Shimabukuro-Vornhagen Alexander, Zoghi Shahram, Liebig Tanja M, Wennhold Kerstin, Chemitz Jens, Draube Andreas, Kochanek Matthias, Blaschke Florian, Pallasch Christian, Holtick Udo, Scheid Christof, Theurich Sebastian, Hallek Michael, von Bergwelt-Baildon Michael S
Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany; Stem Cell Transplantation Program, University Hospital of Cologne, 50924 Cologne, Germany; Intensive Care Unit and Laboratory for Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany;
Cologne Interventional Immunology, University Hospital of Cologne, 50924 Cologne, Germany;
J Immunol. 2014 Nov 15;193(10):5294-305. doi: 10.4049/jimmunol.1203436. Epub 2014 Oct 13.
Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.
B细胞的抗体非依赖效应功能，如抗原呈递和细胞因子产生，已被证明在多种免疫介导的病症中发挥重要作用，如自身免疫性疾病、移植排斥和移植物抗宿主病。当前大多数免疫抑制治疗针对T细胞，相对非特异性，且会导致严重的免疫抑制，使患者发生严重感染和癌症的风险增加。因此，干扰B细胞活化的治疗策略可能是当前免疫抑制手段的有益补充。我们采用转录组学方法，确定了甲羟戊酸途径相关基因的上调是CD40介导的B细胞活化后的关键分子事件。亲脂性他汀类药物如辛伐他汀和阿托伐他汀抑制甲羟戊酸途径的限速酶3-羟基-3-甲基戊二酰辅酶A还原酶，导致通过CD40对B细胞活化的特异性抑制，并损害其作为同种异体特异性T细胞刺激抗原呈递细胞的能力。从机制上讲，抑制作用是由于甲羟戊酸（香叶基香叶基的代谢前体）耗竭后蛋白质香叶基香叶基化受到抑制所致。因此，直接通过香叶基香叶基转移酶抑制剂或间接通过他汀类药物抑制香叶基香叶基化，代表了一种有前景的治疗方法，可用于治疗B细胞抗原呈递起作用的疾病。
