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01-03-2019 | Article

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

Authors: Shin Yoshitake, Tomoaki Murakami, Kiyoshi Suzuma, Tatsuya Yoshitake, Akihito Uji, Satoshi Morooka, Yoko Dodo, Masahiro Fujimoto, Yang Shan, Patrice E. Fort, Shinji Ito, Akitaka Tsujikawa, Nagahisa Yoshimura

Published in: Diabetologia | Issue 3/2019

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

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Title: Anti-fumarase antibody promotes the dropout of photoreceptor inner and outer segments in diabetic macular oedema
Authors: Shin Yoshitake
Tomoaki Murakami
Kiyoshi Suzuma
Tatsuya Yoshitake
Akihito Uji
Satoshi Morooka
Yoko Dodo
Masahiro Fujimoto
Yang Shan
Patrice E. Fort
Shinji Ito
Akitaka Tsujikawa
Nagahisa Yoshimura
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 3/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-018-4773-1

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