Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008

lymphocytes recognize and bind only the activated antigen. Binding the antigen is necessary, but not enough to activate the lymphocytes. A second signal, coming from other cells, is also needed. For B cells, the second signal comes from T cells. For T cells, the second signal, known as costimulation, can be produced by three different types of cells: B lymphocytes, macrophages, and dendritic cells. B lymphocytes recognize the antigens that they find outside the cells and, once activated, produce specific antibodies against the antigen responsible for activation. T cells manage to recognize antigens generated inside cells to determine a different immune response, called cell-mediated. Once the development and maturation of T cells in the thymus is complete, they enter the bloodstream, migrate to the peripheral lymphatic organs and return to the bloodstream until they meet the antigen. To take part in the acquired immune response, the nonactivated or natïve T cells must first be induced to proliferate and then differentiate in cells capable of contributing in the removal of pathogens. These cells are called effectors-armed T cells. These can be divided in three groups: T cytotoxic cells, lymphocytes (CD8+) that kill the infected cells, and the inflammatory T cells (CD4+ [T helper 2]) that, by secreting IL-4, IL-5, IL-6, andIL-10, activate antigen-specific B lymphocytes that produce antibodies.12 Following an inflammatory process caused by viral or bacterial infections, or damage through injury or altered functionality or complement activation, the lymphocytes accumulate in the inflammatory sites and release cytokines that regulate the time and amplitude of the inflammatory-immune mediated response. In this manner, they destroy intracellular pathogens by killing infected cells and by activating macrophages, but also by destroying extra cellular pathogens through the activation of B cells.13

Macrophages

Macrophages are cells with phagocytic activity, coming from the transformation of circulating monocytes. The macrophage is located in various tissues: the liver (Kupffer cells), connective tissue (histiocytes), and nervous tissue (microglia). In the case of destructive or necrotic tissue lesions, the macrophages appear in about 48 hours. These cells come partially from tissue macrophages, but most come from mononuclear cells in the bloodstream. When a macrophage finds the pathogenic agent, it consumes and destroys it. Macrophages release lysosomal enzymes in the phlogistic sites. During phagocytosis, lysosomal enzymes are released in the extra cellular area and, thanks to the wide spectrum of their enzymatic activity, they can degrade a vast gamma of biological substrates, among which are the various components of connective tissue. Among the lysosomal components of phagocytosis, lactoferrin plays a triple role: this protein, together with bacteriostatic activity, increases the function of NK lymphocytes and promotes the production of cytokines, lysozime, A phospholipase, mieloperoxidase, and neutral proteases (serine-protease and metal protease)—all enzymes that are able to degrade the components of interstitial matrix (type IV collagen, elastin, proteoglicans). The endothelial

Fig. 7.1 Transmission electron microscopy picture of human iris. Some nerve fibers (nf), containing numerous pre-synaptic vesicles, appear in photo 1. The anterior epithelium (E) or myoepithelium in normal conditions contains numerous mobile cells. The smooth muscle cells (sm) contain numerous microfilaments (mf). The stroma (st) in aged people contains numerous electron dense substances (granules of lipofuscin, proteoglycans, etc.) (Magnification 8500x)

cells of the trabeculum are partially differentiated cells and among other functions they have macrophage activity (see Fig. 7.1, personal observation).

References

1.William D, Willis J (1995) Il sistema nervoso. In: Berne RM, Levy MN (eds.) Fisiologia. Milano, Casa Editrice Ambrosiana. p l01-117

2.Kandel E (2003) Principi di Neuroscienze. Milano, Editrice Ambrosiana, p 20-22

3.Ascenzi A (1997) Sistema nervoso. In: Ascenzi A, Mottura G (eds) Anatomia Patologica, vol. 2. Torino, UTET, p1184-1186

4.Barr M, Kiernan JA (1995) Cellule del sistema nervoso. In: Barr M, Kiernan JA (eds) Anatomia del sistema nervoso umano. McGraw-Hill, Milano, p 26-30

5.Burt AM (1996) Trattato di neuroanatomia. Piccin, Milano, p 50-52

6.Monesi V (1998) Tessuto nervoso e neuroglia. In: Monesi V (ed) Istologia. Piccin, Padova, p 830-834

7.Nobak CR, Strominger NL, Demarest RJ (1999) La neuroglia. In: Nobak CR, Strominger NL (eds) Sistema nervoso. Piccano, Milano, p 25-27

