Serum and CSF immunological findings in ALS

Apostolski, Slobodan; Nikolić, Jasmina B.; Bugarski-Prokopljević, C.; Miletić, V; S, Pavlovic; Filipović, Saša R.

doi:10.1111/j.1600-0404.1991.tb04656.x

Cited by 104 publications

(59 citation statements)

References 15 publications

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“…Indeed, other studies have shown that many complement factors and their receptors can be synthesized by both neurons and glia in the CNS (17). Although there is breakdown of the blood-brain barrier in the end stages of ALS (34,35), the accumulating evidence for abundant local complement expression in many cell types in the CNS may indicate that this provides a local microenvironment for exacerbating ALS pathology compared with that provided by infiltration of systemic complement factors.…”

Section: Expression Of Complement Factors and Receptors For C5a Are Amentioning

confidence: 99%

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

141

177

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Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1G93A transgenic rats). With end-stage disease, SOD1G93A rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.

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Section: Expression Of Complement Factors and Receptors For C5a Are Amentioning

confidence: 99%

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

Woodruff¹,

Costantini²,

Crane

et al. 2008

The Journal of Immunology

141

177

View full text Add to dashboard Cite

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“…The concept of BBB dysfunction in ALS is not new, and was suggested in a few human studies of spinal fluid characteristics that demonstrated an elevated CSF albumin/ serum albumin ratio in a large percentage of ALS patients (19,20). However, enthusiasm for treating ALS patients with APC might be dampened by several factors, including the disappointing experience of trying to translate therapeutic successes in mutant SOD1 animals to ALS patients (21).…”

Section: Limitations Of the Mouse Model Of Alsmentioning

confidence: 99%

The APCs of neuroprotection

Esmon¹,

Glass²

2009

J. Clin. Invest.

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“…suggesting local production in response to disturbance in CNS homeostasis due to immunoglobulin deposits and auto-antibodies in the CNS of ALS patients (Donnenfeld et al, 1984, Niebroj-Dobosz et al, 2006. Also the circulation could be a source of these complement factors as there is BBB breakdown in the end stages of ALS (Apostolski et al, 1991). Overall, evidence from these clinical studies helps us to propose that complement system activation occurs in ALS patients, and may play a role in the disease pathology.…”

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 89%

“…Subsequent studies measured C3c, C4, C1 inactivator and C3 activator fractions in the serum and CSF of 13 ALS patients but only detected increased levels of C3c in the CSF of ALS patients compared to normal individuals (Annunziata and Volpi, 1985). Furthermore Apopstolski and colleagues (1991) measured serum C4, C3 and Factor B levels in 33 ALS patients and found an increase in C4 levels when compared to normal individuals (Apostolski et al, 1991). Increased clusters of C3d and C4d coated fibers on oligodendroglia and degenerating neurites in spinal cord and motor cortex was also found in 8 ALS patients compared to 5 normal individuals (Kawamata et al, 1992).…”

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 99%

“…Several studies have been conducted on ALS patients in an attempt to identify whether complement components are up-regulated in disease progression ( (Annunziata and Volpi, 1985, Apostolski et al, 1991, Goldknopf et al, 2006, Kawamata et al, 1992, Trbojevic-Cepe et al, 1998. The first of these studies examined C3 immunofluorescence in spinal cord and motor cortex of 16 ALS patients and demonstrated significant C3 deposition, which appeared to be on astrocyte-like cells with no apparent neuronal staining (Donnenfeld et al, 1984).…”

Section: Clinical Evidence Of Complement Involvement In Alsmentioning

confidence: 99%

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The role of complement system in amyotrophic lateral sclerosis

Lee¹

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There is increasing evidence that neuro-inflammation drives disease progression in many neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) is a debilitating, late onset neurodegenerative disorder that is characterized by the progressive death of upper and α-motor neurons within the central nervous system (CNS). Components of the innate immune complement system have been implicated in the pathogenesis of ALS. Within the complement signalling cascade C3a and C5a are regarded as potent inflammatory and immunomodulatory peptides with various biological functions. In the CNS their functions include chemotaxis and proliferation of microglia and astrocytes; generation of superoxide radicals; and induction of pro-inflammatory cytokine synthesis -all thought to be achieved via their main signalling receptors C3aR and CD88. Some of these functions have been observed in neurodegenerative disease, suggesting that these complement factors may play a role in ALS pathogenesis. However a comprehensive examination of complement expression and function of C3aR and CD88 in this disease has not been performed.The initial aim of this thesis was to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5, CD88 and C3aR) and regulators (CD55 and CD59a) in the lumbar spinal cord of the transgenic hSOD1 G93A mouse model of ALS. This was conducted during distinct disease stages, which were defined in this thesis. We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1 G93A mice. CD88 and C3aR was also increased during disease progression, with immunolocalization demonstrating expression on motor neurons and increasing expression of CD88 on microglia and increasing expression of C3aR on astrocytes surrounding the regions of motor neuron death.Our previous studies have demonstrated that hSOD1 G93A rats treated with the selective CD88 antagonist PMX205 had reduced gliosis and improvements in behavioural deficits, consistent with reduced neuropathology; suggesting CD88 has a pathogenic function in ALS. However, the contribution of C3aR to disease progression in ALS is still unknown. This thesis therefore next aimed to confirm the function of CD88, and determine the function of C3aR, in the disease progression of ALS in hSOD1 G93A mice. The function of CD88 signalling was investigated using two different approaches (pharmacological and genetic). Inhibition of CD88 using PMX205 (pharmacological approach) or hSOD1 G93A mice lacking CD88 (genetic approach) showed similarly extended survival when compared to vehicle and hSOD1 G93A mice. There was also a reduction in microglia, monocytes and cytokines (TNFα and IL-1β) transcripts in the spinal cord at the end-stage of disease. Taken together these results indicate that inhibition of CD88 significantly attenuates III disease progression potentially by reducing microglia/monocyte activation...

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Serum and CSF immunological findings in ALS

Cited by 104 publications

References 15 publications

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

The Complement Factor C5a Contributes to Pathology in a Rat Model of Amyotrophic Lateral Sclerosis

The APCs of neuroprotection

The role of complement system in amyotrophic lateral sclerosis

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