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. 2024 Dec 12;144(24):2528-2545.
doi: 10.1182/blood.2024025850.

Complement biosensors identify a classical pathway stimulus in complement-mediated thrombotic microangiopathy

Michael A Cole  1 , Nikhil Ranjan  1 , Gloria F Gerber  1 , Xiang-Zuo Pan  1 , Daniel Flores-Guerrero  1 , George McNamara  2 , Shruti Chaturvedi  1 , C John Sperati  3 , Keith R McCrae  4 , Robert A Brodsky  1
Affiliations

Complement biosensors identify a classical pathway stimulus in complement-mediated thrombotic microangiopathy

Michael A Cole et al. Blood. .

Abstract

Complement-mediated thrombotic microangiopathy (CM-TMA) or hemolytic uremic syndrome, previously identified as atypical hemolytic uremic syndrome, is a TMA characterized by germ line variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors" by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-TMA and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies immunoglobulin M (IgM)-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ∼50% of patients with CM-TMA who lack an alternative pathway "driving" variant and suggests at least a subset of CM-TMA is characterized by a breakdown of IgM immunologic tolerance.

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Conflict of interest statement

Conflict-of-interest disclosure: M.A.C. served on the advisory board of Alexion Pharmaceuticals and holds individual stock in AstraZeneca, Novo Nordisk, and Omeros Pharmaceuticals. G.F.G. serves on advisory boards of Apellis Pharmaceutical and Alexion Pharmaceuticals. C.J.S. reports research support from Novartis Pharmaceuticals Corp and Alnylam Pharmaceuticals; honoraria for serving on data safety monitoring board for Alexion Pharmaceuticals and Omeros Corporation; and consulting fees from DiscMedicine and Q32 Bio. S.C. reports consultancy or advisory board fees from Alexion, Sanofi, Takeda, Sobi, and Sanofi. K.R.M. reports consultancy or advisory board fees from Sanofi, Novartis, and Sobi. M.A.C. and R.A.B. are pursuing patents/diagnostic licensing of technology reported in this manuscript. The remaining authors declare no competing financial interests.

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