KargerGazettePublished January 2001

No. 64

Russell D.Fernald

Thomas Kohnen

Lasers in Eye Surgery

The Evolution of Eyes

J. Wayne Streilein

Christina Fasser

Ocular Immune Privilege – Protection That Preserves Sight!

Face to Facewith an Untreatable Disease

Retina International

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Eyein Focus

The

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Among the known eye types are atleast eleven distinct optical methodsof producing images, the most re-cently described is a telephoto lens,identified in the chameleon in 1995.Indeed, six of the optical mecha-nisms have only been discovered inthe past 25 years.

Since camera-type eyes aredemonstrably superior in several re-spects [5], why don’t all animalshave them? Certainly, camera-typeeyes require big heads and bodies tohold them which may have restrict-ed the number of animals that havefollowed this evolutionary path. Al-so, it is likely that having evolvedone eye type, conversion to anothertype requires intermediate stagesthat are much worse or useless com-

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Fig.1. Attenuation (dB/m) of electromagnetic (EM) radiation in sea waterplotted as a function of frequency (Hz) and wavelength (nm) of that radia-tion. The narrow band of electromagnetic energy which corresponds to visible light is shown, as are the bands used for radio and television trans-mission. The band of EM radiation we now consider visible light is trans-mitted through water with an attenuation 6 orders of magnitude less thanthat of adjacent wavelengths. Redrawn from Fernald [1].

The Evolution of Eyes

in both Africa and South America,and species from both groups uselow frequencies to signal con-specifics about reproduction andother important things in murky wa-ter where normal vision is not muchuse.

How Do Eyes Work andHow Did They Evolve?To be useful to their owners,

eyes must collect light from the en-vironment, resolve it into images,and then capture and forward thoseimages to the brain. Despitedecades of research, westill have only limitedunderstanding of howvision actually works.It remains a deeppuzzle how a seam-less representation ofthe world is knittedtogether by the brainfrom visual snapshots.The functioning of theeye itself, however, is fairlywell understood. This is, in part,because the evolution of eyes hasbeen strictly constrained by thephysical properties of light. Lighttravels in straight lines, can be re-flected, and varies in wavelength(subjective hue or color) and intensi-ty (subjective brightness). Many ofthe structural principles and evenapparent flaws we find in existingeyes result from constraints due tothe physical properties of light.

By the time of the Cambrian pe-riod (570 – 500 million years ago),eyes were present in the form of verysimple eyecups, useful for detectinglight but not for processing direc-tional information. Although thecauses are unknown, explosive spe-ciation, or the ‘Big Bang’ of animalevolution happened during theCambrian [3]. Existing eye types im-proved radically, coincident withthe appearance of carnivory andpredation. The evolution of ocularstructures has proceeded in twostages (fig. 2) [4]. First was the pro-duction of simple eye spots whichare found in nearly all the major an-imal groups and contain a smallnumber of receptors in an open cupof screening pigment [4]. Such de-tectors cannot play a role in recog-nizing patterns but are useful for dis-tinguishing light from dark. The sec-ond stage in eye evolution is the ad-dition of an optical system that canproduce an image. Image-formingeyes occur in 96% of known speciesdistributed among 6 phyla [4].

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Light is the ultimate source ofearth’s energy and serves as the pre-mier source of information for manyspecies. Indeed, since the beginningof biological evolution over 5 billionyears ago, sunlight has fueled all or-ganic life and defined biologicaltime on earth. Light and the light/dark cycle have probably been themost important selective forces everto act on biological organisms. Oneof the most remarkable conse-quences of light on earth has beenthe evolution of eyes that has madevision possible. At present, we donot know whether eyes arose once ormany times, and, in fact, many fea-tures of eye evolution are still puz-zling.

How did eyes evolve? Darwin,the great English naturalist who firstbrought the systematic explanatorypower of evolution to bear on the be-wildering biological complexity ofour planet, felt that eyes offered aspecial challenge to evolutionarythinking because they are such ‘...or-gans of extreme perfection and com-plication...’ (1859). He was quite ex-plicit on this point, saying ‘...that theeye....could have been formed bynatural selection seems, I freely con-fess, absurd in the highest possibledegree’. More than a century later,with new insights that reach frommolecular to macroscopic levels ofanalysis, new mysteries reinforceDarwin’s prescient writing. We still

have much to learn from the evolu-tion of eyes, both about the existingeyes as well as the processes of evo-lution that produced them.

Current interest and excitementabout eye evolution comes from dis-coveries at both ends of the full spec-trum of biological investigation.Molecular biologists who seek fun-damental similarities among organ-isms have found some genes impli-cated in eye development that areconserved in eyes from animalsacross a large phylogenetic distance.Evolutionary biologists interested inunderstanding why organisms andtheir parts are so different havefound new types of eyes, both in thefossil record and in living animals.What do these different approachesto the evolution of eyes tell us? To-gether they offer complementaryviews of eye evolution and possiblythe beginnings of a clear story. Thisarticle will examine features of eyesfor clues about their origins.

Why Do We See WhatWe See?All eyes are sensitive to a com-

mon, rather narrow range of wave-lengths within the broad spectrum ofenergy produced by the sun. Why isthis? Why can’t we see more of thisspectrum? The most likely explana-tion is that eyes first evolved in ani-mals living in water, and, water, dueto its fundamental nature, filters out

all but two quite narrow ranges ofelectromagnetic (EM) radiation [1,2]. As shown in figure 1, the range ofEM radiation ‘visible’ for most or-ganisms is a narrow, sharply definedband, ranging from the very shortwavelengths we think of as having ablue color to longer wavelengths weidentify as red. It is particularly nar-row when compared with the fullrange of EM radiation produced bythe sun. In our language, we dividethis narrow range of perceivedwavelengths into seven names (red,orange, yellow, green, blue, indigo,violet), also called spectral colors. Asis clear from the figure, in this verynarrow band, EM radiation pene-trates water better than the adjacentwavelengths by about 6 orders ofmagnitude. So, since our ultimateancestors existed in a watery slime,the only radiation to penetrate watermust have been the primary selec-tive force. As we see now, this earlyselection for the narrow spectrumultimately drove the evolution ofbiochemical mechanisms sensitiveto these colors of light. This is trueboth for perception of light by ani-mals and for photosynthesis byplants. Now, five billion years later,though many animal species havemoved onto land where the sun’s fullspectrum is available, eyes remainsensitive only to this narrow region.That limit comes now, not from thefiltering properties of water butrather from the biochemical mecha-nisms that evolved in response tothe limited wavelengths penetratingthe original slime. Once selectionstarted organisms down that path,mechanisms that evolved limited fu-ture options.

It is true that many insectspecies as well as some species of fishand birds can ‘see’ in the ultraviolet,or very short wavelength end of thevisible spectrum. However, they doso with slight modifications of thesame biochemical system that therest of us use to see, not with newmechanisms. This particular ex-ploitation is remarkable because theenergy in photons at the short wave-lengths is very high.

As seen in figure 1, EM radiationpenetrates water quite well at thevery low frequency end of the spec-trum (<103 Hz) explaining why it isdangerous to put power wires intowater, among other things. Thisrange of wavelengths is actually usedby some organisms to gather sensoryinformation. For example, weaklyelectric fish evolved independently

Neuroscience ProgramStanford University, Stanford, Calif.

Russell D. Fernald

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pared with the existing design. Thiswould make a switch essentiallylethal to animals that depend onsight. Although this argumentmakes sense intuitively, some exist-ing cases of novel optical combina-tions suggest this is probably not thewhole story.

Textbooks tend to group animaleyes into two groups, the camera-type or ‘simple’ eyes and the com-pound eyes. Although this dichoto-my reflects a real and fundamentaldifference in optical mechanisms, itconceals a remarkable diversity ofoptical systems subsumed undereach heading [4, 5].

In 1994, Nilsson and Modlindescribed a mysid shrimp (Diop-tromysis paucispinous) that has a

combined simple and compoundeye: partly compound with multiplefacets exactly like the eye of an in-sect, and partly simple with a singlelens focusing an image on a sheet ofreceptors like that of a human. Theshrimp are about 5 mm long withnearly spherical eyes at the ends ofstalks. In addition to the facets (ca.800–900) there is a single giant facetfacing the shrimp’s tail, which theshrimp frequently rotates forwardprobably to get a better look atsomething since it has ca. 5 timesthe acuity (but much lower sensitiv-ity) than the rest of the eye. It is as ifthe shrimp is carrying a pair ofbinoculars for the occasional de-tailed look at something ahead of it.The discovery that simple and com-pound eye types can be found in asingle animal raises the question ofhow a developmental programcould produce this outcome.

