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Heat shock protein-derived peptides and autoimmunity in glaucoma · Glaucoma, Vision & Longevity: Supplements & Science

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  SPEAKER_00: Heat shock proteins and immune responses in glaucoma.
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  SPEAKER_00: Glaucoma is a leading cause of irreversible vision loss, affecting tens of millions of people worldwide.
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  SPEAKER_00: Normally, glaucoma is linked to high eye pressure, but many patients, especially those with normal tension glaucoma, have nerve damage despite normal pressure.
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  SPEAKER_00: This has led researchers to look beyond pressure and investigate the immune system's role.
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  SPEAKER_00: In particular, eye experts have focused on heat shock proteins, HSPs, which are stress-related proteins that help keep nerve cells alive.
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  SPEAKER_00: Under some conditions, these HSPs themselves may become targets of the immune system, contributing to nerve damage.
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  SPEAKER_00: Evidence suggests that T cells, a type of white blood cell, reacting against HSPs can harm the optic nerve.
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  SPEAKER_00: For example, patient studies have found abnormally high levels of antibodies, proteins made by immune B cells, against HSPs in many glaucoma patients.
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  SPEAKER_00: In fact, multiple studies report that glaucoma patients often have elevated serum autoantibodies to HSP27 and HSP60, two common HSPs.
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  SPEAKER_00: In the lab, adding these patient antibodies to retinal cells can trigger cell death, suggesting they are not just markers, but may be damaging.
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  SPEAKER_00: In eye fluid, aqueous humor, glaucoma patients also show unique autoantibody fingerprints, including unusually high anti-HSP27 levels compared to healthy controls.
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  SPEAKER_00: Taken together, these human findings point to an autoimmune tendency against HSPs in glaucoma.
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  SPEAKER_00: Evidence from animal model studies in animals strongly support the idea that HSP-specific immune reactions can cause glaucoma-like damage.
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  SPEAKER_00: In classic experiments, scientists immunized healthy rats with HSP-derived peptides, for example, pieces of HSP27 or HSP60.
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  SPEAKER_00: Remarkably, these rats later developed nerve damage very similar to glaucoma.
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  SPEAKER_00: For instance, Wax and Colleagues 2008 found that rats given HSP27 or HSP60 peptides lost large numbers of retinal ganglion cells, RGCs, the neurons that form the optic nerve, and their axons in a pattern that closely mimics human glaucoma.
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  SPEAKER_00: This damage occurred even though eye pressure stayed normal.
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  SPEAKER_00: Another group confirmed that immunizing rats with an optic nerve extract, which contains many antigens, including HSPs, similarly caused RGC death and optic nerve thinning.
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  SPEAKER_00: Importantly, these models also showed earlier immune changes.
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  SPEAKER_00: T cells infiltrated the retina days after immunization, and support cells, microglia, became activated long before the neurons started dying.
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  SPEAKER_00: These animal experiments provide direct proof that an HSP-driven immune response can cause glaucoma-like neurodegeneration.
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  SPEAKER_00: Autoantibody profiles in patients.
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  SPEAKER_00: Studies of glaucoma patients have found immune signatures consistent with HSP involvement.
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  SPEAKER_00: Many patients, especially with normal tension glaucoma, carry autoantibodies against retina and optic nerve proteins, including HSPs.
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  SPEAKER_00: For example, researchers have detected antibodies to HSP27 and HSP60 in the blood of these patients.
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  SPEAKER_00: In postmortem analyses, donor retinas from glaucoma patients showed antibody binding to HSP27 and HSP60.
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  SPEAKER_00: Laboratory tests imply these antibodies could be harmful.
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  SPEAKER_00: When anti-HSP27 antibodies from patients are applied to living retinal cells, the cells undergo apoptosis, self-destruct.
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  SPEAKER_00: Even the eye fluid of glaucoma patients contains distinct antibody patterns.
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  SPEAKER_00: One study found especially high anti-HSP27 levels in patients versus controls.
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  SPEAKER_00: Altogether, patient data show a consistent profile of immune reaction against HSP peptides in glaucoma.
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  SPEAKER_00: Molecular mimicry and other mechanisms.
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  SPEAKER_00: One key question is why the immune system targets HSPs in glaucoma.