8.Fazio C et al (2003) Neuroanatomia. SEU, Roma, p 550-557

9.Vernadakis, A, (1986) Changes in astrocytes with aging. In: Federoff S, Vernadakys A (eds) Biochemistry, Physiology and Pharmacology of Astrocytes. Academic Press, Orlando, USA, p 377-407

10.Chen L, Yang P, Kijlstra A, (2002) Distribution, markers, and functions of retinal microglia. Ocul. Immunol. Inflamm. 10:27-39

11.Madigan WP, Wertz D, Cockerham GC, Thach AB (1994) Retinal detachement in ostegenesis imperfecta. J. Pediatr. Ophthalmol Strabismus 31:268-269

12.Janeway C, Travers P (1996) Immunobiologia. Piccin, Padova

13.Salerno A (1996) Le immunodeficienze. In: Pontieri M (ed) Patologia generale. Piccin, Padova p 567-612

Other Linked and Recent References

1.McMenamin PG, Holthouse I (1992) Immunohistochemical characterization of dendritic cells and macrophages in the aqueous outflow pathways of the rat eye. Exp Eye Res. August 55(2):315-24

2.Camelo S, Shanley AC, Voon AS, McMenamin PG (2004) An intravital and confocal microscopic study of the distribution of intracameral antigen in the aqueous outflow pathways and limbus of the rat eye. Exp Eye Res 79(4):455-64

3.McMenamin PG, Crewe J (1995) Endotoxin-induced uveitis. Kinetics and phenotype of the inflammatory cell infiltrate and the response of the resident tissue macrophages and dendritic cells in the iris and ciliary body. Invest Ophthalmol Vis Sci. 36(10):1949-59

4.Yang P, Das PK, Kijlstra A (2000) Localization and characterization of immunocompetent cells

in the human retina. Ocul Immunol Inflamm. 8(3):149-57

6.Butler TL, McMenamin PG (1996) Resident and infiltrating immune cells in the uveal tract in the early and late stages of experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 37(11):2195-210

7.Diaz-Araya CM, Madigan MC, Provis JM, Penfold PL (1995) Immunohistochemical and topographic studies of dendritic cells and macrophages in human fetal cornea. Invest Ophthalmol Vis Sci. 36(3):644-56

8.Becker MD, Planck SR, Crespo S, Garman K, Fleischman RJ, Dullforce P, Seitz GW, Martin TM, Parker DC, Rosenbaum JT (2003) Immunohistology of antigen-presenting cells in vivo: a novel method for serial observation of fluorescently labeled cells. Invest Ophthalmol Vis Sci. 44(5):2004-9

9.Poulter LW, Campbell DA, Munro C, Janossy G (1986) Discrimination of human macrophages and dendritic cells by means of monoclonal antibodies. Scand J Immunol. 24(3):351-7

10.Takase H, Sugita S, Rhee DJ, Imai Y, Taguchi C, Sugamoto Y, Tagawa Y,Nishihira J, Russell P, Mochizuki M (2002) The presence of macrophage migration inhibitory factor in human trabecular meshwork and its upregulatory effects on the T helper 1 cytokine. Invest Ophthalmol Vis Sci. 43(8):2691-6

11.Romeike A, Brugmann M, Drommer W (1998) Immunohistochemical studies in equine recurrent uveitis (ERU). Vet Pathol. 35(6):515-26

12.Weinstein BI, Iyer RB, Binstock JM, Hamby CV, Schwartz IS, Moy FH, Wandel T, Southren AL (1996) Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma. Exp Eye Res. 62(1):39-45

13.Ueno H, Tamai A, Iyota K, Moriki T (1989) Electron microscopic observation of the cells floating in the anterior chamber in a case of phacolytic glaucoma. Jpn J Ophthalmol. 33(1):103-13

14.Latina M, Flotte T, Crean E, Sherwood ME, Granstein RD (1988) Immunohistochemical staining of the human anterior segment. Evidence that resident cells play a role in immunologic responses. Arch Ophthalmol. 106(1):95-9

15.Lutjen-Drecoll E, Kaufman PL, Barany EH (1977) Light and electron microscopy of the anterior chamber angle structures following surgical disinsertion of the ciliary muscle in the cynomolgus monkey. Invest Ophthalmol Vis Sci. 16(3):218-25

transparent optical media and as a structural support for the outer tunics of the globe. The vitreous is one of the least cellular tissues in the body, being composed of 99 percent water and several key macromolecules.