How Do Eyes CapturePhotons?Visual information from the en-

vironment is detected by special-ized cells called photoreceptors lo-cated in a sheet covering the back ofthe eye. These cells are part of theretina, a thin (ca. 100 µm) layer ofcells that is responsible for gettingvisual information to the brain.Photoreceptors contain two molec-ules that act together to collect pho-tons. One, opsin, is a protein thatsits in a membrane in close associa-tion with the other, a visual pigmentor chromophore (11-cis-retinal),which is surrounded and held byopsin (fig. 3). When a photon is absorbed by the chromophore, itlengthens by 5 Å by rotating arounda double bond. Through this slight

transformation, the chromophoremakes opsin enzymatically active,ultimately causing, via an amplify-ing cascade, a decrease in currentflow across the outer segment mem-brane. The main result of this in-teraction is that the photon energyis transduced into electrical energywhich can be interpreted by the ner-vous system.

The opsins have a family histo-ry that precedes eyes as evidencedby comparisons of their DNA. Theyconsist of seven transmembrane he-lices with short loops on both sidesof the membrane. The chromo-phore, retinal, is attached covalent-ly to opsin at a site in the seventhtransmembrane domain. These fea-tures are common to all metazoanopsins and, based on comparison ofthe DNA sequences, they mustshare a common ancestry. In par-ticular, several regions of themolecule show close similarityamong opsins from vertebrates, in-sects and Octopus, whose ancestriesdiverged in the Cambrian [4]. Thishomology suggests that the molec-ule responsible for the initial ab-sorption of photons has beenexquisitely tuned over evolutionarytime. In addition, the high level ofconservation has allowed relativelyeasy recovery of the cDNAs that en-code opsin from the eyes of manydifferent species, giving us a re-

markable amount of informationon its evolutionary history.

One source of evolutionary in-formation has been the evolution ofcolor vision. There are many selec-tive advantages for animals havingcolor vision including improved de-tection of food, mates and enemies.To see colors, animals must havephotoreceptors sensitive to differ-ent wavelengths of light. This is pos-sible through the evolution of slightvariants in the opsin moleculethrough which subtle differences inthe amino acids at particular sites‘tune’ the chromophore to a partic-ular peak absorbance wavelength.The discovery and clarification of adirect causal link between a molec-ular structure and its importancefor a perceptual process is remark-able in its own right, but also be-cause these features are common toall metazoan opsins. These evolu-tionary experiments have alloweddetailed phylogenetic comparisons,suggesting that vertebrate visualpigments have evolved along atleast five lines and diverged from anancestral type before teleost fish di-verged from other vertebrates.

Although metazoan opsins ap-pear to have evolved along severalseparate lines from a common an-cient ancestor, what happened ear-lier is not clear. Bacteriorhodopsin,from Halobacterium does not show

significant amino acid similaritywith cattle rhodopsin. Moreover, itis the double bond 13 of the chro-mophore, rather than 11 that is altered by light. Nonetheless, likemetazoan opsins, bacteriorhodop-sin belongs to a large superfamily ofproteins, all of which have seventransmembrane helices and operateby activating second-messenger cas-cades. This family of proteins in-cludes neurotransmitter and pep-tide receptors as well as the familyof odorant receptor molecules.Whether similarities within the su-perfamily result from a very ancientcommon ancestry or a more recentrecruitment is not yet known.

Where Do Lenses ComeFrom?The vertebrate eye develops

from a diverse collection of embry-onic sources through a complex setof inductive events [6]. Whereasthe neural retina is derived from thediencephalon and is a part of thebrain, the lens comes from surfaceectoderm and the iris and ciliarybody arise primarily from the neu-ral crest. Mapping the genes knownto play a role in mouse eye develop-ment, for example, shows that someof these genes are present on everychromosome [6]. The apparentpatchwork assembly of the eyemakes it all the more surprising that

Fig. 2. The likely evolution of single-chambered eyes. Arrows indicate functional developments, not specificevolutionary pathways.From Land and Fernald [4].

a Pit eye, common throughout the lower phyla.

b Pinhole of Haliotis (abalone) or Nautilus.

c Eye with a lens.d Eye with homogeneous lens,

showing failure to focus.e Eye with lens having a gradient

of refractive index.f Multiple lens eye of male

Pontella.g Two-lens eye of the copepod

crustacean Copilia. Solid arrow shows image position and open arrow the movement of the second lens.

h Terrestrial eye of Homo sapienswith cornea and lens; Ic= image formed by cornea alone; Ir= final image on the retina.

i Mirror eye of the scallop Pecten.

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Fig. 3. Schematic illustration showing the location of the visual pigment (opsin plusretinal) at several levels of magnification. A rod photoreceptor is shown on the left.Light enters the rod from below and strikes visual pigment molecules contained inthe disc membranes as seen in the top right illustration. The lower right figure showsthe opsin protein amino acid structure with the site of retinal attachment within thedisc membrane on the 7th transmembrane domain.

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References

1 Fernald RD: Aquatic Adaptationsin Fish Eyes. New York, Springer,1988.

2 Fernald RD: The evolution of eyes.Brain Behav Evol 1997;50:253-259.

3 Conway-Morris S.: The Crucible ofCreation. Oxford, Oxford Universi-ty Press, 1998.

4 Land MF, Fernald RD: The evolu-tion of eyes. Annu Rev Neurosci1992;15:1-29.

5 Nilsson DE: Vision optics and evo-lution. Bioscience 1989;39:298-307.

6 Graw J: Genetic aspects of embry-onic eye development in verte-brates. Dev Gen 1996;18:181-197.

7 Halder G, Callaerts P, Gehring WJ:Induction of ectopic eyes by target-ed expression of the eyeless gene inDrosophila. Science 1995;267:1788-1792.

8 Doolittle RF: More molecular op-portunism. Nature 1988;336:18.

9 Gehring WJ, Ikeo K: Pax 6: Master-ing eye morphogenesis and eye evo-lution. Trends Genet 1999;15:371-377.

10 Fernald RD: Evolution of eyes.Curr Opin Neurobiol 2000;10:444-450.

similar information about wave-length and intensity of light to theirowners. Different tissues have beenrecruited to build lenses and retinasacross the phyla. In contrast, all eyesshare the same mechanism of ab-sorbing photons, i.e. the opsin-chro-mophore combination has beenconserved across phylogeny. De-spite new findings yielded by pow-erful molecular techniques, all evi-dence still suggests that eyes have apolyphyletic origin, with the caveatthat they contain homologousmolecules responsible for manystructural, functional and even de-velopmental features (fig. 5). Givena growing list of homologous genesequences amongst molecules in theeye across vast phylogenetic dis-tances, the challenge is now to dis-cover what makes the eyes ofDrosophila, squid and mouse so dif-ferent. Since strictly homologousdevelopmental processes must pro-duce homologous structures, keyelements responsible for the devel-opment of nonhomologous eyes re-main missing. Understanding whatmakes eyes different may be a big-ger challenge than finding what theyhave in common.

parts of the eyes of fish and squidarise from very different embry-ological sources during develop-ment, suggesting different originsfor these eye types.

Paired eyes in the three majorphyla, vertebrates, arthropods andmollusks (fig. 4), have long beenconsidered to be classic examples ofevolutionary convergence. At themacroscopic level, this must be truesince they arise from different tis-sues and have evolved radically dif-ferent solutions to the commonproblem of collecting and focusinglight. However, as discussed above,opsin has a significant DNA se-quence homology across all phyla.Remarkably, recent work byGehring and Ikeo [9] has shownthat features of ocular developmentin different phyla can be coordinat-ed by a homologous ‘master’ gene,Pax-6. That a single gene could trig-ger construction of an animal’s eyein diverse species led to their pro-posal that eyes are monophyletic,i.e. evolved only once. This is an in-teresting hypothesis that goesagainst all the previous suggestionsof multiple (i.e. polyphyletic) ori-gins for eyes. There are several rea-sons why this hypothesis seems dif-ficult to support. It is well knownthat Pax-6 organizes other struc-tures besides eyes and is even neces-sary for the onset of various actionsoutside the nervous system. Also,other genes can cause developmentof eyes [reviewed in 10]. Whethereyes are monophyletic or not, thework of Gehring and his colleagueshas stimulated a great deal of newwork on eye evolution, which is agood thing in itself.

Clearly, eyes have common mol-ecular constituents whether they beopsins, Pax-6, or others. Yet, ho-mology at the molecular level of or-ganization does not predict homol-ogy at the organ or organismic level.Molecules are not eyes.

