Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

GLAUCOMA AND AUTOIMMUNITY

The relationship of glaucoma and the immune system has been the subject of recent investigation. Wax (20) has provided laboratory evidence supporting the possibility that an autoimmune mechanism may underlie glaucomatous optic atrophy. He noted that small heat shock antibodies, or immune mimicry mechanism to rhodospsin antibodies, may cause optic nerve damage. Tezel and Wax (21) noted that the production of tumor necrosis factor-alpha (TNF- ) increased when glial cells were exposed to a simulated ischemia condition or elevated hydrostatic pressure. It has also been shown that serum autoantibodies to optic nerve head glycosaminoglycans and serum autoantibodies against glutathione-S transfers may increase in patients with glaucoma (22,23). It has become evident that many disease processes, including autoimmunity and cancer, can be caused by deregulation of the apoptotic process (24), which may also be true in at least some forms of glaucoma. The role of the immune system in glaucoma is likely one of surveillance, in which signal pathways of the immune system regulate cell death in response to conditions that stress retinal neurons. These might include mechanical stress from high IOP, ischemia, and excessive excitatory amino acid, glutamate.

GLAUCOMA AND CYTOKINES

Cytokine is the general term for a large group of molecules involved in signaling between cells during the immune response. An increasingly well-defined chain of protein–protein recognition events ties the binding of a cytokine at the cell surface to initiate a downstream signaling cascade and induce the actions of diverse transcription factors inside the nucleus. Consequently, we investigated the roles of some genes related to the immune system in OAG and found some useful markers for predicting OAG in Chinese populations. These include interleukin-1-beta (IL-1 ) exon 5, TNF-

-308 , transporter associated with antigen processing 1–1 (TAP1-1) codon 333, and

TAP1-2 codon 637 gene polymorphism.

GLAUCOMA AND INTERLEUKIN-1

IL-1, one of the most potent pro-inflammatory agents, is important in transmitting between cells as inflammatory reactions develop. In the initial stages, IL-1 may be released from cells of the tissue where the inflammatory reaction is occurring. IL-1 receptor antagonist (IL-1 Ra) plays a role as an important regulator of inflammation. IL-1 Ra is the natural competitive inhibitor of IL-1, which acts by occupying the IL-1 cell surface receptor without bringing out cell signal (25). The IL-1 Ra gene has been mapped to the long arm of chromosome 2 (q14-q21). There are five polymorphic site tandem repeat polymorphisms (VNTRs) in intron 2 and four single nucleotide polymorphisms, including one in exon 2. These IL-1 Ra gene polymorphisms have been associated with altered production rates of IL-1Ra protein (26,27). IL-1 can activate the membrane of the MPK, resulting in increased binding of the transcription factors AP-1, NFkB and NFIL-6 to DNA (28). The genes of IL-1 are located on chromosome 2, in close linkage with another gene of the IL-1 gene family. Among the polymorphisms in IL-1 and IL-1 Ra, IL-1 exon 5 gene polymorphism is the only meaningful marker for OAG patients in our Chinese population. The distribution of the

IL-1 exon 5 polymorphism between our OAG patients and controls is significantly different. The E2 allele of IL-1 exon 5 is more frequently found in OAG patients than in healthy patients. The distribution of the other polymorphisms in IL-1 and IL-1 Ra is not significantly different between the two groups. Although this exonic polymorphisms in IL-1 does not alter the encoded amino acid sequence, the gene of IL-1 exon 5 is located on chromosome 2, in close linkage with the IL-1 Ra gene (29). Hence, linkage disequilibrium of the genes during recombination may be one of the mechanisms of glaucomatous damage. IL-1 is a key mediator of immune and inflammatory responses and is considered to be extraordinarily potent, as a very low level of binding to the signal, IL-1 receptor, is sufficient to elicit a full response (30). IL-1 can act directly to mediate a number of cellular responses, including production of IL-1, and also serve to amplify the activity of the immune system. The E2 allele of IL-1 exon 5 is a useful marker in the search for the genetic basis of glaucoma mechanisms in Chinese OAG patients.

