补体激活与多发性硬化症的疾病严重程度相关。
Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.
机构信息
From the Department of Neurology (J.O., A.M.M., A.O., S. Meier, E.W., T.D., M.D.S., M.L., B.F.-B., C. Granziera, L.K., D.L., J.K.); Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB) (J.O., S.A.S., A.M.M., A.O., S. Meier, E.W., T.D., P.B., M.D.S., M.L., B.F.-B., C. Granziera, L.K., D.L., J.K.), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Switzerland; Department of Neurology with Institute of Translational Neurology (K.S., H.W., J.D.L.), University Hospital 4 Münster, Germany; Clinical Trial Unit (S.A.S., P.B.), Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; Octavebio Bioscience (F.Q.), Menlo Park, CA; Division of Medical Immunology (I.H.), Laboratory Medicine, University Hospital Basel, Switzerland; Medica Laboratory (A.R.), Zürich; Department of Neurology (L.A.), Cantonal Hospital, Aarau; Department of Neurology (S. Mueller), Cantonal Hospital St. Gallen; Department of Neurology (A.S.), Inselspital, Bern University Hospital and University of Bern; Department of Clinical Neurosciences (P.H.L., C.B.), Division of Neurology; Diagnostic Department (P.H.L.), Division of Laboratory Medicine; Department of Pathology and Immunology (P.H.L.), Faculty of Medicine, University of Geneva; Division of Neurology (C.P., R.A.D.P.), Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne; Neurocentre of Southern Switzerland (C. Gobbi), Multiple Sclerosis Centre, Ospedale Civico; Faculty of Biomedical Sciences (C. Gobbi), Università della Svizzera Italiana (USI), Lugano, Switzerland; Translational Imaging in Neurology (ThINk) Basel (C. Granziera), Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel; and Division of Internal Medicine (M.T.), University Hospital Basel and Clinical Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2024 Mar;11(2):e200212. doi: 10.1212/NXI.0000000000200212. Epub 2024 Feb 14.
BACKGROUND AND OBJECTIVES
Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression.
METHODS
CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient.
RESULTS
CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; = 0.016) and 0.32 (0.02-0.62; = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; < 0.01) and 0.74 (0.18-1.31; = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; < 0.0001).
DISCUSSION
CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.
背景与目的
组织病理学研究已将免疫球蛋白（Ig）沉积和补体激活确定为多发性硬化症（MS）中枢神经系统组织损伤的原因。鞘内 IgM 合成与更高的 MS 疾病活动度和严重程度相关，并且 IgM 是最强的补体激活免疫球蛋白。在这项研究中，我们调查了补体成分（CC）和补体激活产物（CAP）是否在 MS 患者中增加，尤其是在那些鞘内 IgM 合成增加的患者中，以及它们是否与疾病严重程度和进展相关。
方法
在巴塞尔脑脊液数据库研究中，我们定量了 112 例临床孤立综合征（CIS）患者、127 例 MS 患者（90 例复发缓解型、14 例原发性进展型和 23 例继发性进展型）、31 例炎症性神经病和 44 例症状性对照者的血浆和脑脊液中的 CC 和 CAP 水平。来自瑞士 MS 队列研究的 CIS/MS 患者进行了随访（中位数为 6.3 年）。比较了诊断组之间的 CC/CAP 水平；在 CIS/MS 中，通过线性回归调查 CC/CAP 水平与鞘内 Ig 合成、基线扩展残疾状况量表（EDSS）评分、MS 严重程度评分（MSSS）和神经丝轻链（NfL）水平之间的相关性，调整了年龄、性别和白蛋白商。
结果
CIS/MS 患者的脑脊液（而非血浆）中 C3a、C4a、Ba 和 Bb 水平升高，在伴有额外鞘内 IgM 产生的患者中最为明显。在 CIS 中，C3a 和 C4a 在脑脊液中的加倍与 0.31（CI 0.06-0.56； = 0.016）和 0.32（0.02-0.62； = 0.041）增加的腰椎穿刺时的 EDSS 评分相关。同样，CIS/MS 中 C3a 和 Ba 的加倍与 0.61（0.19-1.03； < 0.01）和 0.74（0.18-1.31； = 0.016）增加的未来 MSSS 相关。在 CIS/MS 中，C3a、C4a、Ba 和 Bb 的脑脊液水平与增加的脑脊液 NfL 水平相关，例如，C3a 的加倍与增加 58%（估计值 1.58；CI 1.37-1.81； < 0.0001）相关。
讨论
补体经典和替代途径在中枢神经系统中的激活在 CIS/MS 中增加，并与鞘内 IgM 产生有关。CSF 中补体激活的增加与 EDSS、未来 MSSS 和 NfL 水平相关，支持补体激活导致 MS 病理学和疾病进展的概念。抑制补体应作为治疗靶点进行探索，以减轻 MS 的严重程度和进展。
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