Journal Article

DZNE-2025-01479

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Complement C4d Informs the Differential Diagnosis of Inflammatory Demyelinating CNS Diseases.

Landt, C. ; Held, F. ; Kolotourou, K. ; Guranda, M. ; Vakrakou, A. G. ; Franz, J. ; Thomas, C. ; Schmiedeknecht, M. U. H. ; Bergann, K. ; Wrzos, C. ; Endmayr, V. ; Tsaktanis, T. ; Zechel, S. ; Ancău, M.DZNE* ; Misgeld, T.DZNE* ; Hakroush, S. ; Hametner, S. ; Rothhammer, V. ; Höftberger, R. ; Hemmer, B. ; Stadelmann, C. ; Nessler, S.

2026
Wolters Kluwer Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1212/NXI.0000000000200528

Abstract: Complement-targeting therapies are pivotal in managing neuromyelitis optica spectrum disorder (NMOSD), calling for a deeper understanding of complement activation across idiopathic inflammatory demyelinating diseases (IIDDs) of the CNS. C4d, a covalently bound complement split product, offers prolonged detectability at activation sites. This study explores whether C4d immunohistochemistry (IHC) extends the detection window for complement activation in CNS biopsies of IIDDs and evaluates its usefulness as a fluid biomarker.Forty-four IIDD biopsies with active demyelination were analyzed for complement deposition using IHC for C9neo and C4d. C4d levels were also quantified in blood and CSF of patients with IIDDs. The persistence of C4d in CNS tissue was further evaluated in an in vivo NMOSD model.C4d IHC enhanced the sensitivity to detect complement activation, surpassing C9neo by twofold in NMOSD and by sixfold in ADEM, while remaining undetectable in MS biopsies. Exclusive C4d immunopositivity at the glia limitans distinguished NMOSD from ADEM. Furthermore, CSF C4d levels were significantly elevated in both seronegative and seropositive NMOSD compared with MS.C4d detection extends the window for identifying complement activation in CNS biopsies of IIDDs and emerges as a valuable CSF biomarker, enhancing diagnostic precision, autoantibody target identification, and patient stratification for complement-targeting therapies.

Keyword(s): Humans (MeSH) ; Complement C4b: cerebrospinal fluid (MeSH) ; Complement C4b: metabolism (MeSH) ; Complement C4b: analysis (MeSH) ; Female (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Adult (MeSH) ; Neuromyelitis Optica: diagnosis (MeSH) ; Diagnosis, Differential (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Biomarkers: blood (MeSH) ; Peptide Fragments: cerebrospinal fluid (MeSH) ; Aged (MeSH) ; Demyelinating Autoimmune Diseases, CNS: diagnosis (MeSH) ; Complement Activation (MeSH) ; Young Adult (MeSH) ; Animals (MeSH) ; Multiple Sclerosis: diagnosis (MeSH) ; Complement C4b ; complement C4d ; Biomarkers ; Peptide Fragments

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Contributing Institute(s):

1. Neuronal Cell Biology (AG Misgeld)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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