ABSTRACT
OBJECTIVES: In myelin oligodendrocyte glycoprotein IgG-associated disease (MOGAD) and aquaporin-4 IgG+ neuromyelitis optica spectrum disorder (AQP4+NMOSD), the autoantibodies are mainly composed of IgG1, and complement-dependent cytotoxicity is a primary pathomechanism in AQP4+NMOSD. We aimed to evaluate the CSF complement activation in MOGAD. METHODS: CSF-C3a, CSF-C4a, CSF-C5a, and CSF-C5b-9 levels during the acute phase before treatment in patients with MOGAD (n = 12), AQP4+NMOSD (n = 11), multiple sclerosis (MS) (n = 5), and noninflammatory neurologic disease (n = 2) were measured. RESULTS: CSF-C3a and CSF-C5a levels were significantly higher in MOGAD (mean ± SD, 5,629 ± 1,079 pg/mL and 2,930 ± 435.8 pg/mL) and AQP4+NMOSD (6,017 ± 3,937 pg/mL and 2,544 ± 1,231 pg/mL) than in MS (1,507 ± 1,286 pg/mL and 193.8 ± 0.53 pg/mL). CSF-C3a, CSF-C4a, and CSF-C5a did not differ between MOGAD and AQP4+NMOSD while CSF-C5b-9 (membrane attack complex, MAC) levels were significantly lower in MOGAD (17.4 ± 27.9 ng/mL) than in AQP4+NMOSD (62.5 ± 45.1 ng/mL, p = 0.0019). Patients with MOGAD with severer attacks (Expanded Disability Status Scale [EDSS] ≥ 3.5) had higher C5b-9 levels (34.0 ± 38.4 ng/m) than those with milder attacks (EDSS ≤3.0, 0.9 ± 0.7 ng/mL, p = 0.044). DISCUSSION: The complement pathway is activated in both MOGAD and AQP4+NMOSD, but MAC formation is lower in MOGAD, particularly in those with mild attacks, than in AQP4+NMOSD. These findings may have pathogenetic and therapeutic implications in MOGAD.
Subject(s)
Aquaporin 4 , Complement Activation , Immunoglobulin G , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica , Humans , Neuromyelitis Optica/cerebrospinal fluid , Neuromyelitis Optica/immunology , Neuromyelitis Optica/blood , Aquaporin 4/immunology , Male , Female , Middle Aged , Adult , Myelin-Oligodendrocyte Glycoprotein/immunology , Immunoglobulin G/cerebrospinal fluid , Immunoglobulin G/blood , Immunoglobulin G/immunology , Autoantibodies/cerebrospinal fluid , Autoantibodies/blood , Aged , Complement C5a/cerebrospinal fluid , Complement C5a/metabolism , Complement C5a/immunology , Young Adult , Multiple Sclerosis/cerebrospinal fluid , Multiple Sclerosis/immunology , Complement C3a/metabolism , Complement C3a/cerebrospinal fluid , Complement C3a/immunology , Complement Membrane Attack Complex/metabolism , Complement Membrane Attack Complex/cerebrospinal fluid , Complement Membrane Attack Complex/immunologyABSTRACT
Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.
Subject(s)
Adipokines , Aortic Aneurysm, Thoracic , Complement C3a , Fibrillin-1 , Marfan Syndrome , Receptors, Complement , Animals , Female , Humans , Male , Mice , Adipokines/genetics , Aorta, Thoracic/pathology , Aortic Aneurysm, Thoracic/prevention & control , Aortic Aneurysm, Thoracic/etiology , Aortic Aneurysm, Thoracic/metabolism , Aortic Aneurysm, Thoracic/pathology , Complement C3a/antagonists & inhibitors , Complement C3a/metabolism , Cytokines/metabolism , Disease Models, Animal , Fibrillin-1/genetics , Inflammation Mediators/metabolism , Macrophages/metabolism , Macrophages/drug effects , Marfan Syndrome/complications , Marfan Syndrome/genetics , Marfan Syndrome/drug therapy , Mice, Inbred C57BL , Receptors, Complement/antagonists & inhibitors , Receptors, G-Protein-Coupled , Signal TransductionABSTRACT
BACKGROUND AND OBJECTIVES: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS). METHODS: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up). RESULTS: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025). DISCUSSION: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.
Subject(s)
Disease Progression , Multiple Sclerosis, Chronic Progressive , Humans , Male , Female , Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid , Multiple Sclerosis, Chronic Progressive/blood , Multiple Sclerosis, Chronic Progressive/physiopathology , Middle Aged , Adult , Follow-Up Studies , Complement C3/metabolism , Complement C3/analysis , Complement C3a/metabolism , Complement C3a/cerebrospinal fluid , Disability Evaluation , Complement System Proteins/cerebrospinal fluid , Complement System Proteins/metabolismABSTRACT
Recent advances in cryo-electron microscopy (Cryo-EM) have revolutionized our understanding of the complement C5a/C3a receptors that are crucial in inflammation. A recent report by Yadav et al. has elucidated the activation, ligand binding, selectivity, and signaling bias of these receptors, thereby enhancing structure-guided drug discovery. This paves the way for more effective anti-inflammatory therapies that target these receptors with unprecedented precision.