, Volume 62, Issue 3, pp 504–516 | Cite as

Anti-fumarase antibody promotes the dropout of photoreceptor inner and outer segments in diabetic macular oedema

  • Shin Yoshitake
  • Tomoaki MurakamiEmail author
  • Kiyoshi Suzuma
  • Tatsuya Yoshitake
  • Akihito Uji
  • Satoshi Morooka
  • Yoko Dodo
  • Masahiro Fujimoto
  • Yang Shan
  • Patrice E. Fort
  • Shinji Ito
  • Akitaka Tsujikawa
  • Nagahisa Yoshimura



In diabetic macular oedema (DMO), blood components passing through the disrupted blood–retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries.


Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries.


After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p < 0.001) and were related to photoreceptor damage and visual dysfunction. Passively transferred fumarase IgG from DMO sera in concert with complement impaired the function and structure of rodent photoreceptors. This was consistent with complement activation in the damaged photoreceptors of mice immunised with fumarase. Fumarase was recruited to the cell surface by complement and reacted to this autoantibody. Subsequently, combined administration of anti-fumarase antibody and complement elicited mitochondrial disruption and caspase-3 activation.


This study has identified anti-fumarase antibody as a serum biomarker and demonstrates that the generation of this autoantibody might be a pathological mechanism of autoimmune photoreceptor injuries in DMO.


Anti-fumarase antibody Autoantibody Complement Diabetic macular oedema Optical coherence tomography Photoreceptor damage Serum biomarker 



Blood–retinal barrier


Cancer-associated retinopathy


Cytochrome C oxidase


Diabetic macular oedema


Human embryonic kidney


Logarithm of the minimum angle of resolution


Membrane attack complex


Optical coherence tomography


Vascular endothelial growth factor



We would like to thank R. H. Rosa Jr (Texas A&M Health Science Center, Bryan, TX, USA) for providing discussion, and K. Okamoto-Furuta and H. Kohda (Division of Electron Microscopic Study, Center for Anatomical Studies, Graduate School of Medicine, Kyoto University, Kyoto, Japan) for technical assistance in electron microscopy.

Contribution statement

SY conceived and designed the study, acquired data, drafted the manuscript and approved its final version. TM, KS, TY, AU, SM, YD, MF, AT and NY contributed to the conception and design of the study and acquisition, analysis and interpretation of data, revised the article’s intellectual content and approved the final version. YS, PEF and SI contributed to the acquisition and analysis of data, revised the article’s intellectual content and approved the final version. TM is the guarantor of this work.


The study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (26462637, 17K11423, 18K19610). Immunostaining of human retinas, which used the Core Center for Vision Research funded by P30 EY007003 from the National Eye Institute, was supported by awards from Eversight and the Diabetes Consortium (National Institutes of Health). MS studies were performed at the Medical Research Support Center, Graduate School of Medicine, Kyoto University, which was supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4773_MOESM1_ESM.pdf (1.1 mb)
ESM (PDF 1137 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shin Yoshitake
    • 1
  • Tomoaki Murakami
    • 1
    Email author
  • Kiyoshi Suzuma
    • 1
  • Tatsuya Yoshitake
    • 1
  • Akihito Uji
    • 1
  • Satoshi Morooka
    • 1
  • Yoko Dodo
    • 1
  • Masahiro Fujimoto
    • 1
  • Yang Shan
    • 2
  • Patrice E. Fort
    • 2
    • 3
  • Shinji Ito
    • 4
  • Akitaka Tsujikawa
    • 1
  • Nagahisa Yoshimura
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Department of Ophthalmology and Visual SciencesUniversity of Michigan, Kellogg Eye CenterAnn ArborUSA
  3. 3.Department of Molecular and Integrative PhysiologyUniversity of Michigan, Kellogg Eye CenterAnn ArborUSA
  4. 4.Medical Research Support Center, Graduate School of MedicineKyoto UniversityKyotoJapan

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