TY  - JOUR
AU  - Landt, Carolin
AU  - Held, Friederike
AU  - Kolotourou, Konstantina
AU  - Guranda, Mihaela
AU  - Vakrakou, Aigli G
AU  - Franz, Jonas
AU  - Thomas, Carolina
AU  - Schmiedeknecht, Max Ulrich Heiner
AU  - Bergann, Klaus
AU  - Wrzos, Claudia
AU  - Endmayr, Verena
AU  - Tsaktanis, Thanos
AU  - Zechel, Sabrina
AU  - Ancău, Mihai
AU  - Misgeld, Thomas
AU  - Hakroush, Samy
AU  - Hametner, Simon
AU  - Rothhammer, Veit
AU  - Höftberger, Romana
AU  - Hemmer, Bernhard
AU  - Stadelmann, Christine
AU  - Nessler, Stefan
TI  - Complement C4d Informs the Differential Diagnosis of Inflammatory Demyelinating CNS Diseases.
JO  - Neurology: Neuroimmunology & Neuroinflammation ; official journal of the American Academy of Neurology
VL  - 13
IS  - 2
SN  - 2332-7812
CY  - Philadelphia, Pa.
PB  - Wolters Kluwer
M1  - DZNE-2025-01479
SP  - e200528
PY  - 2026
AB  - 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.
KW  - Humans
KW  - Complement C4b: cerebrospinal fluid
KW  - Complement C4b: metabolism
KW  - Complement C4b: analysis
KW  - Female
KW  - Male
KW  - Middle Aged
KW  - Adult
KW  - Neuromyelitis Optica: diagnosis
KW  - Diagnosis, Differential
KW  - Biomarkers: cerebrospinal fluid
KW  - Biomarkers: blood
KW  - Peptide Fragments: cerebrospinal fluid
KW  - Aged
KW  - Demyelinating Autoimmune Diseases, CNS: diagnosis
KW  - Complement Activation
KW  - Young Adult
KW  - Animals
KW  - Multiple Sclerosis: diagnosis
KW  - Complement C4b (NLM Chemicals)
KW  - complement C4d (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41435221
C2  - pmc:PMC12735299
DO  - DOI:10.1212/NXI.0000000000200528
UR  - https://pub.dzne.de/record/283072
ER  -