ConclusionsEyes exist in a variety of shapes,

sizes, optical designs and locationson the body, but they all provide

common developmental programsseem to produce comparable out-comes across a broad phylogeneticdivide [7]. Could we use the com-position of lenses to gain insight in-to eye evolution?

Vertebrate lenses are formedfrom modified epithelial cells thatcontain high concentrations of solu-ble proteins known as crystallins be-cause they are packed in a highly or-ganized fashion. It is the change in

relative concentration of these pro-teins from the periphery to the cen-ter of vertebrate lenses that pro-duces the refractive index gradientnecessary for a lens to be useful tothe animal. In fact, the identity ofthe proteins seems not to be impor-tant since the crystallin proteins arenot more transparent than others.Instead, the distribution of proteinconcentration as a function of ra-dius is the key to a successful lens.Thus, the challenge in understand-ing lens evolution lies in discover-ing how the distribution of proteinswithin a lens is established andmaintained.

Of the eleven lens crystallinsnow known, only three, �-, �- and �-crystallins, are common to all verte-brates. In fact, until recently, allcrystallins were thought to beunique to lens tissue and to haveevolved for this special function.However, despite their apparentlyspecialist role, most of the crys-tallins are neither structural pro-teins nor lens specific. There aretwo major groups of lens crystallins,those present in all vertebrates andthose specific to a particular taxon.For example, in crocodiles andsome bird species, the glycolytic en-zyme lactate dehydrogenase B is amajor protein in the lens. Indeed, 4of the 8 taxon-specific crystallinsare identical to metabolic enzymesand products of the same genes, sug-gesting these products share a gene.

Why might enzymes be recruit-ed to make vertebrate lenses? Per-haps the robust regulation of en-zyme production is advantageousfor producing sufficient protein fora lens, but there is not much beyondspeculation to support this notion.There may be some deeper reason,

however, because this molecularopportunism seemed such a goodidea, that certain invertebrates, e.g.mollusks, independently evolvedthe same strategy [8]. Squids havelenses whose protein content isnearly entirely the enzyme glu-tathione S-transferase. The com-mon strategy of constructing lensesfrom different proteins seems to bea convergent evolutionary solution.This convergence of molecular

strategy suggests that enzymes aslenses may have a functional mean-ing, or that it is easy to get lens cellsto make a lot of enzyme, or theremay be other as yet not understoodreasons.

Eyes: Convergence orHomology?Have the structural similarities

among eyes resulted from evolu-tionary convergence due to similarselective pressures (analogous) orfrom descent from a common an-cestor (homologous)? This distinc-

tion is particularly hard to drawwhen comparing eyes because thephysical laws governing light great-ly restrict the construction of eyes.Similar eye structures may havearisen in unrelated animals simplybecause of constraints imposed bylight.

The most commonly cited ex-ample of evolutionary convergenceare the eyes of squids and fish. Bothof these are ‘camera-type’ eyes, in

which an image is formed on thephotosensitive retinal layer at theback. Moreover, both have evolveda spherical lens with an exquisitelyconstructed gradient of refractiveindex that allows good focus despitetheir spherical shape. In addition,both types of eyes use the samelight-sensitive molecule, opsin, toconvert photons into neural energy.However, the fish retina is inverted,meaning the light-sensing cells areat the very back of the eye (inverse)while those in squid are at the frontof the retina (everse). Moreover, the

Russell D. Fernald is BenjaminScott Crocker Professor of Human Biol-ogy and professor of psychology at Stan-ford University, California. His re-search is focused on understanding howthe vertebrate visual system developsand how vision influences the behaviorof animals. Dr. Fernald is an editorialboard member of the Karger journalBrain Behavior and Evolution.

Fig. 5. A possible landscape of eye evolution created by Mike Land. Height represents optical quality and the ground plane evolutionary distance. Land writes that ‘Climbing the hillsis straightforward but going from one hilltop to another is near impossible’. From Dawkins R: Climbing Mount Improbable. New York, Norton, 1996.

Fig. 4. Building plans of three different types of eyes.

a A vertebrate eye. b An arthopod compound eye. c A cephalopod lens eye.

The construction of eyes varies considerably. In vertebrates, photoreceptor cells differentiate from the central nervous system, whereas in cephalopod and arthropodeyes, they differentiate from the epidermis. In addition, the retina is inverse (i.e. photo-receptors are at the back of the eye) in vertebrates and everse (i.e. photoreptors are atthe front of the eye) in cephalopods. From Fernald [10].

Neural tissue

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The Eye’s DilemmaThe eye is an essential organ for

survival – for humans, and for thevast majority of other vertebrates.Like other vital organs and tissues, itis vulnerable to a variety of externaland internal pathogens that canabolish its critical function andthreaten the host’s survival. Toavoid this catastrophe, evolutionhas provided vertebrates with a widespectrum of general and local de-fense mechanisms designed to neu-tralize the virulence of pathogens.The fact that the spectrum of de-fense mechanisms is wide reflects,on the one hand, the extreme diver-sity of pathogens, each with a unique‘spin’ on virulence strategies, and,on the other, the unique vulnerabili-ty of different organs and tissues tothe distinct virulence strategies ofdifferent organisms. Thus, the pro-tection against injury frompathogens that is conferred at anyparticular site in the body is bothdistinctive and appropriate for therange of potential pathogens and forthe physiologic functions of thatsite. The term ‘regional immunity’has been used to identify this di-mension of immune protectionagainst patho-gens. The eye is a goodexample of an organ that possesses‘regional immunity’, and immuneprivilege in the eye is the experimen-tal and clinical expression of thisconcept.

Especially for humans, precisevision of detailed images is vital forsurvival. This property depends up-on absolute integrity of the so-calledvisual axis: the structures of the eyethat permit light to enter the organ,

cells that are summarily rejectedwhen placed subcutaneously formprogressively growing tumors wheninjected into the anterior chamberof eyes of immunologically normalmice and rats. (2) Corneal tissue ob-tained from the eye of one individu-al enjoys extended survival whengrafted orthotopically to the anteriorsurface of the eye of a normal indi-vidual, even though corneal tissuegrafted heterotopically to the skinsurface is rejected promptly. The ex-perience of corneal surgeons makesthe same point. The most commonsolid tissue transplantion performedin humans is corneal transplanta-tion, and these transplants enjoy thehighest rate of success compared toall other types of solid tissue grafts.This is true even though the im-munosuppression used to control re-jection is applied topically, ratherthan systemically.

Over the past 30 years, inves-tigators have learned much aboutthe physiologic processes responsi-ble for immune privilege in the eye: special architectural fea-tures of the anterior chamber, and unique immunomodulatorymolecules present in the ocular flu-ids and expressed on ocularparenchymal cells. Together theygovern and modify the manner inwhich antigenic material placed inthe anterior chamber is recognizedby cells and molecules of the sys-temic immune apparatus. In addition, these processes alter theways in which immune effectormolecules and cells respond to for-eign and antigenic material that ispresent within the eye. The net ef-fect of these forces is to limit the in-traocular development of inflamma-tion.

Inflammation in Relation to Innate and Adaptive Immune ResponsesImmunity is a complex re-

sponse made by the body in an effort to avoid invasion bypathogens and to nullify their viru-lence strategies. Two complemen-tary forms of immunity conspire inthis effort: the innate immune sys-tem and the adaptive immune sys-tem (table 1). In the effort to eradi-cate invading pathogens, inflamma-tion is usually the final commonpathway employed, and both innateand adaptive immune responses areknown to trigger inflammation to-ward this end. Not surprisingly, im-mune privilege in the anterior cham-ber of the eye acts to thwart the trig-gering of inflammation by bothtypes of immune response.

Innate immunity is activat-ed by sets of rather stereotypicmolecules that are expressed on microbial pathogens; thesemolecules are called pathogen-associated molecular patterns(PAMPs). Bacterial lipopolysaccha-ride (LPS) and (�-lipotechoic acid,expressed by gram-negative andgram-positive organisms, respec-tively, are good examples. AlthoughPAMPs vary a lot among differentpathogens, there is nonetheless con-siderable sharing, and therefore anygiven PAMP is not ‘specific’ to anyparticular organism in a molecularsense. PAMPs are recognized bycells of the innate immune system

J. Wayne StreileinSchepens Eye Research Institute,

Boston, Mass.

Ocular Immune PrivilegeProtection That Preserves Sight!

