Complement and CD4+ T cells drive context-specific corneal sensory neuropathy.

Derek J Royer,Daniel Jj Carr,Rose Mathew,Daniel R Saban,Grzegorz B Gmyrek,Liwen Lin,Jose Echegaray-Mendez,Victor L Perez

doi:10.7554/elife.48378

Derek J Royer, Daniel Jj Carr + Show 6 more

Open Access

https://doi.org/10.7554/elife.48378

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Abstract

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.

Highlights

Dysregulated complement activation is increasingly recognized as a significant pathological event in a variety of neurodegenerative and neuroinflammatory diseases of the central nervous system (Tenner et al, 2018)
We hypothesized that local complement activation and T cell engagement coordinate corneal nerve damage during herpes simplex virus type 1 (HSV-1) infection
Complement-targeted drug development for ophthalmic use has almost exclusively focused on age-related macular degeneration (AMD) with some interest in neuromyelitis optica (NMO), Stargardt disease, and autoimmune uveitis (Harris et al, 2018; Pittock et al, 2013)

Summary

Introduction

Dysregulated complement activation is increasingly recognized as a significant pathological event in a variety of neurodegenerative and neuroinflammatory diseases of the central nervous system (Tenner et al, 2018). Inflammatory events that damage corneal nerves can have insidious consequences in terms of ocular surface health and transparency (Muller et al, 2003; Shaheen et al, 2014; Stepp et al, 2017) One such pathway that can rapidly initiate inflammation following activation is the complement cascade. To further qualify the possible role of complement in corneal nerve damage independent of infection, we evaluated corneal mechanosensory function in two noninfectious T celldependent ocular surface inflammatory diseases For this purpose, we utilized established murine models of allergic eye disease (AED) and ocular graft-versus-host disease (GVHD) (Herretes et al, 2015; Lee et al, 2015). A majority of patients with chronic presentations of GVHD suffer from ocular surface involvement (Shikari et al, 2013)

Results

Discussion

Materials and methods