Mountz John D, Wang John H, Xie Shutao, Hsu Hui-Chen
Department of Medicine, University of Alabama at Birmingham, 35294, USA.
Discov Med. 2011 Jan;11(56):76-85.
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.
趋化作用对于塑造免疫反应至关重要，趋化因子受体拮抗剂目前正作为各种炎症性和自身免疫性疾病的治疗方法进行评估。然而，自身免疫性疾病中趋化作用的失调可能涉及促进和抑制B细胞迁移。本综述重点关注两种与自身免疫性疾病相关的炎症细胞因子，即α干扰素（IFN-α）和白细胞介素-17（IL-17），调节B细胞迁移反应的不同机制。趋化反应在协调生发中心（GCs）中的细胞间相互作用方面起着关键作用。这个过程涉及携带抗原的B细胞在边缘区和生发中心之间的活跃穿梭。我们已经表明，在自身免疫性BXD2小鼠中，边缘窦中的浆细胞样树突状细胞产生的高水平IFN-α促进了边缘区前体B细胞的迁移，该IFN-α拮抗S1P(1)趋化因子受体的活性。相反，在生发中心内，白细胞介素-17A（IL-17A）上调B细胞中G蛋白信号调节剂（RGS）的表达，使CXCL12和CXCL13趋化因子的G蛋白偶联受体（GPCR）信号通路脱敏。这促进了生发中心中B细胞和T细胞的长期稳定相互作用，从而诱导高水平的活化诱导胞苷脱氨酶（AICDA），进而使产生致病性自身抗体的B细胞得以发育。