Fig. 1. Visual axis of the normal humaneye. Unimpeded light passing throughthe ocular surface, anterior chamber,pupil, vitreous body, and inner retinafalls, as a focused image, on the outersegments of the photoreceptor cells ofthe retina.

and encourage and focus light im-ages onto the neuronal retina (fig. 1).These structures include the ocularsurface (tear film, cornea), the ante-rior chamber (aqueous humor) andpupil of the iris, the lens, the vitre-ous body, and the layers of retinaimmediately anterior to the pho-toreceptor cells. Each of these struc-tures is uniquely endowed with theproperty of transmitting light with aminimum of distortion and diffrac-tion. The precise anatomic relation-ships of these structures are criticalto achieve a focused image at thelevel of the retina. Even very minordeviations (millimeters or less) inthe anatomic integrity of the visualaxis can result in impaired vision.

Not surprisingly, inflammation,if it occurs within the eye, is a pro-found threat to vision. In an in-flamed eye, light transmissionthrough the visual axis can be im-peded and diffracted by leukocytesand plasma proteins, and the visualaxis itself can be distorted, causingthe focused light image to fall awayfrom the photoreceptor outer seg-ments. Thus, the dilemma! Inflam-mation is one of the most importantpathways by which immune mecha-nisms protect a tissue against

munology, which applied to most or-gans of the body, was relaxed in theeye. He found that foreign tissuegrafts placed in the anterior cham-ber of the eye (as well as in the brain)often displayed prolonged survivalwithout evidence of rejection, andcoined the term ‘immune privilege’to refer to this special property of theanterior chamber (and the brain).

By now, many other investiga-tors have performed similar experi-ments by placing foreign tissuegrafts at numerous special sites inthe body. There is a long, but proba-bly still incomplete, list of immune-privileged sites: anterior chamber,vitreous cavity and subretinal spaceof the eye, brain, pregnant uterus,ovary, testis, adrenal cortex and cer-tain tumors. As researchers haveprobed the mechanisms responsiblefor immune privilege, it has becomeclear that similar, but not identical,processes are involved in conferringimmune privilege on these variousbody sites.

Anterior Chamber of the Eye as an Immune-Privileged SiteOur understanding of the anteri-

or chamber of the eye as an immune-privileged site is based on solid ex-perimental evidence and is support-ed by considerable clinical experi-ence. Allografts prepared from a va-riety of different tissues (skin, thy-roid, islets of Langerhans, cornea,retina) experience prolonged, evenindefinite survival when placed inthe anterior chamber. Two types ofexperimental grafts make this pointdramatically: (1) Allogeneic tumor

pathogens. It is this dilemma – theneed for immune protection, andthe vulnerability to the conse-quences of inflammation – that liesat the heart of immune privilege inthe eye. Through adaptation, evolu-tion has devised a special form ofimmune protection (we call it im-mune privilege) that enables the eyeto resist the vast majority ofpathogens by using processes largelydevoid of inflammation, therebyavoiding loss of vision. We shouldremember that adaptations of thistype represent biologic compromis-es, and in the case of ocular immuneprivilege, the compromise rendersthe eye vulnerable to those organ-isms whose pathogenicity and viru-lence can only be eliminated withthe aid of overt inflammation.

Immune PrivilegeEven before the modern concept

of immunity had formed, scientistshad discovered that certain tumorswould grow progressively whentransplanted into the anterior cham-ber of the eye, but not when trans-planted elsewhere. With Medawar’sdiscovery of the principles of trans-plantation immunology in the1940s, it became possible to explainthe biologic reasons for the surpris-ing growth of tumors in the anteriorchamber. Medawar demonstratedthat foreign tissue grafts expressedtransplantation antigens that wererecognized by the recipient’s im-mune system. In mounting a re-sponse against these antigens, im-munity caused graft rejection.Medawar further demonstrated thatthis rule of transplantation im-

Anterior chamber

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Retina

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Table 1. Comparison of innate and adaptive immune responses

Property Innate immunity Adaptive immunity

Triggering molecules repetitive molecular units antigen + association structures

Recognition mechanism direct indirect

Onset of response immediate (hours) delayed (days)

Clonal expansion of responder cells no yes

Induces inflammation always often

Memory (to prevent reinfection) no yes

that express receptors that recog-nize these patterns directly (calledpattern recognition receptors,PRR). Examples of PRRs includecertain complement components,C-reactive protein, mannose recep-tors, LPS-binding protein, CD14,and KIRs. PRRs are expressed onvirtually all cells of the innate im-mune system: macrophages, den-dritic cells, neutrophils, naturalkiller (NK) cells, mast cells,platelets, �/� T cells, and B-1 B lym-phocytes. When PRRs bind PAMPsthey trigger an immediate cellularor molecular response (immediate� 3 h), and no prior exposure to thesame PAMP is required for this immediate response. Mediators (cytokines, chemokines, prosta-glandins, etc.) that are released dur-ing this response modify the localmicrovasculature and recruit addi-tional inflammatory cells andmolecules to the site. While cellularproliferation is not an importantcomponent of the ensuing response,an intense and potentially destruc-tive inflammation is. Once the of-fending pathogen is eliminated, in-nate immunity subsides, along withits attendant inflammation. Veryoften an inflammatory episode, ifespecially intense, may produce tis-sue damage and leave a scar. How-ever, no imprint of the encounter isleft upon the innate immune sys-tem, and therefore ‘memory’ of theoffending pathogen does not exist.

Adaptive immunity uses ratherdifferent mechanisms to detect andrespond to pathogens, although theprinciple of using specialized recep-tors to recognize foreign moleculesremains the same. Adaptive im-mune cells and molecules respondto unique ‘fingerprints’ onmolecules expressed by pathogens(often very small peptides and car-bohydrates derived from complexmacromolecules). These moleculesare called ‘antigens’, there are esti-mated to be more than 109 suchmolecules in our universe. Morethan one antigen may be expressedby any single pathogen, and eachpathogen displays antigens whichare uniquely its own. In an effort todevise a receptor system sufficient-ly diverse to detect this enormousdiversity of antigens, receptors aregenerated somatically in the cells ofthe adaptive immune system: T andB lymphocytes. The recognitionstructures on B lymphocytes are an-tibodies (immunoglobulins) thatcan bind directly to their specificantigen. When B cells are activatedby exposure to antigen, they secretesoluble versions of their surface re-ceptors. Secreted antibodies are theeffector modalities generated by Blymphocytes. Antigens are also rec-

ognized by specialized receptors onT lymphocytes (T-cell receptor –TCR – for antigen). In this case,what is recognized are small pep-tides derived from complex macro-molecules that have been loadedonto special recognition structures(class I and II molecules encodedwithin the major histocompatibilitycomplex, MHC) that are displayedby specialized antigen-presentingcells (APC). Thus, the conditionsfor recognition of antigen by T cellsis that the antigen be processed andpresented to the T cell by an APC.Unlike the cells of the innate im-mune system, T and B lymphocytesare not activated simply by havingtheir receptors engage the relevantligand. Instead, a second signal isneeded for T-cell activation, andthis is also prepared by the APC.This ‘second signal’ arises whenAPC is activated by an innate im-mune signal. Thus, activation of theadaptive immune system is depen-dent upon prior or simultaneous ac-tivation of the innate immune sys-tem.

Clonal expansion and differen-tiation of T and B lymphocytes areimportant consequences of antigen-specific activation. Not only are thenumbers of antigen-reactive T cellsincreased because of clonal prolifer-ation, but the emergent progeny dis-play the capacity to carry out effec-tor functions – delayed hypersensi-tivity, cytotoxicity, complementfixation. Moreover, many of theseprogeny become long-lived, helpingto account for the acquisition ofantigen-specific immunologic mem-ory. Both clonal expansion and ac-quisition of antigen-specific memo-ry are unique attributes of adaptiveimmunity, compared to innate im-

munity. Adaptive immune effectorsare able to traffic via the blood vas-culature to sites containing the of-fending, antigen-bearing pathogen.Upon local recognition of the anti-gen, these effectors trigger an in-flammatory response that elimi-nates the pathogen. This is the sec-ond important point when theadaptive and innate immune sys-tems cooperate in conferring pro-tection. CD4+ T cells can only trig-ger a full-scale delayed hypersensi-tivity response if they are assistedby innate immune cells such asmacrophages. Similarly, antibodiescan only trigger phagocytosis of bac-teria with the assistance of comple-ment components. By contrast, inthe case of CD8+ cytotoxic T cells,elimination of pathogens may occurwithout significant inflammation,and non-complement-fixing anti-bodies that neutralize viruses maysimilarly terminate an infectionwithout inflammation. Thus, only asubset of adaptive immune effec-tors trigger destructive immunitywhen attacking their pathogenictargets, and it is to these effectorsthat immune privilege in the eye isdirected.