GLAUCOMA AND TUMOR NECROSIS FACTOR-ALPHA

TNFhas been shown to be a component of astroglial activation, with apparent up-regulation in the glaucomatous optic nerve head (31). The same researchers believe that TNFcontributes to the progression of optic nerve degeneration in glaucoma both by a direct effect on the axons of the RGCs and by inducing NOS-2 in astrocytes (31). In addition, glial cells have been found to secrete TNFas well as other noxious agents, such as nitric oxide, after exposure to stress (32). It has also been noted that apoptosis of RGCs can be attenuated by neutralized antibodies against TNF- (32). The expression of TNFmay play an important role in the progression of glaucomatous optic neuropathy (33). Our study reveals that the distribution of TNF--308 gene polymorphism is significantly higher in the OAG patients than in the control group and that the A−308 allele appears to be associated with OAG, providing a possible genetic marker for the disease OAG in our Chinese patients (34). A−308may influence the susceptibility of OAG by way of immune effects. Moreover, TNF A−308 may be involved in the formation of the disease through a complex pathway, such as a change from signal transduction between cells and then changes the function of transformation (35). The A−308 allele locates at TNFpromoter and it affects the binding of transcription factors and increases transcription promoter activity, which may further alter the TNF production, the immune response, and susceptibility to diseases (36). TNF - -308 polymorphism is a useful marker for Chinese OAG patients and also may provide a novel therapeutic target for neuro-protection in the treatment of glaucomatous optic neuropathy.

GLAUCOMA AND TRANSPORT OF ANTIGENIC PEPTIDES

The transport of antigenic peptides from the cytosol to the lumen of the endoplasmic reticulum (ER) is an essential process for presentation of the antigen to cytotoxic T- lymphocytes. The transporter associated with antigen processing (TAP) is responsible for the intracellular translocation of peptides across ER membrane (37). The TAP complex (TAP1 and TAP2) is the trans-membrane transporter for degraded peptide

fragments from the cytoplasm into the ER (38). It functions during the loading of peptides onto partially folded major histocompatability complex class I (MHC I) (39). TAP gene polymorphisms have been known since the discovery of genes (40). Each of the two dimorphic sites in the TAP1 gene encodes one of two possible amino acids. One of the four dimorphic sites in the TAP2 gene encodes a transition that creates a premature stop codon. Each of the other three remaining sites also encodes two possible amino acids. TAP gene polymorphisms are believed to cause alterations in the peptide processing pathway, selecting the peptide by its size and amino acid sequence (41–44). Consequently, TAP genes are considered to be candidate-genetic markers for disease susceptibility.

TAP1-1 and TAP1-2 play important roles in the immune system, possibly by way of post-transcriptional effects and disequilibrium of TAP1-1 and TAP1-2 gene polymorphisms. In our study, we found that TAP1-1 and TAP1-2 are genetic markers of OAG. Among the polymorphisms of TAP1-1, there is a significant difference between “GG” homozygote and the “GA” heterozygote of TAP1-1 codon 333 (45). In TAP1-2 codon 637, there is also a significant difference between “GG” homozygote and “GA” heterozygote and between “GG” homozygote and “AA” homozygote (45). Therefore, TAP1-1 codon 333 and TAP1-2 codon 637 gene polymorphisms are considered to be genetic markers of OAG. The prevalence of the TAP1-1 and TAP1-2 “GG” homozygote is between OAG patients and normal controls although the alleles of the both TAP genes revealed no significant differences between the two groups. TAP1-1 and TAP1- 2 “GG” homozygote are, therefore, useful genetic markers for OAG in a Chinese population (45).

Although TAP is closely related to human diseases (46), there is little known about the associated phenotypia. The homozygous TAP1-2 siblings of one family had reduced expression of MHC class I molecules on the cell surface and reduced amounts of cytotoxic T-lymphocytes. However, these people did not show an increased susceptibility to infections. In some tumor tissues, a down-regulation of TAP mRNA by either a mutation of TAP or an unknown mechanism was observed, and the suppression of TAP may be a mechanism by which tumor cells escape the immune response (47). Both TAP genes are up-regulated 10-fold within 24 h of exposure to interferon, which is accompanied by an increased peptide transport capacity. The TAP genes do not contain TATA box motifs in the 5´-flanking sequences, but they do contain putative GC-rich elements (Sp1-binding sites, 128 nucleotides upstream of the translation start codon for TAP1-1, and 79 nucleotides upstream for TAP1-2) (48). Site-directed mutagenesis of the Sp1-binding site leads to a threefold reduction of basal promoter activity of TAP1 (49). Both TAP1-1 and TAP1-2 genes are induced by TNFthrough an NF-B element, which is also found in the class I response element (50). The cytokine-induced expression of TAP1 and LMP2 concordantly with class I genes suggests a mechanism that links transporter levels with class I production. The immune system acts as an arbiter to help determine whether a neuronal cell under stress will survive or succumb to injuries (20–23).

