514
Correspondence / Medical Hypotheses 83 (2014) 509–515
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA ⇑ Address: Slone Epidemiology Center at Boston University, 1010 Commonwealth Avenue, Boston, MA 02215, USA.
Tel.: +1 617 734 6006; fax: +1 617 738 5119. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.08.017
Primary open-angle glaucoma: Neuroendocrine–immune disorder? Ting Zhang ⇑, Xuelu Xie⇑, Fang Lu ⇑ Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
a r t i c l e
i n f o
Article history: Received 13 August 2013 Accepted 11 August 2014
a b s t r a c t Glaucoma is no longer simply viewed as a pathological process involving damage to the visual system by an elevated intraocular pressure (IOP). Mounting evidence suggests that primary open-angle glaucoma (POAG) may be associated with systemic disorders, mainly those related to the nervous system, endocrine system and immune system. It has been firmly established that the neuroendocrine system and immune system closely interact through mediators such as hormones, neuropeptides, neurotransmitters and cytokines. The neuroendocrine–immune system can synthesize and release these molecules, which in turn affect the activity of immune or neuroendocrine cells by binding to their receptors. In POAG patients, the alterations of the nervous, endocrine and immune systems observed in various studies have been linked to their POAG. Here, we hypothesize that the onset and development of POAG is closely associated with abnormalities in neuroendocrine–immune communication; thus, the interrupted homeostatic state might have a significant influence on the course of the disease. Based on the effects on the secretions of the aqueous humor, the inflow/outflow pathways of the neuroendocrine system, and the survival of retinal ganglion cells (RGCs) in the immune system, we propose that POAG is likely to be a consequence of a neuroendocrine–immune system disorder. Ó 2014 Elsevier Ltd. All rights reserved.
Primary open-angle glaucoma (POAG) is an irreversible optic neuropathy characterized by a progressive loss of retinal ganglion cells (RGCs) and an open anterior chamber angle. The intraocular pressure (IOP) is usually but not always elevated. It is the most common form of several types of glaucoma, affecting an estimated 44.7 million people worldwide in 2010 [1]. Although the pathogenesis of POAG is still unclear, a variety of hypotheses have been developed to elucidate its pathological mechanism. In the pressure-mechanic theory, pressure compresses the axons and thus results in the loss of the neurotrophic support of the RGCs [2,3]. However, this theory fails to explain why the damage to the visual field progresses even when the IOP is controlled within a normal range. Alternatively, the vascular theory, based on the hypothesis of a reduction in the ocular blood flow [4], claims to explain the progression of POAG while failing to illustrate the important role of IOP in the development of high tension glaucoma. Additionally, it has been suggested that glaucomatous damage is the pathological consequence of oxidative stress [5,6]; however, the evidence for this phenomenon is not extensive or clear. We propose that POAG is not only a pathological process involving the visual system, but it is also a disorder of the neuroendocrine–immune system.
⇑ Address: 37 Guoxue Lane, Wuhou District, Chengdu 610041, China. Tel.: +86 13882212851 (T. Zhang), +86 18011305951 (X. Xie), +86 18980602062 (F. Lu). E-mail addresses: [email protected] (T. Zhang), [email protected] (X. Xie), [email protected] (F. Lu)
There is accumulating evidence that POAG may be associated with systemic dysfunctions, such as disorders of the nervous system, endocrine system, immune system, and cardiovascular system, as well as psychological disturbances [7]. It is well established that elaborate anatomical and functional interactions exist between the central nervous system, endocrine system and immune system. Neuroendocrine–immune interactions are disrupted in many diseases, including depression, diabetes mellitus, cancer, hypertension, and autoimmune disease. A large amount of neurotransmitters, hormones, cytokines and other molecules act as a common chemical language for communication within and between the neuroendocrine and immune systems [8]. The ciliary epithelium (CE), the site of aqueous humor secretion in the mammalian eye, is believed to have a key function in the signaling mechanisms that regulate the rate of secretion. Coca-Prados and Escribano suggested that the ciliary body is a multifunctional neuroendocrine gland and neuropeptides released into the aqueous humor by the CE can serve as important signaling molecules [9]. The immune system, the body’s defense mechanism, has been considered to influence the ability of the retina and optic nerve to fight off ischemic and glaucomatous injuries [10]. It is believed that an immune response to the degeneration of the optic nerve may cause a secondary degeneration of the RGCs around the initially degenerated neurons. The regulation of the immune system plays a key role in deciding the fate of RGCs and may lead to glaucomatous optic nerve degeneration. Because a reciprocal regulatory system exists among these systems, any interruptions to the regulatory loop of one system will affect the others.