Ocular Factors That Promote Immune Tolerance of Eye-Derived AntigensInjection of antigen into the an-

terior chamber of the eye leads tothe development of a systemic im-mune response that is deviant andunexpected. This response, termedanterior chamber-associated im-mune deviation (ACAID), repre-sents a selective, antigen-specificdeficit of T cells that mediate de-layed hypersensitivity and B cells

that secrete complement-fixing an-tibodies, i.e. immune effectors thattrigger immunogenic inflamma-tion. The selective deficiency ofACAID is due to the generation ofantigen-specific regulatory T cells(CD4+ and CD8+) that inhibit bothinduction and expression of pro-in-flammatory effector modalities. Atthe same time, these regulators haveno effect on other effector modali-ties, leaving cytotoxic T-cell re-sponses and non-complement-fix-ing antibodies intact.

Factors within the eye play a keyrole in the generation of ACAID.APC indigenous to the eye (stromaof iris and ciliary body) expressCD1 and are heavily influenced bysoluble molecules in the ocular mi-croenvironment, especially trans-forming growth factor-�2 (TGF-�2).When these cells capture local anti-gen, they display the capacity toprocess and present peptides onclass I and II MHC molecules, andthey even express certain costimu-latory molecules (B7-1). However,they fail to secrete IL-12 and theyare impaired in their ability to up-regulate expression of CD40 – cos-timulatory molecules that are cen-tral to the induction of T cells thatmediate delayed hypersensitivity.In addition, eye-derived APC se-crete active TGF-�. This is the dis-tinct functional phenotype of anti-gen-bearing APC that leave the an-terior chamber by migrating acrossthe meshwork directly into the venous circulation (fig. 2). Travers-ing the bloodstream, eye-derivedAPC migrate preferentially to the marginal zone of the spleenwhere they secrete MIP-2, achemokine that attracts NK T cells.The latter cells bear a special T-cell

receptor that recognizes CD1.When APC-NK T-cell conjugatesform, the NK T cells secrete addi-tional chemokines which bring tothe site antigen-specific T cells.From this multicellular aggregateemerge the regulatory T cells ofACAID.

The importance of ACAID toocular immune privilege is that itpre-empts the systemic immune re-sponse to eye-derived antigens,molding all subsequent responses tothe same antigens such that inflam-mation doesn’t develop when theseantigens are encountered within theeye (or anywhere else for that mat-ter). The ocular factors that con-spire to produce this form of toler-ance are: (a) TGF-�2, which endowsocular APC with special costimula-tory properties, and (b) an outflowpath for aqueous humor (AqH) thatdirects mobile antigen-bearing APCdirectly to the blood (rather than in-to the lymphatics) and therefore tothe spleen. It is the spleen that pre-sides over the inductive events thatlead to ACAID. In animals devoidof a spleen, ACAID fails to develop.

Factors That Modify Expression of OcularAdaptive Immunity Under normal circumstances,

the anterior chamber is located be-hind a blood:tissue barrier. Thecontent of plasma proteins withinAqH is extremely low (<0.01%),and only T and B lymphocytes areever detected within the tissues sur-rounding the anterior chamber.This anatomical barrier representsan important factor in preventingexpression of adaptive immunitywithin the eye. In fact, only whenthis blood:tissue barrier is breacheddoes the possibility of immune ex-pression in the eye exist. This is be-cause adaptive immune responsesare necessarily triggered by antigen-specific T cells and antibodies, bothof which are carried in the blood-stream and can only enter the eyefrom this source.

There are also soluble factorswithin the anterior chamber that actto modify adaptive immune effec-tors that gain access to this com-partment. It has been known formore than a decade that AqH in-hibits activation of T lymphocytesin vitro. Since this initial observa-

Fig. 2. Vascular-anatomic relationshipsthat enable eye-derived, antigen-bea-ring APC to migrate via the blood to thespleen where they recruit NK T cells toassist in generation of the regulatory Tcells responsible for anterior chamber-associated immune deviation.

Antigen

Trab

ecul

ar m

eshw

ork

Marginal zone

6KargerGazette

Anterior chamber

APC

Spleen

Blood vessels

1

APCAPCAPC

APC

7KargerGazette

tion, an ever-growing number ofsoluble factors with this capacityhas been identified in AqH (fig. 3).TGF-�2 and vasoactive intestinalpeptide (VIP) are present in AqH atconcentrations that completely shutdown T-cell proliferation in re-sponse to antigen or stimula-tion with anti-CD3 antibodies. �-Melanocyte-stimulating hormone(�-MSH) is also present, and al-though this neuropeptide does notsuppress T-cell proliferation, it se-lectively inhibits activated T cellsfrom producing either IFN-� or IL-4. Of even greater interest is the re-cent discovery by Taylor and hiscolleagues that immune T cells ex-posed to antigen in the presence of�-MSH are converted into regulatorT cells. By secreting TGF-�, these Tcells can suppress the activities ofother T cells activated in their mi-croenvironment.

It is important to point out thatAqH is not able to prevent cytotox-ic T cells from lysing their specifictargets. This is important because itindicates that the negative effects ofAqH on adaptive immune effectorsare not global; rather, they are selec-tive, targeting the T cells most like-ly to induce inflammation.

AqH also prevents antibodiesfrom triggering complement activa-tion. To date, AqH is known to con-tain (a) a very small molecularweight factor (<1,000 daltons) thatprevents C1q from binding to theFc portion of IgG antibodymolecules, and (b) a larger molecu-lar weight factor (>30,000 daltons)that inhibits the generation of C3bfrom C3. Once again it is importantto note that AqH does not interferewith the effectiveness of antibodiesthat neutralize viruses, indicatingthat the immunoglobulin target ofAqH factors are adaptive immuneeffectors (complement-fixing anti-bodies) that threaten to cause in-flammation.

The sources of the factors inAqH that modulate T-cell and anti-body functions are not completelydefined. Since supernatants of cul-tures of explanted iris and ciliarybody and of cultures of explantedcornea inhibit T-cell activation in amanner similar to AqH it is likelythat pigment epithelial cells, as wellas corneal endothelium, secretesome of the immunomodulatoryfactors. Another likely source areterminii of autonomic nerves foundwithin the iris and ciliary body.

Not all local factors that inhibitadaptive immune effectors are solu-ble. Yoshida and coworkers recent-ly reported that pigment epithelialcells, cultured from the iris and cil-iary body, suppress activation ofnaïve and immune T cells through adirect cell-to-cell contact mecha-nism. Moreover, T cells that havemade contact in this manner withcultured pigment epithelial cellsare, on the one hand, spared fromapoptosis when given a signal thatpromotes programmed cell death,and, on the other, converted intoregulatory cells that suppress bystander T cells through the secre-tion of TGF-�. The cell surfacemolecules responsible for the interaction between pigment ep-ithelia and T cells remain elusive.Nonetheless, a theme emerges fromthese considerations.

The ocular microenvironment(anterior chamber) is protectedfrom the ravages of inflammationtriggered by adaptive immune ef-fectors at two biologic levels: Archi-tecturally, a blood:tissue barrieracts to limit access to the compart-ment of blood-borne cells andmolecules with receptors specificfor antigens expressed locally.

Molecularly, the AqH (through sol-uble factors) and the cells that sur-round the anterior chamber(through cell surface molecules)prevent adaptive T cells and anti-bodies from triggering inflammato-ry cells and molecules directly, andeven endow the T cells with theproperty of further suppressing in-flammation. Together, these forceshelp to explain why it is virtuallyimpossible to elicit delayed hyper-sensitivity reactions within the an-terior chamber of fully sensitizedmice, and they make it possible tounderstand why corneal allograftsand xenografts are completely im-pervious to antibody-mediated re-jection mechanisms. These arepowerful expressions of the exis-tence of adaptive immune privilegeat this site.

Innate Immune Privilege in the Eye Until very recently, the notion

that privilege directed at innate im-munity exists was not seriously con-sidered. However, within the pastfew years, reports from several lab-oratories have produced irrefutableevidence that the ability of the in-nate immune system to express it-self in the eye is impaired and mod-ified. Perhaps the most dramaticexample comes from the laboratoryof Dr. J.Y. Niederkorn where workwas carried out with a mouse tumorcell line that is susceptible to lysis byNK cells. When this tumor cell linewas injected into the flank of micewith a severe deficit in adaptive im-munity, the tumor was rejected –because these mice still possess anintact innate immune system. Thistumor rejection was shown to bemediated by NK cells. When thesesame tumor cells were injected intothe anterior chamber of the eye ofadaptive immunodeficient mice, norejection occurred. Instead, the in-jected cells formed progressivelygrowing tumors. This result formal-ly demonstrates the existence of in-nate immune privilege in the eye.