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  SPEAKER_00: An important concept is molecular mimicry.
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  SPEAKER_00: Bacterial and human HSPs share very similar parts because HSPs are highly conserved evolutionarily.
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  SPEAKER_00: For example, T cells primed to fight a bacterial HSP can mistakenly attack a similar HSP in our own cells.
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  SPEAKER_00: As Say et al.
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  SPEAKER_00: explain, T cells raised against a foreign, e.g.
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  SPEAKER_00: microbial HSP, may cross-react with the body's own HSPs and cause autoimmune damage.
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  SPEAKER_00: In line with this, researchers have found T cells in glaucoma patients that react to human HSPs, possibly reflecting past microbial exposure.
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  SPEAKER_00: Some mouse studies even suggest that normal gut microbes can prime HSP-specific T cells that later enter the eye and attack retinal ganglion cells expressing HSP27.
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  SPEAKER_00: In short, the similarity between microbial and host HSPs could teach the immune system to target the host's HSPs, molecular mimicry, leading to glaucoma damage.
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  SPEAKER_00: Another mechanism involves the glial cells, the supporting immune cells of the eye, at the optic nerve head.
• 4:56
  SPEAKER_00: Retinal ganglion cells under stress, for instance from age or intraocular pressure, release more heat shock proteins.
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  SPEAKER_00: These HSPs act as danger signals, damage-associated molecular patterns to the immune system.
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  SPEAKER_00: In response, resident microglia, the eye's local immune cells, become activated.
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  SPEAKER_00: Activated microglia release inflammatory cytokines like TNFA, IL6, and complement proteins, which can harm neurons.
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  SPEAKER_00: In animal models, immunization with HSP peptides caused a surge of microglial activity.
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  SPEAKER_00: The microglia began expressing factors that promote cell death in RGCs, for example, upregulating death receptor pathways.
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  SPEAKER_00: Reinair et al., 2022, also showed that HSP27 immunization triggers complement activation and microglial response in the retina.
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  SPEAKER_00: In glaucoma patients, the optic nerve head often shows activated glial cells and complement deposition.
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  SPEAKER_00: Together, these findings suggest that HSP-related immune reactions can tip off the optic nerve head glia to launch an inflammatory attack, accelerating RGC loss.
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  SPEAKER_00: Antigen-specific immunotherapy, inducing tolerance.
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  SPEAKER_00: If HSP-driven autoimmunity contributes to glaucoma, then a logical treatment strategy is to retrain the immune system to tolerate these antigens.
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  SPEAKER_00: Rather than broadly suppressing immunity, which can have side effects, researchers are exploring antigen-specific tolerance approaches.
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  SPEAKER_00: One idea is to give patients small controlled doses of the disease-related antigen, in this case HSP peptides, in a way that signals don't attack.
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  SPEAKER_00: This is similar in principle to allergy shots or experimental therapies for other autoimmune diseases.
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  SPEAKER_00: For example, some clinical trials in type 1 diabetes have tested an HP60-derived peptide, DIAPEP277, to promote tolerance.
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  SPEAKER_00: In these strategies, the HSP peptides are often modified or delivered with special carriers to avoid an allergic response and to encourage the immune system to become regulatory rather than inflammatory.
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  SPEAKER_00: A key goal is to induce or expand regulatory T cells, TEGs, immune cells that dampen autoimmunity.
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  SPEAKER_00: Normally, young T cells that see self-antigens in a friendly context can become tregs and help keep autoreactive cells in check.
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  SPEAKER_00: Santa Maria and colleagues highlight that successful tolerance therapies often work by de novogeneration of inducible regulatory T cell types.
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  SPEAKER_00: In practice, this might mean injecting tolerizing HSP peptides together with immune modulating signals, like certain antibodies or nanoparticles, that skew the response toward tregs.
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  SPEAKER_00: There are even ideas to engineer a patient's own immune cells, for example, expanding their HSP-specific tregs in the lab and re-infusing them back.
• 7:44
  SPEAKER_00: Antigen-specific immunotherapy covers a range of such approaches.
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  SPEAKER_00: One concept is to attach HSP peptides to inert carriers, like red blood cells or nanoparticles, that present the antigen without cost stimulatory signals, promoting tolerance.