Correspondence / Medical Hypotheses 83 (2014) 509–515
Our hypothesis suggests that neuroendocrine–immune disorder may play a vital role in the pathogenesis and progression of POAG. Through the effects on the secretions of the aqueous humor, the inflow/outflow pathways by the neuroendocrine system, and survival of RGCs by the immune system, POAG is most likely the consequence of a neuroendocrine–immune system disorder. A better understanding of the relevance of the neuroendocrine–immune system and POAG will lead to novel treatment strategies for POAG. Of course, further experimental and clinical studies are needed to investigate the mechanisms of inter-system communication in POAG patients. Conflict of interest
[4] Flammer J. The vascular concept of glaucoma. Surv Ophthalmol 1994;38:S3–6. [5] Saccà SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol 2005;123:458–63. [6] Tezel G, Yang X, Luo C, Peng Y, Sun SL, Sun D. Mechanisms of immune system activation in glaucoma: oxidative stress-stimulated antigen presentation by the retina and optic nerve head glia. Invest Ophthalmol Vis Sci 2007;48:705–14. [7] Pache M, Flammer J. A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma. Surv Ophthalmol 2006;51(3). 179-12. [8] Mašek K, Slánsky´ J, Petrovicky´ P, Hadden JW. Neuroendocrine immune interactions in health and disease. Int Immunopharmacol 2003;3:1235–46. [9] Coca-Prados M, Escribano J. New perspectives in aqueous humor secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog Retin Eye Res 2007;26(3):239–62. [10] Tezel G, Wax MB. The immune system and glaucoma. Curr Opin Ophthalmol 2004;15:80–4.
The authors declare no conflicts of interest. http://dx.doi.org/10.1016/j.mehy.2014.08.017
References [1] Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3):262–7. [2] Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res 1999;18:39–57. [3] Ko ML, Hu DN, Ritch R, Sharma SC, Chen CF. Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 2001;305:139–42.
515
Correspondence / Medical Hypotheses 83 (2014) 509–515
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA ⇑ Address: Slone Epidemiology Center at Boston University, 1010 Commonwealth Avenue, Boston, MA 02215, USA.
Tel.: +1 617 734 6006; fax: +1 617 738 5119. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.08.017
Primary open-angle glaucoma: Neuroendocrine–immune disorder? Ting Zhang ⇑, Xuelu Xie⇑, Fang Lu ⇑ Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
a r t i c l e
i n f o
Article history: Received 13 August 2013 Accepted 11 August 2014
a b s t r a c t Glaucoma is no longer simply viewed as a pathological process involving damage to the visual system by an elevated intraocular pressure (IOP). Mounting evidence suggests that primary open-angle glaucoma (POAG) may be associated with systemic disorders, mainly those related to the nervous system, endocrine system and immune system. It has been firmly established that the neuroendocrine system and immune system closely interact through mediators such as hormones, neuropeptides, neurotransmitters and cytokines. The neuroendocrine–immune system can synthesize and release these molecules, which in turn affect the activity of immune or neuroendocrine cells by binding to their receptors. In POAG patients, the alterations of the nervous, endocrine and immune systems observed in various studies have been linked to their POAG. Here, we hypothesize that the onset and development of POAG is closely associated with abnormalities in neuroendocrine–immune communication; thus, the interrupted homeostatic state might have a significant influence on the course of the disease. Based on the effects on the secretions of the aqueous humor, the inflow/outflow pathways of the neuroendocrine system, and the survival of retinal ganglion cells (RGCs) in the immune system, we propose that POAG is likely to be a consequence of a neuroendocrine–immune system disorder. Ó 2014 Elsevier Ltd. All rights reserved.
