second action in the germinal center (GC) results from production of CXCL13 by follicular dendritic cells (FDCs). CXCR5 is highly expressed on marginal zone precursors and CXCL13 from FDCs can attract these B cells into an active developing GC. A third action comes from IL-17 produced by T helper 17 cells (T_H17) that were in the GC region. IL-17 signals through the NF-κB pathway in B cells to upregulate RGS. This locks the marginal zone precursor B cells into their position in the GC FDC region to interact with effector CXCR5⁺ CD4 T cells. Thus, the formation of spontaneous GCs in the spleens of BXD2 mice is highly associated with localized imbalance of cytokines that are normally invoked during immune responses. Such coupled effects of cytokines on different cells at different anatomic locations within a lymphoid organ may result in responses that are not predicted by the analysis of the effects the isolated cytokines on stationary cells (Ag: antigen; FDC: follicular dendritic cells; MZ: marginal zone; pDC: plasmacytoid dendritic cells; Rgs: regulators of G-protein signaling; S1P: sphingosine-1- phosphate; T_H-17: T helper 17 cells)