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Immune Tolerance to HSP60 Attenuates Neurodegeneration in Glaucoma

ABSTRACT: Our previous study suggests that CD4+ T cells primed by bacterial heat shock proteins (HSP) mediate an autoimmune mechanism contributing to the pathogenesis of glaucoma. The present study showed that the activity of CD4+ T cells from the peripheral blood mononuclear cells (PBMC) of POAG patients was significantly higher than control subjects as revealed by single-cell RNA sequencing. The notion of antigenic mimicry between gut bacteria and mouse HSPs expressed in the eye causes glaucomatous degeneration remains unclear. Here, we report that the induction of immune tolerance by nasal administration of bacterial HSP60 protein led to an increase in regulatory T (Tr1) cells and suppression of HSP-specific Th1 cell frequencies in glaucoma mice. leading to protections against retinal ganglion cell loss and preservation of spatial vision in glaucoma mice. Moreover, this neuroprotective effect on retinal ganglion cells in HSP-immune-tolerant mice was compromised by IL-10 deficiency. Our data suggests that induction of immune tolerance to HSP60 presents a potential therapeutic strategy protecting against retinal degeneration and vision loss in glaucoma by partial restoration of T cell-mediated immune balance. Detailed information: https://github.com/mcrewcow/PBMC_Glaucoma_human CellXGene web-browser: https://cellxgene.cziscience.com/collections/de2cde16-c8d3-4a6d-80be-1be9e879aaca

ORGANISM(S): Homo sapiens

PROVIDER: GSE268936 | GEO | 2025/06/11

REPOSITORIES: GEO

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Project description:Glaucoma is a neurodegenerative disease in which vision is lost as a result of the apoptosis of retinal ganglion cells. When the trabecular meshwork cells, that regulate aqueous humor outflow, are stressed as they are in some forms of glaucoma, they considerably up-regulated secretion of a protein called myocilin into the aqueous. The function of this protein is unclear; but since some aqueous humor flows to the posterior of the eye, the effects of myocilin will also be felt by the retinal cells. We have a transgenic mouse that secretes large amounts of myocilin into aqueous humor. In these mice, there is a deposition of myocilin on membranes of certain cells suggesting myocilin might have some signaling functions. This signaling function could explain why stresses that increase intraocular pressures can increase the likelihood for glaucoma, cause the myocilin to be secreted at very high levels by the trabecular meshwork. Myocilin may be important in treating glaucoma. This experiment will determine if myocilin is altering gene expression in the retina. The results should show variations in expression levels and will give us some indication of the pathways that are important to preserve retinal ganglion cells after a diagnosis of glaucoma. Our hypothesis is that myocilin is acting like a signaling protein in the eye. It acts not only in the anterior segment but also in retina as a result of the flow of some aqueous to the back of the eye. This signaling function is protective to certain ocular cells. This function of myocilin may influence cells in the retina and may counter the apoptotic signals in the retinal ganglion cells that occur during glaucoma. Retinas from transgenic mice and from mice of the same strain that do not have the transgene will be dissected. The mice will be three weeks of age. Because of the small size of the retina, samples will be pooled to obtain the RNA necessary to run the microarray. Three control and three transgenic samples will be run and compared with each other. We have data indicating that myocilin is at high levels in the aqueous humor of the transgenic animals.

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Immune Tolerance to HSP60 Attenuates Neurodegeneration in Glaucoma

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