Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood

Mantovani, Susanna; Gordon, Richard D.; Macmaw, J.K.; Pfluger, Casey M. M.; Henderson, Robert D.; Noakes, Peter G.; McCombe, Pamela A.; Woodruff, Trent M.

doi:10.1016/j.jneuroim.2014.09.005

Cited by 67 publications

(55 citation statements)

References 53 publications

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“…There is clear evidence of activation of innate immune complement system in human subjects with ALS, with raised C5a levels and increased expression of C5a on human leukocytes (74). A two dimensional gel electrophoresis was used to study serum proteins in ALS subjects and found that components of complement C3 were increased compared to controls (75) and another study using nephelometry showed increased levels of complement C3 in the blood of ALS patients (59).…”

Section: Complement Systemmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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Section: Complement Systemmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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“…Levels of complement factors are elevated in the serum or CSF of patients with ALS (Table 2). [42][43][44] In SOD1 mice, deletions of C1q and C3, upregulated in SOD1 mice or patients with ALS (Table 2), did not contribute to the survival time. 45 Therefore, the role of the complement system in ALS is undetermined.…”

Section: Complement System In Alsmentioning

confidence: 93%

“…The complement system is another component of the innate immune system that enhances the ability of antibodies to opsonize pathogens and the phagocytic function of macrophage/microglia to clear pathogens. Levels of complement factors are elevated in the serum or CSF of patients with ALS (Table ) . In SOD1 mice, deletions of C1q and C3, upregulated in SOD1 mice or patients with ALS (Table ), did not contribute to the survival time .…”

Section: Innate Immunity In Alsmentioning

confidence: 99%

Neuroinflammation in motor neuron disease

Endo

Komine

Yamanaka

2016

Clinical & Exp Neuroim

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Increasing evidence suggests that the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) is not restricted to the neurons but attributed to the abnormal interactions of neurons and surrounding glial and lymphoid cells. These findings led to the concept of non-cell autonomous neurodegeneration. Neuroinflammation, which is mediated by activated glial cells and infiltrated lymphocytes and accompanied by the subsequent production of proinflammatory cytokines and neurotoxic or neuroprotective molecules, is characteristic to the pathology in ALS and is a key component for non-cell autonomous neurodegeneration. This review covers the involvement of microglia and astrocytes in the ALS mouse models and human ALS, and it also covers the deregulated pathways in motor neurons, which are involved in initiating the disease. Based on the cell-type specific pathomechanisms of motor neuron disease, targeting of neuroinflammation could lead to future therapeutic strategies for ALS and could be potentially applied to other neurodegenerative diseases.

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“…Moreover, up-regulation of C1q, C4d, C2, C3c, C3dg, and Factor H has been seen in various tissues in ALS patients (Tsuboi and Yamada, 1994, Trbojevic-Cepe et al, 1998, Grewal et al, 1999, Jiang et al, 2005, Goldknopf et al, 2006. A recent study conducted by our lab has also shown elevated levels of C5a and C5b-9 in the plasma of ALS patients (Mantovani et al, 2014).…”

Section: Discussionmentioning

confidence: 69%

Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS

Wang¹

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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease. It is characterised by progressive loss of motor neurons and muscle atrophy. Recently, mounting evidence has suggested that complement, part of the innate immune system, is involved in the pathogenesis of ALS in both human patients and in animal models.Activation of complement in the central nervous system (CNS) has been well defined and has been proved to be critical to the death of motor neurons. However, less is known about the roles of complement in the skeletal muscle during the ALS disease progression.The initial aim of this study was to examine the complement activation in skeletal muscle of hSOD1 G93A mice, a well-characterised ALS animal model. Expressions of major complement factors (C1qB, C3, factor B, C4, C5, C5aR1, and C3aR) and regulators (CD55, CD59) were determined, and shown to be significantly elevated in the skeletal muscle of hSOD1 G93A when compared to wide-type (WT) mice as disease progressed,suggesting that complement activation in the skeletal muscle of hSOD1 G93A mice is achieved through classical and possibly other complement cascades. In addition, expression levels of C5aR1 and C3aR, receptors for complement peptides C5a and C3a respectively, were also increased. Immunolocalisation studies shows that C5aR1 and C3aR are expressed on invading immune cells, CD11b + macrophage and CD4 + helper T cells, in skeletal muscle of hSOD1 G93A mice.The second aim of this study was to investigate the physiological roles of complement signalling in regulating immune cell migration in skeletal muscle of hSOD1 G93A mice.Massive invasions of macrophage and helper T cell were observed in tibialis anterior muscles of hSOD1 G93A mice when compared to age-matched wild-type mice. These infiltrations were remarkably attenuated in hSOD1 G93A mice lacking either C5aR1 or C3aR.By contrast, there was significantly less immune cell invasion into soleus muscles of hSOD1 G93A mice, but like for the tibialis anterior muscle, this invasion is significantly greater when compared to soleus muscles from age-matched wild-type mice, and attenuated in soleus muscle from hSOD1 G93A mice lacking either C5aR1 or C3aR. The soleus muscle, predominantly a slow-twitch muscle, is less vulnerable to denervation in hSOD1 G93A mice. Taken together, these results indicate that C5a-C5aR1 and C3a-C3aR signalling regulates the migration of immune cells into the skeletal muscle during ALS disease progression, and the extent of immune cell influx is related to physiological ii function of skeletal muscle.In summary, I have shown activation of the complement system in the skeletal muscle of hSOD1 G93A ALS mouse model, suggesting a role of complement C5a-C5aR1 and C3a-C3aR signalling in recruiting immune cells into skeletal muscle during disease progression.As skeletal muscle is the prime target for ALS, these findings may promote skeletal muscle as a therapeutic target for effects of complement factors in ALS treatment.iii

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Elevation of the terminal complement activation products C5a and C5b-9 in ALS patient blood

Cited by 67 publications

References 53 publications

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

Neuroinflammation in motor neuron disease

Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS

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