Vitreous Composition

The two major components of mammalian vitreous are collagen and glycosaminoglycans. Collagen is the major structural macromolecule of the insoluble phase of the vitreous gel.2 Most vitreous collagen is type II, characterized by three alpha polypeptide chains twisted into a right-handed helix.3 Although vitreous collagen shares many physiochemical properties with that of type II collagen in cartilage, there are differences in their degree of hydroxylation.4 Bovine collagen of the vitreous contains significantly more hydroxylated residues of lysine and proline compared to bovine cartilage of the nasal septum.4 Lesser amounts of types V, IX and XI collagen have also been identified in mammalian vitreous.4,5,6 While their roles as nonfibrous collagen are not well understood, type IX collagen fibers appear to lie in close proximity to the surface of type II collagen fibers where they likely affect the three-dimensional interactions with glycosaminoglycans.7,8 The thin, heterotypic fibrils of type IX collagen appear to bond noncovalently to chondroitin sulfate, which in turn, may help maintain appropriate spacing between other larger collagen fibrils.9 When peptide sequences from types V and XI collagen of vitreous are compared, their close homology suggests that they are members of a single collagen family rather than distinct types of collagen.8

The network of collagen fibers in the vitreous is designed to loosely envelope soluble macromolecules collectively known as glycosaminoglycans. Hyaluronic acid, a long, unbranched polymer of repeating sugar units, is the major soluble macromolecule of the vitreous.10,11 When the carboxy groups of its gluconic acid are dissociated in solution, the macromolecule becomes a polyanion. The configuration of hyaluronic acid allows it to hold a large volume of water compared to its weight. Athough hyaluronic acid is dependent on several physical-chemical variables for its final molecular weight, its molecular weight can range upward to one million.12 Once hyaluronic acid is removed from the vitreous or destroyed, it is not replaced.

Chondroitin sulfate is the second important high molecular weight glycosaminoglycan of the vitreous. Found at lower concentrations than hyaluronic acid in most mammalian vitreous bodies, chondroitin sulfate differs from hyaluronate in its ability to covalently bind to noncollagenous core proteins.13,14 While both hydrated glycosaminoglycans create highly viscous fluids, they interact differently with their surrounding lattice of collagen fibrils.

The soluble proteins are the least well-characterized component of the vitreous, but may prove to exert considerable influence over the interaction of the larger macromolecules. In bovine vitreous, there are small amounts of albumin and globulin (between 0.4 to 0.8 g/ml). The concentration of serum proteins in the vitreous is

kept low by the blood-retinal barrier.15 While any breakdown in the blood-retinal barrier allows serum proteins to enter the vitreous with greater ease, the gel itself acts to minimize diffusion of these molecules.

Although there is limited information on how the collagen components maintain spacing to form a stable meshwork, water molecules are stabilized or trapped in the latticework of collagen by the two major glycosaminoglycans. A similar mechanism for hydrating cartilage exists, although the amount of water molecules trapped by hyaluronic acid in cartilage is much less than in vitreous.

Bos et al.16 observed three morphologically distinct types of single fibrils that form links within the fibrillar network of the vitreous. Hyaluronic acid and chondroitin sulphate aggregrate individually and with one another as they attach to collagen fibrils.17 In this way, the glycosaminoglycans create a potentially infinite meshwork in which water is entwined.14

The negatively charged hyaluronic acid interacts with the collagen lattice at specific sites along the fiber referred to as globules.18 Although there is no apparent direct attachment between the two phases of gel (soluble/insoluble), ultrastructural studies reveal an aggregation of soluble vitreous at the globular regions of the collagen fiber.19 When hyaluronic acid is enzymatically digested within the vitreous, it also destroys the thin filamentous links between the larger type II collagen fibrils, suggesting that hyaluronic acid is necessary for their integrity.15 The greatest concentration of collagen and soluble proteins exist in the vitreous cortex.

The hypocellular vitreous contains a small number of cells called hyalocytes, found predominantly in the cortex. Their overall morphology resembles a macrophage, but there is evidence that they can become functional fibroblasts.20 The life span of hyalocytes within the vitreous is relatively brief—approximately one week.11 While the function of the hyalocyte is poorly understood, researchers speculate that the cell plays an important role in intraocular homeostasis.

