Terminal complement activation is increased and associated with disease severity in <scp>CIDP</scp>

Quast, Isaak; Keller, Christian W.; Hiepe, Falk; Tackenberg, B.; Lünemann, Jan D.

doi:10.1002/acn3.331

Cited by 28 publications

(21 citation statements)

References 26 publications

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“…Supporting the hypothesis that complement activation can be a potential pathogenic mechanism for this disease, complement component C3d deposition has been detected on the outer surface of PNS Schwann cells in biopsies from patients with CIDP [60,64,65]. Moreover, clinical studies demonstrated that CIDP patients have increased serum and cerebrospinal fluid levels of C5a [66], which is the result of the proinflammatory function of C3d aimed at recruiting myeloid cells, such as macrophages, to inflammation sites through complement receptors and inducing tissue injury through formation of the MAC. These findings suggest that systemic and local terminal complement activation is a characteristic feature of inflammatory demyelinating polyneuropathies and support a role of complement activation in the pathogenesis of CIDP.…”

Section: Chronic Inflammatory Demyelinating Polyradiculoneuropathymentioning

confidence: 76%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

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The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

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Section: Chronic Inflammatory Demyelinating Polyradiculoneuropathymentioning

confidence: 76%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

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“…In CIDP, complement and IgG are deposited on myelinated fibres 47 and serum levels of terminal complement activation components increase with disease severity 48 . However, complement-fixing antibodies to compact myelin, which would explain the active demyelination and conduction block, have not been identified in CIDP.…”

Section: Inappropriate Complement Activationmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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“…To support the efficacy of eculizumab in patients with AIDP, a recent study of sural nerve biopsy specimens obtained from patients with AIDP demonstrated the deposition of complements [40]. The activation of complements has also been reported in some patients with CIDP [28,[74][75][76]. As described earlier, humoral immunity may be more predominant in typical CIDP than in atypical CIDP, and complement inhibition might be another therapeutic option in a subpopulation of patients with CIDP.…”

Section: Insights Into Classification and Therapeutic Strategiesmentioning

confidence: 91%

Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification and Therapeutic Strategy

Koike

Katsuno

2020

Neurol Ther

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Chronic inflammatory demyelinating polyneuropathy (CIDP) is classically defined as polyneuropathy with symmetric involvement of the proximal and distal portions of the limbs. In addition to this ''typical CIDP'', the currently prevailing diagnostic criteria proposed by the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) define ''atypical CIDP'' as encompassing the multifocal acquired demyelinating sensory and motor (MADSAM), distal acquired demyelinating symmetric (DADS), pure sensory, pure motor, and focal subtypes. Although macrophage-induced demyelination is considered pivotal to the pathogenesis of CIDP, recent studies have indicated the presence of distinctive mechanisms initiated by autoantibodies against paranodal junction proteins, such as neurofascin 155 and contactin 1. These findings led to the emergence of the concept of nodopathy or paranodopathy. Patients with these antibodies tend to show clinical features compatible with typical CIDP or DADS, particularly the latter. In contrast, classical macrophage-induced demyelination is commonly found in some patients in each major subtype, including the typical CIDP, DADS, MADSAM, and pure sensory subtypes. Differences in the distribution of lesions and the repair processes underlying demyelination by Schwann cells may determine the differences among subtypes. In particular, the preferential involvement of proximal and distal nerve segments has been suggested to occur in typical CIDP, whereas the involvement of the middle nerve segments is conspicuous in MADSAM. These findings suggest that humoral rather than cellular immunity predominates in the former because nerve roots and neuromuscular junctions lack blood-nerve barriers. Treatment for CIDP consists of intravenous immunoglobulin (IVIg) therapy, steroids, and plasma exchange, either alone or in combination. However, patients with anti-neurofascin 155 and contactin 1 antibodies are refractory to IVIg. It has been suggested that rituximab, a monoclonal antibody to CD20, could have efficacy in these patients. Further studies are needed to validate the CIDP subtypes defined by the EFNS/PNS from the viewpoint of pathogenesis and establish therapeutic strategies based on the pathophysiologies specific to each subtype.

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Terminal complement activation is increased and associated with disease severity in CIDP

Cited by 28 publications

References 26 publications

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Complement in neurological disorders and emerging complement-targeted therapeutics

Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification and Therapeutic Strategy

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