Editors Selection IGR 19-4

Basic Science: Immunobiology and neurodegeneration

Derek Welsbie

Comment by Derek Welsbie on:

78502 Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma, Chen H; Cho KS; Vu THK; Vu THK et al. et al., Nature communications, 2018; 9: 3209

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Nearly 30 years ago, Martin Wax and colleagues noted that glaucoma patients have an increased prevalence of circulating autoantibodies compared to controls (see Wax, 2011 for a comprehensive review).1 However, it was unclear whether these autoantibodies arose secondary to the injury of retinal ganglion cells (RGCs) or whether autoimmunity played a primary role in glaucoma pathophysiology. In this paper, Chen et al. address this question using the mouse microbead glaucoma model. They transiently raise intraocular pressure (IOP) in mice and produce a gradual loss of RGCs that continues even after the return to baseline IOP. When they examine these retinas after two weeks, they observe an infiltration with CD4+ TH1 cells, some of which seem to be specific for heat shock protein 27 (HSP27). To test whether this immune response is causally involved in the RGC degeneration, the authors repeat the experimental glaucoma model in mice deficient in T and/ or B cells and find that the loss of T cells attenuates the late, progressive RGC loss, but has little effect on the initial RGC loss. Moreover, they can reconstitute the immune system of these mice with T cells from mice that have been immunized with HSP27 (but without experimental glaucoma) and restore the RGC degeneration, suggesting that anti-HSP immunity is involved in the late phase of RGC degeneration. Finally, using two different glaucoma models, the authors show that mice reared in germ-free conditions (without gut microflora) have markedly attenuated RGC loss. The authors conclude that IOP elevations might compromise the immune privilege status of the retina and allow T cells that have been primed by exposure to gut bacterial HSPs to respond to the HSP27 autoantigen in RGCs (i.e., molecular mimicry) and trigger a chronic neurodegeneration.

There is little-to-no data in the literature confirming the presence of lymphocytes in tissue specimens from glaucoma patients

While potentially exciting, both glaucoma models used in this paper have relatively robust IOP increases that have been shown to cause pan-retinal injury2,3 so it will be interesting to see the contribution of the autoimmune mechanism at more modest IOP elevations. Also, while immunoglobulins have been detected in retinas from glaucoma patients and these authors themselves demonstrate anti-HSP antibodies in some glaucoma patients, there is little-to-no data in the literature confirming the presence of lymphocytes in tissue specimens from glaucoma patients so the relevance to the clinical disease is still an open question. Nonetheless, the work has provided a key insight into RGC loss in mouse models of glaucoma.


  1. Wax MB. The case for autoimmunity in glaucoma. Exp Eye Res 2011;93:187-190.
  2. Ferna?ndez-Sa?nchez L, de Sevilla Mu?ller LP, Brecha NC, Cuenca N. Loss of outer retinal neurons and circuitry alterations in the DBA/2J mouse. Invest Ophthalmol Vis Sci 2014;55:6059-6072.
  3. Huang W, et al. Comparative analysis of retinal ganglion cell damage in three glaucomatous rat models. Exp Eye Res 2018;172:112-122.

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