Staun-Ram Elsebeth, Najjar Eiman, Volkowich Anat, Miller Ariel
Rappaport Faculty of Medicine (E.S.-R., E.N., A.M.), Technion-Israel Institute of Technology; and the Department of Neurology (A.V., A.M.), Neuroimmunology Unit & Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel.
Neurol Neuroimmunol Neuroinflamm. 2018 Oct 16;5(6):e508. doi: 10.1212/NXI.0000000000000508. eCollection 2018 Nov.
To elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a "1st-line" vs "2nd-line" therapy.
B cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up
1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10 B-cell subsets and TGFβ B cells were increased. Proinflammatory LTα and TNFα B cells were reduced, while IL4 B cells elevated, whereas IFNγ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86 B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased.
DMF is associated with increased transitional and IL10 and TGFβ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.
阐明富马酸二甲酯（DMF）对复发型多发性硬化症（MS）患者B细胞的免疫调节作用，这些患者接受DMF作为“一线”或“二线”治疗。
从43例MS患者基线期及DMF治疗15周后分离B细胞。通过流式细胞术评估表型、功能标志物和细胞因子谱。分析包括1年随访期间记录的临床和MRI参数。
一线和二线患者在基线免疫特征方面存在若干差异，这与他们对DMF治疗的免疫反应差异相对应。DMF降低了B细胞和CD8 T细胞的比例，而增加了单核细胞比例。DMF仅在二线患者中减少了记忆B细胞，包括浆细胞，而强烈增加了过渡性B细胞。几个IL10 B细胞亚群和TGFβ B细胞增加。促炎LTα和TNFα B细胞减少，而IL4 B细胞升高，而IFNγ B细胞在一线和二线患者中表现出相反的作用。HLA和ICAM-1表达增加，但CD86 B细胞百分比降低。B细胞活化因子受体的表达和活化CD69 B细胞的比例增加。
DMF与过渡性、IL10和TGFβ调节性B细胞增加以及向更抗炎的免疫特征转变有关。共刺激能力降低的细胞活化可能诱导免疫低反应性。二线患者先前治疗的遗留效应和疾病阶段影响患者的免疫特征以及DMF的免疫调节作用。