Autoantibodies to protein in the retina or optic nerve may contribute to glaucomatous optic neuropathy (20–23), with direct response to the autoantibodies or indirectly by way of a “mimicry” autoimmune response to a sensitizing antigen (20). Many reports

have implicated a causative role of autoantibodies in a variety of neuropathies, including multiple sclerosis, myasthenia gravis, and Guillain–Barre, whereby autoantibodies to specific neural targets have been found to impair physiologic neural function. An understanding of immune-regulated neuronal cell death may provide insight into why lowering IOP, the mainstay of glaucoma treatment, is ineffective in halting glaucomatous progression in some patients. The immune system may influence whether RGCs will survive or undergo apoptosis in response to stress (20–23).

GLAUCOMA AND TISSUE MORPHOGENESIS

Morphogenesis is the process by which cells become organized into distinctive structures and histological patterns in the tissues and organs of the body. It has been postulated that aberrant morphogenetic processes play fundamental roles in the cellular basis of many diseases, with cell adhesion being a fundamental determinant of tissue morphogenesis (51–54). For example, cadherins (CDHs), which comprise a large family of Ca2+-dependent, homophilic cell–cell adhesion molecules, are essential for morphogenic movement and tissue formation during development and for the maintenance of tissue integrity in the adult organism (55–57). The CDH family comprises a large superfamily of cell-surface glyoproteins that have in common a repeated 110- amino-acid subdomain (called the “cadherin” domain) in their extracellular region (51). CDH-based adhesion is responsible for physiological regulation of CDHs by aberrant function of the signaling pathways. E-cadherin (E-CDH) is closely related to matrix metalloproteinases (MMPs), which is involved in the outflow of aqueous humor in the trabecular meshwork. Recently, MMPs have also attracted attention in the IOP-lowering mechanism of prostaglandin analog eye drugs (58) by increasing the uveoscleral outflow (59). These drugs stimulate prostaglandin F-2 receptors upregulating MMP enzymes, thereby reducing extracellular matrix collagen within the longitudinal ciliary muscle, which enhances uveoscleral outflow (59). The disorganization of E-CDH complexes and the expression of MMPs are frequently involved in the mechanism of tissue disruption. When a critical level of IOP causes deformation of the lamina cribrosa, RGC axons are distorted and compressed, eventually causing axonal death. The MMP/E-CDH ratio is a significant independent causative risk factor of many diseases (60,61), and the expression in the lamina cribrosa may be important in the mechanism of glaucomatous optic neuropathy. Therefore, we chose E-CDH as a candidate gene, and we found that there is a significant difference in the distribution of the E-CDH gene 3-UTR C/T polymorphism between persons with OAG and normal controls (62). It has been proposed that the E-CDH 3´-UTR sequence may trigger mRNA instability and down-regulation of E-CDH in mesenchymal tumor cells (63). In our study, the distribution of C allele and CC homozygote of E-CDH gene –3´-UTR C/T polymorphism was significantly higher in the OAG group than in the normal control group, positioning the “CC” genotype as a useful marker for OAG in a Chinese population (62). Our understanding of the E-CDH gene 3´-UTR is limited, but there are many examples that 3´-UTR may change the expression of genes. One example is p53 3´-UTR, which contains an Alu-like repetitive element and a deletion of the distal end of the p53 3´-UTR and increases the efficiency of translation (64). 3´- UTR is also critical for cAMP-mediated Na(+)-coupled glucose co-transporter SGLT1

message stabilization (65). The exact role of “C” allele of E-CDH gene –3´-UTR gene polymorphism needs to be resolved by further studies.

GLAUCOMA AND OXIDATIVE STRESS

Association of Glaucoma and Nitric Oxide and Myeloperoxidase

The influence of superoxide on RGCs and outflow system has been the focus of considerable study in recent years. It has recently been demonstrated that an anti-oxidative agent complements the protective effect of brain-derived neurotrophins against elevated IOP-induced ganglion cell damage, suggesting a potential role of oxidation in retinal toxicity (66,67). Nitric oxide (NO) is an active biological agent involved in the regulation of diverse physiological and pathological processes. It is synthesized from the amino acid l-Arg by NO synthase (NOS). In the eye, NO regulates the baseline ocular blood flow rate in response to physiological stress, and suppression of NO production reduces the choroidal blood flow (68,69). A number of studies have indirectly shown that ocular NOS activity may increase under physiological stress such as ischemia and IOP elevation (70,71). It has also been proposed that total NO in the retina is consistently higher in eyes with either well-controlled or elevated IOP, suggesting that the retina may be subjected to a significant risk of oxidative damage (72,73). NO can autoxidize to nitrite (NO2−) and nitrate (NO3−) (74). NO2− is a substrate for myeloperoxidase (MPO), a hematologic enzyme secreted by activated phagocytes, which may also be involved in tyrosine nitration (75). MPO is an abundant enzyme, involved in the production of free radicals by reaction of hydrogen peroxide (H2O2) and NO2− to generate reactive nitrogen species, and is reduced by nitrate tyrosyl in vitro (75,76). Recently, an important functional SNP has been identified in the promoter region of the MPO-463 gene, consisting of a G to A substitution. Previous studies have demonstrated that the G allele (in contrast to the A allele) creates a strong SP1 binding site, which correlates with a 25-fold enhancement of the gene transcription activity (77). Although superoxide may be related to glaucoma, with NOS and MPO as two important enzymes in the free radical pathway, our study showed no significant difference in the distribution of polymorphisms in NOS and MPO between OAG patients and controls (78).