It is of interest that the tissueswithin the eye display considerablevulnerability to the deleterious ef-fects of effectors of innate immuni-

ty. Corneal endothelial cells expressvery low levels of MHC class Imolecules; NK cells are particularlyequipped to recognize and kill cellswith low class I MHC expression.Thus, corneal endothelium is vul-nerable to lysis by NK cells. Cornealendothelial cells also express CD14,the receptor for the LPS-bindingprotein. This receptor targets LPSto the endothelium, thereby invit-ing LPS to recruit inflammatorycells that could harm this delicate,crucial inner layer of the cornea.The corneal endothelium isexquisitely sensitive to reactiveoxygen intermediates and nitric ox-ide (NO), and these toxic moleculesare the products of LPS-activatedmacrophages and neutrophils. Mostocular parenchymal cells expressCD95 ligand constitutively. Recip-rocally, neutrophils constitutivelyexpress CD95, and when neu-trophils interact with CD95 ligand-bearing cells, the neutrophils aretriggered to release pro-inflamma-tory mediators and destructive hy-drolytic enzymes. Since these medi-ators additionally attract neu-trophils and macrophages, andsince both cells quickly releaseTNF-� when activated, the highlevel of expression of receptors forTNF-� on ocular cells renders thesecells vulnerable to the deleteriousconsequences of this powerful,pleiotropic cytokine. It is a smallwonder that the eye has acquired aprotective adaptation that enablesit to blunt the harmful effects of in-nate immunity.

Factors That Modify Expression of InnateOcular ImmunityNiederkorn and his associate

Apte demonstrated that AqH fromnormal eyes can prevent the lysis ofsusceptible target cells by NK cellsin vitro. Apte determined that atleast two factors in normal AqHmitigate NK cell killing: TGF-� andmacrophage migration inhibitoryfactor (MIF). TGF-�’s inhibitoryactivity on NK cells is delayed intime, whereas MIF acts quickly todisarm NK cells. These are the fac-tors in the ocular microenviron-ment that permit tumor cells togrow progressively in the anteriorchamber of mice with an intact in-nate immune system. Immigrationof neutrophils and macrophages in-to the ocular microenvironmentfrom the blood is inhibited by thepresence of �-MSH and TGF-�,and both of these factors interferewith the activation of these inflam-matory cells within the anteriorchamber. In addition, the ability ofactivated macrophages to produceNO is inhibited by calcitonin gene-

Lens

CD4 CD8

IL-10

Fig. 3. Immunosuppressive ocularmicroenvironment where leukocytesthat penetrate through the microves-sels encounter immunomodulatory for-ces: pigmented epithelium of iris, ciliarybody, retina, and AqH containing so-luble immunosuppressive factors. Tcells that enter this microenvironmentacquire regulatory properties that sup-press inflammation.RPE = Retinal pigment epithelium; PE =pigmented ciliary epithelium; NPE =nonpigmented ciliary epithelium; AC =anterior chamber; PC = posteriorchamber; CB = ciliary body.

Cornea

Vitreous body

Retina

Choriocapillaries

RPE

Iris

Ciliary body

IL 12 CD 4D

Cla

ss II

CD

1

NK T

TCR

TGF-�IL-10

TCR

TGF-�

TGF-�

TCR

B

A

MIP-2

APCC

D1

CD

1

CD

1

TCR TC

R

TCR

NK T

MIP-2

CXC

R2

TGF-�

IL-10NK T

APC

ACAID

APC

2 3

MIP-2

TGF-�

Class II

IL-10

Anterior chamber(aqueous humor)

PC

AC

NPE

PE

Iris

Cornea

Ciliary body

Vessel

Sclera

Choroid

RPERetina

PCAqueous humor��MSH, TGF-�2

Ciliary bodyStroma

NPE PEVessel

Extravasation

T cell

CB

RegulatoryT cell

8KargerGazette

Face to Facewith an Untreatable Disease

Christina FasserPresident of Retina International Zürich

ty other young people normally en-joy. Since I had no other choice, Iwas open about my visual impair-ment, but I knew that my peerscould never guess how severelyimpaired I really was. As we alllearn to do, I invented a lot of dif-ferent strategies to help me over-come or avoid uncomfortable ordifficult situations.

RP causes a gradual loss of vi-sion and the sight that you do haveis never really stable. Dependingon the lighting, you may see every-thing very clearly, if it is good butif it is bad, you may see nothing atall. This means that from one mo-ment to the other, I had to performfirst as a sighted person and thenbehave as a perfectly trained blindperson. Looking back, I would de-scribe this period of slow visionloss (about 15 years) as the mostdifficult time of my life. Being inthis no-man’s-land between theworld of the sighted and the worldof the blind was an enormousstress. I always believed what I sawat first sight, but soon came to re-alize that this was not always cor-rect and that I could not necessari-ly trust my own eyes. This was es-pecially difficult in social interac-tion: Family members and friendsnever knew when I actually need-ed help and when not. Today, I amcompletely blind and for both my-

Patients with retinal degenera-tive diseases have one thing incommon: We are all faced with thethreat of blindness, and, in ourhearts, we all carry the hope thatone day a treatment for our condi-tion will be found which may haltor cure the process. Ophthalmolo-gists call us patients, but as a mat-ter of fact we are ‘impatients’, go-ing steadily blind day by day with-out a cure in sight. Researchers arewalking step by step beside usalong the stony path towards anunderstanding of the causes ofretinal degenerative diseases andtowards our mutual goal of findinga cure.

We all remember the momentwhen we or one of our loved oneswas first diagnosed with the dis-ease. I was only 13 years old whenthey told me I had retinitis pig-mentosa (RP). My parents werevery open and tried to explain theextent of the disease to me, gentlybut without hiding the fact thatone day this condition would leaveme blind. Contrary to common ex-pectations, this news did not reallybother me at the time. The expla-nation of my night blindness aswell as the fact that my field of vi-sion had decreased to about 8 de-grees helped me understand themany strange things that had beenhappening to me: I always won-

dered why other people could findthings so quickly in the dark orwhy they didn’t seem to have anyproblems catching a ball or jump-ing over an obstacle. The diagnosissomehow gave me a new freedom– I no longer had to play volleyballand other competitive games;games in which I could never fullyparticipate and which embar-rassed me each time none of theother children wanted to have meplay on their team.

The first time I realized the im-pact of the disease on my personallife was when I was ready to choosea profession. My interests were inscience or medicine, but beingseverely visually impaired thesedreams were not to come true. Re-alizing that my future was not inmy own hands sometimes mademe frustrated and angry, and Ikept asking myself: Why me?However, I was lucky to havegrown up in a very supportive fam-ily who have a positive attitude to-wards the future. I decided to gointo advertising where I gave mybest and was successful. Since Ihad so-called tunnel vision and avery good central visual acuity,reading was not a problem for meand helped me continue to live mylife as normally as possible. Driv-ing was never an option and Isometimes missed the free mobili-

related peptide (CGRP), anothernormal constituent of AqH. Solublefactors in AqH also inhibit the acti-vation of complement via the alter-native pathway. As of yet, the iden-tity of the inhibiting molecule is un-known. Undoubtedly, other factorsexist in AqH that contribute to thesuppression of innate immune cellsand molecules; so much remains tobe learned.

Molecules expressed on cellslining the anterior chamber also in-hibit innate immune effectors. Sev-eral membrane-associated in-hibitors of complement activation(CD55, CD59, CD46) are constitu-tively expressed, and act to inhibitcomplement-dependent inflamma-tion. Very recently, Kaplan and hisassociates have discovered that afourth membrane complement in-hibitor (Scrry) that is expressed inthe normal eye plays a key role in in-hibiting LPS-induced inflamma-tion in the eye. Mice in which thegene for this inhibitor has beentransgenically knocked out have aheightened susceptibility to LPS-in-duced uveitis.

