Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system

Jongen, Peter Joseph; Doesburg, W.H.; Ibrahim-Stappers, J. L. M.; Lemmens, W.A.J.G.; Hommes, O.R.; Lamers, K.J.B.

doi:10.1034/j.1600-0404.2000.101002116.x

Cited by 81 publications

(63 citation statements)

References 12 publications

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“…Proteins of the complement cascade are generally considered the product of hepatic synthesis, with distribution in plasma to their site of action, although increasingly it is recognized that local synthesis in injured tissues also occurs. Because CSF complement concentration is several hundred-fold lower than that in serum (Jongen et al, 2000), transfer from serum is unlikely to be the source of complement in the CNS. Microglia, astrocytes, and oligodendrocytes synthesize complement proteins in the CNS after injury, infection, and ischemia (Laufer et al, 2001;van Beek et al, 2003) and, as we now show, after peripheral nerve injury.…”

Section: Discussionmentioning

confidence: 99%

Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Griffin¹,

Costigan²,

Brenner³

et al. 2007

J. Neurosci.

221

225

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Microarray expression profiles reveal substantial changes in gene expression in the ipsilateral dorsal horn of the spinal cord in response to three peripheral nerve injury models of neuropathic pain. However, only 54 of the 612 regulated genes are commonly expressed across all the neuropathic pain models. Many of the commonly regulated transcripts are immune related and include the complement components C1q, C3, and C4, which we find are expressed only by microglia. C1q and C4 are, moreover, the most strongly regulated of all 612 regulated genes. In addition, we find that the terminal complement component C5 and the C5a receptor (C5aR) are upregulated in spinal microglia after peripheral nerve injury. Mice null for C5 had reduced neuropathic pain sensitivity, excluding C3a as a pain effector. C6-deficient rats, which cannot form the membrane attack complex, have a normal neuropathic pain phenotype. However, C5a applied intrathecally produces a dose-dependent, slow-onset cold pain in naive animals. Furthermore, a C5aR peptide antagonist reduces cold allodynia in neuropathic pain models. We conclude that induction of the complement cascade in spinal cord microglia after peripheral nerve injury contributes to neuropathic pain through the release and action of the C5a anaphylatoxin peptide.

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Section: Discussionmentioning

confidence: 99%

Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Griffin¹,

Costigan²,

Brenner³

et al. 2007

J. Neurosci.

221

225

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“…Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5].…”

Section: Introductionmentioning

confidence: 99%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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“…Support that complement can contribute to CNS pathology in human SLE includes the increased concentration of the central complement proteins, C3 and C4, in the cerebrospinal fluid (CSF) of SLE patients (10,11). In addition, systemic complement activation, as reflected by increased serum levels of the anaphylatoxins, C3a and C5a, has been shown to correlate with CNS disease (12).…”

Section: H Uman Systemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

Alexander¹,

Jacob²,

Bao³

et al. 2005

The Journal of Immunology

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The role of complement activation in the brains of MRL/lpr lupus mice was determined using the potent C3 convertase inhibitor, CR1-related y (Crry), administered both as an overexpressing Crry transgene and as Crry-Ig. Prominent deposition of complement proteins C3 and C9 in brains of MRL/lpr mice was indicative of complement activation and was significantly reduced by Crry. Apoptosis was determined in brain using different independent measures of apoptosis, including TUNEL staining, DNA laddering, and caspase-3 activity, all of which were markedly increased in lupus mice and could be blocked by inhibiting complement with Crry. Complement activation releases inflammatory mediators that can induce apoptosis. The mRNA for potentially proinflammatory proteins such as TNFR1, inducible NO synthase, and ICAM-1 were up-regulated in brains of lupus mice. Crry prevented the increased expression of these inflammatory molecules, indicating that the changes were complement dependent. Furthermore, microarray analysis revealed complement-dependent up-regulation of glutamate receptor (AMPA-GluR) expression in lupus brains, which was also validated for AMPA-GluR1 mRNA and protein. Our results clearly demonstrate that apoptosis is a prominent feature in lupus brains. Complement activation products either directly and/or indirectly through TNFR1, ICAM-1, inducible NO synthase, and AMPA-GluR, all of which were altered in MRL/lpr mouse brains, have the potential to induce such apoptosis. These findings present the exciting possibility that complement inhibition is a therapeutic option for lupus cerebritis.

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Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system

Abstract: CSF index is a valid tool to detect intrathecal C3 or C4 production. C3 or C4 index contributes little to the differential diagnosis of immunological CNS disorders. C3 might play a pathogenic role in various immunological CNS disorders.

Cited by 81 publications

References 12 publications

Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain Hypersensitivity

Absence of functional alternative complement pathway alleviates lupus cerebritis

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

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