The loose, and seemingly fragile, vitreous gel displays an array of amazing physical properties. Its optical clarity keeps light scatter to a minimum, while its viscoelasticity offers considerable support to the lens without causing mechanical distortion of its surface. Along with the blood-brain barrier, the vitreous acts to inhibit the transgression (diffusion) of foreign macromolecules through the interior of the eye.

Vitreous Architecture

The optical transparency that allows the vitreous to effectively transmit the visible portion of the light spectrum to the retina without adsorption or scatter, also befuddles study of its gross architecture. After the introduction of the slit lamp, there have been a variety of interpretations of vitreous organization.

Based on dissections of human eyes, Eisner concluded that the vitreous consisted of concentrically packed funnels separated by delicate fibrous membranes.21 Worst used India ink to study the organization of the vitreous and found tracks or

membranes similar to those described by Eisner.22 In the process of reporting his findings, he introduced the terms cistern and bursa to describe the spaces and compartments created by these membranes.23

In a series of elegant studies using dark-field slit illumination, Seebag and Balzas showed that the vitreous contains fine fibers that run in an anterior-posterior direction and in parallel to Cloquet’s canal.24 The fibers seen by this technique probably represent packed collagen fibers caused by the exclusion of hyaluronic acid.25

The vitreous base refers to a 3-5 mm band of modified vitreous that overlaps the junction of the inner peripheral retina and ciliary body. Because the vitreous base represents the strongest adhesion between the vitreous and adjacent tissue, it plays an important role in the mechanics of several vitreo-retinal diseases. Because the ability to objectively measure the strength of an adhesion between vitreous and adjacent tissue is limited, terms used to describe the mechanical strength of adhesion need to be interpreted with caution. For the most part, the strength of vitreoretinal adhesion has been inferred from various clinical and morphological observations, and never measured directly.

Seebag dissected the vitreous body from the retina in 59 human eyes from donors aged from 33 weeks of gestation to 94 years of age.26 The vitreous gel peeled easily from the inner retina in all 44 eyes from persons older than 21 years. In six of the 15 eyes (40%) from donors under the age of 20, portions of the inner retina remained adhered to the vitreous along the temporal arcades, macula, and peripapillary retina. Electron microscopy confirmed fragments of Müller’s cells clinging to the vitreous, indicating that the strength of the bond between the vitreous and retina exceeded the intrinsic strength of the cell walls of Müller’s cells.

The method of attachment between vitreous and retina is not entirely clear, although thin collagen fibrils from the vitreous have been observed inserting into the internal limiting membrane.27,28

Aging

The molecular basis of vitreous aging is not completely understood. Central to the aging process is gel liquefaction, which, based on post-mortem studies, is a common phenomenon noted in more than 60 percent of the eyes of persons between 80 to 89 years of age.29 Between the ages of 45 and 50, a clinically detectable decline in the ratio of gel-to-liquid vitreous begins that continues through the tenth decade of life.30 In vivo observations of vitreous morphology using ultrasonography reveal that these changes begin much earlier in life. In a study of more than 400 human eyes, Oksala detected abnormal echographic reflections from the gel-liquid interface in persons with normal slit lamp examinations.31 In a large post-mortem study by Balazas and Flood, evidence of liquefaction was detected in patients as young as four years of age. The authors estimated that approximately 12 percent of vitreous is liquefied by the time the eye attains its adult size at 18 years.32 During each

decade of life, there is a further decrease in the proportion of gel to liquid. By 90 years of age, there is (on the average) more liquid volume to gel volume.26

The transition from gel to liquefaction can be either abrupt or gradual, with a proportional decline in both collagen fibers and soluble vitreous found in the transitional regions.33 In a study of 13 human eyes by light and electron microscopy, Los et al.,28 found that there are neither cellular remnants nor fragments of collagen in the transitional tissue.

The aging vitreous shows rather rapid loss of type IX collagen, along with its chondroitin sulfate side chains. Although type IX collagen is a minor component of the insoluble matrix, it may serve an important role in protecting the surface of type II collagen from exposure.34 It has been proposed that type II collagen may become less resistant to damage and more susceptible to dissolution following the loss of contiguous type IX collagen.29

Laboratory models of vitreous syneresis have shed only limited light onto the mechanism of vitreous degeneration because almost all types of injury, no matter how trivial, induce liquefaction. The introduction of almost any type of foreign substance into the vitreous initiates some degree of syneresis. One of the most potent stimuli for liquefaction is acute inflammation, from any source. Miller et al.35 injected profluoropropaine gas into the vitreous of primates, creating a large syneresis cavity. Despite the size of the cavity, the shell of residual vitreous remained intact, suggesting that size alone may not be a major factor in the development of posterior vitreous detachment.