Clinical Meaning of Ocular Immune PrivilegeAt the beginning of this article,

the argument was advanced thatimmune privilege in the eye is de-signed to limit the intraocular ex-pression of inflammation, primari-ly because inflammation in this or-gan disrupts the visual axis andcauses blindness. In addition to theextraordinary success of orthotopiccorneal transplants in humans, arethere other clinical situations inwhich ocular immune privilegemight be implicated? A few possibleexamples are advanced below:

Sympathetic OphthalmiaTrauma to the eye that pene-

trates the globe and disrupts in-traocular tissues can cause sympa-thetic ophthalmia. Experimentalevidence indicates that the uveitisthat develops in the contralateraleye is directed at retinal autoanti-gens, implying that these powerfulantigens were released by the trau-ma and sensitized the patient. Yet,only a small minority of individualssuffering such an ocular wound ac-tually develop sympathetic oph-thalmia. Perhaps a reason whymore patients don’t develop this au-toimmune complication is thatantigen released by the trauma in-duces ACAID. If true, this is an ex-ample where the physiologic exis-tence of immune privilege provesadvantageous to the eye.

Recurrent Herpes UveitisClearance of the herpes simplex

virus from infected tissue (such asin herpes labialis) depends uponimmunity mediated by CD4+ Tcells of the delayed hypersensitivitytype. In experimental animals,ACAID can be induced to HSVantigens, i.e. the animals fail to ac-quire HSV-specific delayed hyper-sensitivity. Transient inhibition ofCD4+ T-cell immunity early in ocu-lar herpes infection markedly re-duces the incidence of stromal ker-atitis in mice, indicating that ocularimmune privilege protects vision.A similar protective effect of

Selected Reading

Streilein JW (ed): Immune Responseand the Eye. Chem Immunol. Basel,Karger, 1999, vol 73.

Streilein JW: Regional immunity andocular immune privilege. Chem Im-munol. Basel, Karger, 1999, vol 73,pp 11-38.

Streilein JW: Immunobiology and im-munopathology of corneal trans-plantation. Chem Immunol. Basel,Karger, 1999, vol 73, pp 186-206.

Taylor AW: Ocular immunosuppressivemicroenvironment. Chem Im-munol. Basel, Karger, 1999, vol 73,pp 72-89.

Sonoda KH, Exley M, Snapper S, BalkSP, Stein-Streilein J: CD1-reactivenatural killer T cells are requiredfor development of systemic toler-ance through an immune-privilegedsite. J Exp Med 1999;190:1215-1226.

Streilein JW, Stein-Streilein J: Does in-nate immune privilege exist? JLeukoc Biol 2000;67:479-487.

J. Wayne Streilein is Charles L.Schepens Professor of Ophthalmologyat Harvard Medical School, Vice-Chairfor Research of the Harvard Depart-ment of Ophthalmology, and Presidentof the Schepens Eye Research Institutein Boston, Mass. Dr. Streilein is a recip-ient of a Research to Prevent BlindnessSenior Scientific Investigator Award.He is the editor of the book ‘ImmuneResponse and the Eye’ (Chemical Immunology, vol 73), published byKarger in 1999.

ACAID might also occur in hu-mans. However, some patients re-cover from an acute ocular herpesinfection only to develop recurrentherpes uveitis during which livevirus can be recovered from the af-flicted eye. The possibility existsthat in these subjects ACAID maypersist indefinitely and thereby pre-vent immune elimination of virusfrom ocular tissues, thus promotingpersistent, recurrent infections. Iftrue, this would be an examplewhere the existence of immuneprivilege has a disadvantageousoutcome.

It remains to be determined ex-perimentally whether innate andadaptive immune privilege, or itsloss, plays a role in eye diseases.One can imagine that the incidenceand severity of acute anterioruveitis might be reduced because ofthe existence of immune privilege,and one can speculate that rapidgrowth of spontaneous intraoculartumors might depend upon the in-tegrity of immune privilege. Con-sidering the power of ocular privi-lege to suppress innate immune ef-fectors, the possibility even existsthat immune privilege may have arole in the pathogenesis of diseaseswith inflammatory components –such as age-related macular degen-eration, optic neuropathy of glauco-ma, and even diabetic retinopathy.Working out the details of themolecular basis for ocular immuneprivilege promises a cornucopia ofnew approaches to the many multi-factorial diseases that are currentlyuntreatable and that cause signifi-cant loss of sight.

9KargerGazette

op drug therapies that prevent or delay thisprocess. Several new forms of biologicaltreatment approaches are currently beingdeveloped which have shown some efficacy

in animal models but have still to be tested forlong-term effectiveness and safety before they can

be studied in humans. These include the use of growthfactors to delay cell death; cell transplantation, i.e. re-placing photorector cells or retinal pigment epitheliumcells with new healthy ones; and gene therapy whichaims at replacing the mutated genes with nondefectivegenes. With more and more gene mutations being iden-tified, many researchers consider gene therapy apromising approach for the future; however, there arestill many obstacles to overcome, e.g. how to transferDNA of the healthy gene into the diseased cells. Furtherinvestigations focus on the development and assess-ment of neuroretinal implants (microchips), whichwould receive visual information transmitted from acamera mounted on a pair of glasses and thus restorerudimentary vision. The next big step will be the trans-fer of these basic findings into clinical trials.

Challenges for the Member OrganizationsRetina International has emerged into the 21st cen-

tury ready for change and adaptation. This centurypromises new and exciting discoveries thanks to the re-cent progress of research, and there is optimism that thenext few decades will bring about a cure for retinal de-generative diseases. However, this is not the time to sitback! On the contrary, all efforts must be accelerated tomeet the following challenges:

Bringing research from university laboratories intothose of the pharmaceutical industry: It is important todevelop strategies to lobby for the necessary funds forclinical trials which swallow up huge sums of money.

Patient recruitment: To access those patients whofit the criteria for the first clinical trials, national mem-ber organizations must actively promote reliable andupdated patient registries.

Improved cooperation and solidarity between themember organizations: Retina International is a grow-ing organization with members from different econ-omic and cultural backgrounds whose needs will beeven more diverse in the future. The experienced, well-organized and well-established national organizationsshould support the newly emerging ones.

For more information please contact Retina Internationalor one of its member organizations:

Retina InternationalAusstellungsstrasse 36CH–8005 Zürich (Switzerland)Tel. +41 1 444 10 77Fax +41 1 444 10 70www.retina-international.org

Retina International (formerly Interna-tional Retinitis Pigmentosa Association) isa voluntary charitable umbrella organiza-tion of more than 40 national patient orga-nizations for people with retinal degenera-tive diseases (see below) such as retinitis pigmen-tosa (RP), macular degeneration, Usher syndrome andallied retinal dystrophies, as well as their families andfriends. The two main objectives of Retina Internation-al are:

1. To promote and fund research directed at findingthe cause and developing a treatment and, ultimately, acure for retinal degenerative diseases, especially the in-herited forms.

2. To foster mutual support among its members,families and friends.

Furthermore, the organization strives to promotepublic awareness by providing and exchanging infor-mation on retinal degenerative diseases, and to supportthe establishment of new patient societies.

The first two RP organizations were founded simul-taneously and independently in Finland and the USA.People felt the need for more communication and wereconcerned that not enough research was being done tofind a cure for RP. A worldwide movement was thusborn and, in 1978, nine national organizations joinedtogether and founded the International Retinitis Pig-mentosa Association. Later on, the organization decid-ed to broaden the scope of its activities to include allforms of retinal degenerative conditions and changingthe name to Retina International was the logical conse-quence. The Retina International member organiza-tions represent over 140,000 members worldwide andraise more than USD 25 million per year, which is in-vested in research. Each member association and Reti-na International are advised by their own scientific andmedical advisory boards.

Impact of Retinal Degenerative DiseasesRetinal degenerative diseases affect over 10 million

people in Europe. Age-related macular degeneration isthe major cause of severe visual impairment in the pop-ulation over 60 years of age and is on the increase. Thereasons for this increase are unknown. Inherited formsof retinal degenerative diseases such as RP and Ushersyndrome usually affect peripheral vision causing night-blindness and tunnel vision. The age of onset in the ma-jority of cases is during the second decade of life. Thishas severe implications during the patient’s most activeyears, resulting in underemployment, early retirementand severe financial hardship for the affected families.

The Current State of Research Over the last few years, research into the cellular

and genetic defects that cause retinal cell death hasmade great progress. For some inherited retinal dis-eases, the affected genes and proteins have been identi-fied. The challenge now is to understand the connectionbetween the abnormal function of individual proteinsand the death of photoreceptor cells as well as to devel-

self and others it is obvious whenhelp is needed.

Although it might seem para-doxical, it was almost a reliefwhen, 8 years ago at the age of 42,I finally lost my vision complete-ly. At last I knew exactly where Istood. And, despite the pain ofthis loss, going blind can also havesome interesting aspects. I am bynature a very visual person, andthe fact that my brain still workswith images despite the lack of vi-sual input fascinates me. All thethings that I had been able to seebefore now serve as precious trea-sures for my imagination. Goingblind also meant that I had to ex-plore my own limits and over-come my personal anxieties. I al-ways hated being dependent onothers and my wish for indepen-dence spurred on my will toquickly master the different reha-bilitation techniques such aswalking with a white cane as wellas the simple tasks and skills oneneeds just to get through the day.

