The Role of the Complement System in Chronic Inflammatory Demyelinating Polyneuropathy: Implications for Complement-Targeted Therapies

Abstract

SummaryChronic inflammatory demyelinating polyneuropathy (CIDP) is the most common, heterogeneous, immune-mediated neuropathy, characterized by predominant demyelination of motor and sensory nerves. CIDP follows a relapsing–remitting or a progressive course and causes substantial disability. The pathogenesis of CIDP involves a complex interplay of multiple aberrant immune responses, creating a pro-inflammatory environment, subsequently inflicting damage on the myelin sheath. Though the exact triggers are unclear, diverse immune mechanisms encompassing cellular and humoral pathways are implicated. The complement system appears to play a role in promoting macrophage-mediated demyelination. Complement deposition in sural nerve biopsies, as well as signs of increased complement activation in serum and CSF of patients with CIDP, suggest complement involvement in CIDP pathogenesis. Here, we present a comprehensive overview of the preclinical and clinical evidence supporting the potential role of the complement system in CIDP. This understanding furnishes a strong rationale for targeting the complement system to develop new therapies that could serve the unmet needs of patients affected by CIDP, particularly in those refractory to standard therapies.

Repurposing MS immunotherapies for CIDP and other autoimmune neuropathies: unfulfilled promise or efficient strategy?

“…Furthermore, deposition of complement components on nerves 197 and of complement-fixing autoantibodies on the myelin sheath and high systemic complement levels that correlated with disease severity 198 further point to an essential role of complement in the pathogenesis of CIDP and GBS. 199 , 200 …”

Intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): mechanisms of action and clinical and genetic considerations

“…Complement is involved in both antibody-mediated cytotoxicity and macrophage activation. The latter is thought to play a major role in CIDP which is considered to be a macrophagemediated demyelinating neuropathy (Figure 3) [16].…”

What Is in the Literature

“…Immunopathologic mechanisms can include cellular, humoral, and complement pathways that lead to a spectrum of structural changes including segmental demyelination, degrees of axonal damage, and nodal conduction block without structural changes. 4 Despite the lack of detectable antigens and antibodies in typical CIDP, humoral mechanisms are supported by the patient response to plasma exchange. Cellular mechanisms include breakdown of the blood–nerve barrier, interstitial edema with passage of activated T cells, and other lymphocytes and macrophages, which culminate with segmental demyelination and degrees of axonal damage.…”