Although the cause of age-related syneresis is uncertain, there is laboratory evidence that photodegradation of hyaluronic acid contributes to the process.36 This process may be mediated by light-induced, free-radical formation, which could damage vitreous collagen and hyaluronic acid over time.37

Detachment of the Posterior Vitreous

A variety of different conditions, from trauma to inflammation, will cause the separation of the vitreous from its posterior attachments to the surface of the retina and optic nerve. The most common underlying cause in the general population is aging and age-related syneresis of the vitreous. Like syneresis alone, spontaneous posterior vitreous detachment (PVD) is an age-related phenomenon whose fundamental biomechanisms still await clarification. The clinical importance of PVD resides in its association with retinal tears.38

The prevalence of PVD increases both with advancing age and axial length of the eye. In the era of intracapsular cataract surgery, PVD was a common sequel. Partial or complete PVD has been described in 93 percent of autopsy eyes that have undergone prior intracapsular cataract extraction.39 In a study of 61 postmortem eyes, the concentration of hyaluronic acid in the vitreous was greater in globes having no PVD than those with total PVD, although the concentration of hyaluronic acid in gel and liquefied portions of vitreous was similar.40

insoluble and soluble vitreous components is the least.46 The abrupt separation of the posterior vitreous face from the retina and optic nerve head likely occurs when a rush of liquefied vitreous pours through a rent in the cortical vitreous. Much like a small hole in a burlap sandbag, the watery vitreous rushes through the space dissecting the remaining posterior vitreous surface from the underlying retina and optic nerve. The force generated by the flow of fluid is likely great enough to break any vitreous attachments to the retina or to superficial blood vessels. A full-thickness hole could conceivably form if the force between the vitreous and retina exceeds that holding the retina to underlying pigment epithelium.

The prevalence of retinal tear in persons with acute PVD ranges from 8 percent to nearly 50 percent.47,48,49,50,51,52 This variation reflects differences in examination technique and nature of referral practice. In a general ophthalmology practice, the rate of retinal tear found with symptoms of flashes and floaters runs closer to 10 or 15 percent.53,48,54,55 The type of floater also correlates with the likelihood of retinal tear. Multiple small floaters (diffuse or localized) tend to correspond to red blood cells or pigmented cells, which heightens the risk of retinal break.56 In patients who present with a dense vitreous hemorrhage, approximately two-thirds have a retinal tear and one-third have more than a single tear.57 Of 155 patients with symptoms of acute flashes and/or floaters, 11 percent developed similar symptoms in their other eye within two years.47

The mechanism of retinal tear is related to points of firm attachment between the collapsing vitreous and stationary retina. These critical intersections occur along major vessels, at lattice degeneration, enclosed ora bays, and retinal tufts.58 Other sites of firm attachment, like the juxtapapillary retina and vitreous base, are not prone to full-thickness tears.

Vitreous traction can result in avulsion of a retinal vessel in the absence of a full thickness retina break.59,60 Failure to relieve the traction can result in recurrent vitreous hemorrhages.52 Because the identification of retinal breaks by ophthalmoscopy is fallible, and because of the possibly of a new break developing late, some authorities recommend a follow-up fundus examination be performed. In one study of 189 eyes with no retinal tear found after initial symptoms of PVD, three new tears were found (n= 169 [1.8%]) at the six-week follow-up visit.61

Because there are no means of altering the physio-chemical or mechanical factors leading to PVD and rhegmatogenous retinal detachment, the most effective method of reducing the risk of vision-threatening retinal detachment is to screen patients with symptoms of acute PVD.62 The indications for treating symptomatic retinal breaks are not uniformly agreed upon, and have been based on expert opinion and consensus opinion.63 The goal of treating retinal breaks is to establish a firm chorioretinal adhesion surrounding the retinal defect. The strongest evidence for preventative treatment exists for symptomatic horseshoe tears and retinal dialysis. Prophylactic therapy for symptomatic horseshoe tears reduces the risk of retinal detachment from approximately 50 percent to 5 percent.64,65,66 Although retinal dialyses are not caused by PVD, they are occasionally found incidentally when examining a patient for symptoms of acute PVD.67 The issue over whether or not to treat asymptomic retinal tears is complex, because the natural history of these