Complement C4d Informs the Differential Diagnosis of Inflammatory Demyelinating CNS Diseases

Area of Science:

• Neurology
• Immunology
• Biomarker Discovery

Background:

• Complement activation is key in neuromyelitis optica spectrum disorder (NMOSD) and other CNS inflammatory demyelinating diseases (IIDDs).
• C4d, a stable complement split product, offers prolonged detection at activation sites.
• Understanding complement activity aids in developing targeted therapies.

Purpose of the Study:

• To investigate if C4d immunohistochemistry (IHC) extends the detection window for complement activation in CNS biopsies of IIDDs.
• To evaluate C4d's utility as a fluid biomarker in IIDDs.
• To compare C4d detection sensitivity with C9neo in CNS biopsies.

Main Methods:

• Analysis of 44 IIDD biopsies with active demyelination using IHC for C9neo and C4d.
• Quantification of C4d levels in blood and cerebrospinal fluid (CSF) of IIDD patients.
• Evaluation of C4d persistence in CNS tissue using an in vivo NMOSD model.

Main Results:

• C4d IHC showed twofold higher sensitivity than C9neo in NMOSD and sixfold in ADEM, remaining undetectable in MS.
• Distinct C4d immunopositivity at the glia limitans differentiated NMOSD from ADEM.
• CSF C4d levels were significantly elevated in both seropositive and seronegative NMOSD compared to MS.

Conclusions:

• C4d detection via IHC extends the diagnostic window for complement activation in CNS biopsies of IIDDs.
• C4d emerges as a valuable CSF biomarker for enhancing diagnostic precision in NMOSD.
• C4d aids in autoantibody target identification and patient stratification for complement-targeting therapies.