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  SPEAKER_00: Another is to give a cocktail of glaucoma-related antigens, HSP peptides plus other eye proteins under very controlled conditions, hoping to reset the immune balance.
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  SPEAKER_00: Clinical trials and other neurodegenerative or autoimmune diseases, e.g., multiple sclerosis diabetes, have tested similar peptide vaccines.
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  SPEAKER_00: While none are yet approved for glaucoma, the principle is being actively researched.
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  SPEAKER_00: Safety concerns and monitoring.
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  SPEAKER_00: Any immune-based therapy must be approached with caution.
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  SPEAKER_00: Stimulating or altering the immune system carries risks.
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  SPEAKER_00: A major concern is anaphylaxis, a severe allergic reaction.
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  SPEAKER_00: History with peptide therapies shows that if a patient already has a strong immune memory against an antigen, injecting that antigen can trigger dangerous allergy.
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  SPEAKER_00: In rodent models of autoimmunity, systemic injection of self-peptides after disease onset sometimes caused fatal anaphylaxis.
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  SPEAKER_00: For example, in experimental multiple sclerosis, EAE studies, wild-type peptides given late in disease led to deaths.
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  SPEAKER_00: Researchers have had to engineer altered peptide ligands that remove antibody binding sites to avoid this, as in Leech et al.
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  SPEAKER_00: 2007.
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  SPEAKER_00: Similar cautions would apply if trying HSP peptide therapy in glaucoma.
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  SPEAKER_00: There is also the general risk of infection or other immune suppression if regulatory cells are overactivated.
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  SPEAKER_00: Any new treatment would need close monitoring.
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  SPEAKER_00: To track whether immune modulation is working, researchers would monitor biomarkers of the immune response.
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  SPEAKER_00: Possible biomarkers include blood or eye fluid levels of autoantibodies against HSPs, ratios of regulatory to affector T cells, and cytokine levels.
• 9:42
  SPEAKER_00: For instance, a successful tolerizing therapy might reduce harmful anti-HSP antibody titers and increase anti-inflammatory markers like IL-10.
• 9:52
  SPEAKER_00: In animal studies of autoimmune glaucoma, scientists have identified molecular markers of disease, complement components, C1Q, inflammatory cytokines IL18, and chemokines CXCL10 are upregulated in the eye after immune attack.
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  SPEAKER_00: If a therapy is effective, these should return toward normal.
• 10:11
  SPEAKER_00: Clinically, physicians could measure some of these in the aqueous humor or blood.
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  SPEAKER_00: Optical nerve imaging or electrophysiology might also be used to indirectly gauge immune activity.
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  SPEAKER_00: For example, activated microglia can sometimes be imaged with special dyes.
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  SPEAKER_00: In short, successful immune therapies should show changes in both immune markers and in the retinal nerve health over time.
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  SPEAKER_00: Conclusion: In summary, a growing body of evidence links T cell reactivity to HSP peptides with the nerve damage seen in some forms of glaucoma.
• 10:44
  SPEAKER_00: Animal models show that immunizing with HSP27 or HSP60 can by itself produce glaucoma-like degeneration, and many glaucoma patients have antibodies and T cell responses against these same proteins.
• 10:58
  SPEAKER_00: The most likely mechanisms are molecular mimicry, misguided cross-reactions, and activation of innate immune cells in the optic nerve head, glia, that respond to HSP stress signals.
• 11:09
  SPEAKER_00: To counter this, new antigen-specific therapies aim to retrain the immune system, for example, by administering HSP peptides in a tolerogenic form to boost regulatory T cells.
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  SPEAKER_00: These strategies are promising, but still experimental.
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  SPEAKER_00: Safety, especially allergy, and careful monitoring of immune markers are critical.
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  SPEAKER_00: If successful, such approaches could add an important tool to slow or prevent glaucomatous injury in patients whose disease has an autoimmune component, complementing pressure lowering treatments.
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  SPEAKER_00: All links to sources are available in the text version of this article.
• 11:46
  SPEAKER_00: You can find the full article at VisualFieldTest.com.
• 11:50
  SPEAKER_00: Thanks for listening.
• 11:51
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.