Glaucoma and Insulin-Like Growth Factors

It has been noted that insulin-like growth factors (IGFs) have the ability to limit neuronal damage elicited by experimental hypoxia–ischemia conditions, with one possible mechanism being limitation of free radical generation (79–81). IGFs promote neurite outgrowth and are transported retrograde from muscle to nerve cell body in vivo (79,81–83). Pharmacological depletion of endogenous target-derived IGFs in vivo reduces neuron survival by up to 30% (82). IGFs are one of the important neurontrophic factors, and administration of IGFs increases nerve cell survival in vivo during naturally occurring neuron death (82–84). IGFs mRNA also increases during some tissue differentiation (84,85). IGF-II gene expression is higher in brain and spinal cord than in other tissues of the adult rat (86) and is closely correlated with the development of neural synapses (86). The local administration of IGFs increases the regeneration

rate of motor and sensory nerves in rats, whereas anti-IGFs antiserum decreases the regeneration rate. Physiological concentrations of these ligands can enhance neurite formation by acting directly on cultured sensory (87), sympathetic (88), and motor neurons (88).

Among the polymorphisms in IGF, the distribution of the IGF-II exon 9 Apa I C/T gene polymorphism showed statistical differences in the distribution of genotype frequencies between OAG patients and normal controls (89). IGF-II may be a factor in the pathogenesis of OAG. It has been noted that the action of IGF-II does not act in a cell-cycle-specific manner but instead acts by recruiting quiescent cells into G1 (90). In one study, the programmed cell death induced by serum deprivation has been shown to be reversible by simultaneous addition of IGF-II (91). The IGF-II receptor, is a single-chain transmembrane glycoprotein, also known as the cation-independent mannose d-phosphate receptor, and is involved in transport of lysosomal enzymes. A number of studies have indicated that this receptor modulates IGF-II action by removing the growth factor from the extracellular environment (92–94).

Endogenous IGF-II functions as a critical survival factor during the transition from proliferation to the differentiation in some cells. In this study, IGF-II proved a useful genetic marker for OAG. Because glaucomatous optic neuropathy is a type of apoptosis and IGF-II is closely related to the pathway of apoptosis and nerve protection, we suspected that IGF-II may play a role in the regulation of apoptosis in the optic nerve. The GG genotype of IGF-II may change the apoptotic state in the optic nerve when it is under stress, as with an increase in IOP, ischemia sign, or toxic levels of amino acids (e.g., glutamate). Consequently, the C/C homozygote of IGF-II exon 9 Apa I C/T gene polymorphism may be a useful marker of OAG in a Chinese population.

SUMMARY

SNPs are known to play important roles in the development of many diseases, and subsets occur within protein-coding sequences that allow specific SNP alleles to help identify causative factors in human genetic disorders. In our studies, described in this chapter, we found SNPs in apoptosis-related gene (p53), two cytokine genes (E2 allele of IL-1 exon 5 and TNF- -308), two immune-related genes (TAP1-1 codon 333 and TAP1-2 codon 637) and in the oxidative stress and neurotrophic-related gene (IGF-II). Although these may be useful makers for OAG, we do not mean to imply that these SNPS are direct causes in the mechanisms of glaucoma but rather are associated with the causative factors. Other factors, in addition to genetic influences, may include environmental influences and post-translation protein interactions. In addition, it should be noted that, while our studies were performed within Chinese populations, the findings may have broader implications for other ethnic groups, pending further study.

Our understanding of gene polymorphisms will continue to be advanced through studies such as “proteomics,” in which post-translated products of the gene and the protein–protein interaction of the gene-related proteins are clarified. Knowing the genetic basis of various forms of glaucoma is important in understanding the course of the disease and in predicting the susceptibility of glaucoma in individuals. Hopefully, potential IOP-independent neuroprotective agents and new treatments for glaucomatous optic neuropathy will result from the continued study of genetics in glaucoma.

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