Primary open-angle glaucoma (POAG) is an irreversible optic neuropathy characterized by a progressive loss of retinal ganglion cells (RGCs) and an open anterior chamber angle. The intraocular pressure (IOP) is usually but not always elevated. It is the most common form of several types of glaucoma, affecting an estimated 44.7 million people worldwide in 2010 [1]. Although the pathogenesis of POAG is still unclear, a variety of hypotheses have been developed to elucidate its pathological mechanism. In the pressure-mechanic theory, pressure compresses the axons and thus results in the loss of the neurotrophic support of the RGCs [2,3]. However, this theory fails to explain why the damage to the visual field progresses even when the IOP is controlled within a normal range. Alternatively, the vascular theory, based on the hypothesis of a reduction in the ocular blood flow [4], claims to explain the progression of POAG while failing to illustrate the important role of IOP in the development of high tension glaucoma. Additionally, it has been suggested that glaucomatous damage is the pathological consequence of oxidative stress [5,6]; however, the evidence for this phenomenon is not extensive or clear. We propose that POAG is not only a pathological process involving the visual system, but it is also a disorder of the neuroendocrine–immune system.
⇑ Address: 37 Guoxue Lane, Wuhou District, Chengdu 610041, China. Tel.: +86 13882212851 (T. Zhang), +86 18011305951 (X. Xie), +86 18980602062 (F. Lu). E-mail addresses: [email protected] (T. Zhang), [email protected] (X. Xie), [email protected] (F. Lu)
There is accumulating evidence that POAG may be associated with systemic dysfunctions, such as disorders of the nervous system, endocrine system, immune system, and cardiovascular system, as well as psychological disturbances [7]. It is well established that elaborate anatomical and functional interactions exist between the central nervous system, endocrine system and immune system. Neuroendocrine–immune interactions are disrupted in many diseases, including depression, diabetes mellitus, cancer, hypertension, and autoimmune disease. A large amount of neurotransmitters, hormones, cytokines and other molecules act as a common chemical language for communication within and between the neuroendocrine and immune systems [8]. The ciliary epithelium (CE), the site of aqueous humor secretion in the mammalian eye, is believed to have a key function in the signaling mechanisms that regulate the rate of secretion. Coca-Prados and Escribano suggested that the ciliary body is a multifunctional neuroendocrine gland and neuropeptides released into the aqueous humor by the CE can serve as important signaling molecules [9]. The immune system, the body’s defense mechanism, has been considered to influence the ability of the retina and optic nerve to fight off ischemic and glaucomatous injuries [10]. It is believed that an immune response to the degeneration of the optic nerve may cause a secondary degeneration of the RGCs around the initially degenerated neurons. The regulation of the immune system plays a key role in deciding the fate of RGCs and may lead to glaucomatous optic nerve degeneration. Because a reciprocal regulatory system exists among these systems, any interruptions to the regulatory loop of one system will affect the others.
Correspondence / Medical Hypotheses 83 (2014) 509–515
Our hypothesis suggests that neuroendocrine–immune disorder may play a vital role in the pathogenesis and progression of POAG. Through the effects on the secretions of the aqueous humor, the inflow/outflow pathways by the neuroendocrine system, and survival of RGCs by the immune system, POAG is most likely the consequence of a neuroendocrine–immune system disorder. A better understanding of the relevance of the neuroendocrine–immune system and POAG will lead to novel treatment strategies for POAG. Of course, further experimental and clinical studies are needed to investigate the mechanisms of inter-system communication in POAG patients. Conflict of interest
[4] Flammer J. The vascular concept of glaucoma. Surv Ophthalmol 1994;38:S3–6. [5] Saccà SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol 2005;123:458–63. [6] Tezel G, Yang X, Luo C, Peng Y, Sun SL, Sun D. Mechanisms of immune system activation in glaucoma: oxidative stress-stimulated antigen presentation by the retina and optic nerve head glia. Invest Ophthalmol Vis Sci 2007;48:705–14. [7] Pache M, Flammer J. A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma. Surv Ophthalmol 2006;51(3). 179-12. [8] Mašek K, Slánsky´ J, Petrovicky´ P, Hadden JW. Neuroendocrine immune interactions in health and disease. Int Immunopharmacol 2003;3:1235–46. [9] Coca-Prados M, Escribano J. New perspectives in aqueous humor secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog Retin Eye Res 2007;26(3):239–62. [10] Tezel G, Wax MB. The immune system and glaucoma. Curr Opin Ophthalmol 2004;15:80–4.
The authors declare no conflicts of interest. http://dx.doi.org/10.1016/j.mehy.2014.08.017
References [1] Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3):262–7. [2] Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res 1999;18:39–57. [3] Ko ML, Hu DN, Ritch R, Sharma SC, Chen CF. Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 2001;305:139–42.
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