The two things I miss most ofall though are not being able to seethe expression on people’s faceswhen I speak to them and the abil-ity to read print. Being unable tosee who is around means that Ihave to depend on others to ap-proach me and start any social in-teraction that may take place. Ithas happened that I had attendedan event and only realized laterthat people were there who Iwould have loved to meet again. I used to read everything thatcame into my hands. Now, eventhough a great number of booksare available on tape or via talkingcomputers, nothing can reallycompensate for the pleasure youget from visiting a book shop, tak-ing a book in your hands, andbrowsing through the new bookson the shelf. Still, I believe thatthere has never been as good atime as today to be blind: Tech-nology is making immense prog-ress. Computer technology, for example, has opened up totallynew possibilities to acquire infor-mation independently. With theaids available 20 years ago, Iwould never have been able towork in such an interesting and re-warding profession as the one Iam in today.

To be faced with an untreat-able disease is difficult to copewith and each of us deals with it indifferent ways. For me it was thereason I decided to join the RP or-ganization of my country 20 yearsago and to take an active part inthe fight for sight. Despite the factthat there is still no treatmentavailable, I can see the differencebetween now and then: Todaythere is well-founded hope thatthis situation will change sooneror later. Through my work in theorganization I have had the op-portunity of getting to know manywonderful people – patients andresearchers – who I would neverhave met otherwise. Should thisbe the deeper sense of my havingRP? If so, what better rewardcould I get than friendship?

Retina International

cones, resulting in a progressive loss ofvision and, possibly, blindness. Usually,the rod cells are the first to degenerate,causing night blindness and ‘tunnel vi-sion’ (fig. 1). RP is most often diagnosedduring childhood or early adulthood. De-pending on the type of RP, the rate ofprogression varies. To date, there is noknown way to halt the degeneration ofthe retina or to cure the disease.

Macular degeneration refers to agroup of disorders in which the break-down of cells is limited to the macula,leading to a loss of central vision (fig. 2).The most common form, age-related mac-ular degeneration (AMD), usually affectspeople over the age of 60. There are twotypes of AMD: ‘dry’ and ‘wet’. Dry AMDaccounts for about 90% of all cases.With dry AMD, yellow-white depositscalled drusen accumulate in the retinalpigment epithelium tissue beneath the

macula. In wet AMD, abnormal bloodvessel growth forms beneath the macu-la. These vessels leak blood and fluid in-to the macula damaging photoreceptorcells. In some cases, if wet AMD is diag-nosed early, laser surgery has beenshown to reduce the risk of extensivemacular scarring. Hereditary forms ofmacular degeneration with an early on-set, such as Stargardt disease, Best’s dis-ease or progressive cone dystrophy, alsoexist. As a general rule these diseasescause severe visual impairment but rarelyresult in complete blindness.

For the vast majority of MD patientsthere is currently no effective treatment,but a number of effective visual aids andrehabilitation options are available.

Individuals with Usher syndromesuffer from RP and congenital deafnessor progressive hearing loss.

Fig. 1.

Fig. 2.

Normal vision.

Normal vision.

Loss of peripheral vision (‘tunnel vision’) inRP. In some cases small patches of retinal activity on the periphery are preserved, making it possible to detect movement andobjects that help improve orientation.

Loss of central vision in macular degenerati-on. Affected individuals have difficulty rea-ding and recognizing faces, but enough pe-ripheral vision is retained for good orientati-on and mobility.

Retinal Degenerative

Diseases

The retina is a specialized light-sensi-tive tissue at the back of the eye that con-tains photoreceptor cells (rods and cones)and neurons connected to a neural net-work for the processing of visual informa-tion. The rods function in conditions oflow illumination whereas cones are re-sponsible for color vision and all visualtasks that require high resolution (e.g.reading). The rods are mostly locatedaway from the center of the eye in theretinal periphery. The highest concentra-tion of cones is found at the center of theretina, the macula, which is necessary forvisual acuity. For support of its metabolicfunctions, the retina is dependent on cellsof the adjacent retinal pigment epitheli-um.

Retinitis pigmentosa (RP) desig-nates a group of inherited diseases thataffect the retina and are characterized bya gradual destruction of the rods and

Fig. 3. Peripheral YAG laser iridotomyat 12.00 h in the midperipheral iris.

a

b

The origin of light treatment tothe eye dates back to 400 BC, whenPlato recognized the power of lightand described the dangers of staringdirectly at the sun during an eclipse.In 1946, Gerd Meyer-Schwickerath,a German ophthalmologist, firstdemonstrated the use of light to co-agulate retinal tissue (photocoagula-tion) in humans [1]: By focusing thelight of a xenon arc lamp he inducedsmall burns on the retina to seal reti-nal tears – a technique which was torevolutionize the treatment of eyediseases. The first functioning laserwas built by the physicist TheodoreMaiman in 1960, and the first clini-cal ophthalmic laser treatments inhumans were reported by CharlesCampell and coworkers in 1963 andChristian Zweng and coworkers in1964 [2]. Because light can reach al-most any ocular structure noninva-sively, lasers have had a greater im-pact on ophthalmology than on anyother field in medicine.

‘Laser’ is an acronym for ‘lightamplification by stimulated emis-sion of radiation’. Stimulated emis-sion, first predicted theoretically by

Albert Einstein in 1917, is the fun-damental physical process thatmakes lasers possible. There arethree basic interactions betweenlight (photons) and electrons [3]: (1)Absorption – an atom absorbs a pho-ton, which forces one of its electronsto move to a higher energy orbit. (2)Spontaneous emission – an atom inits excited state emits a photonwhen an electron falls back to a low-er energy orbit. (3) Stimulated emis-sion – a photon interacts with anatom that has energy stored andstimulates an electron to fall onto alower energy orbit and produce asecond photon, coherent with thefirst. There are many ways of pro-ducing light, but stimulated emis-sion is the only known method thatproduces coherent light. For an out-put of just 1 mW, a minimium of1016 stimulated emissions per sec-ond are necessary. The realization ofthis concept was so difficult that ittook over half a century between thetheoretical prediction of stimulatedemission and the construction of apractical laser light source. Gas andsolid-state lasers are the most widely

Thermal: Absorption of laser en-ergy (visible or infrared light) by tis-sue pigment results in temperatureincrease (e.g. photocoagulation,Ho:YAG).

Photochemical: Ultraviolet andvisible light absorption induces theformation or destruction of chemi-cal bonds (e.g. photodynamic thera-py, excimer laser).

Mechanical: Plasma formation(optical breakdown) leads to tissuedisruption (e.g. photodisruptionwith Nd:YAG)

Vaporization: Micro-explosionoccurs due to the sudden rise in wa-ter temperature to above boilingpoint (e.g. Er:YAG)

Ophthalmology was the firstmedical discipline to apply lasers assurgical tools. Over the last 30 years,lasers have become the treatment ofchoice for disorders involving al-most every part of the eye, and wecan distinguish their use in anteriorsegment, refractive, pediatric andretinal surgery.

Anterior SegmentSurgery The use of lasers in treating an-

terior segment anomalies becamepopular in the last 30 years. As theanterior segment is easily accessiblewith conventional surgery, it tooklonger until laser surgery was usedroutinely in this part of the eye. Dis-orders for which lasers are used to-day are cataract (a clouding of the

eye’s natural lens which leads toblurred or decreased vision) andglaucoma (vision loss due to damageto the optic nerve, which is oftencaused by increased intraocularpressure).

Laser Surgery for Cataract Cataract RemovalThe current standard surgical

technique to remove a cataract isphacoemulsification, introduced byCharles Kelman in 1967. A small in-cision of about 3 mm is made on theside of the cornea, the center of thelens is softened with ultrasoundwaves and removed, followed by theimplantation of an artificial foldableintraocular lens. Removal of the hu-man crystalline lens by laser (laser-phaco) has been a dream for a long

used in clinical ophthalmology (fig. 1). In gas lasers, atoms of aworking gas (e.g. argon or krypton)are enclosed in a cylindric tube andeventually one of the high-energyelectrons undergoes spontaneousemission and generates a photon ofthe correct frequency to cause stim-ulated emission. By repeatedly re-flecting the photons back and forthacross the cylinder tube with thehelp of mirrors placed at oppositeends of the tube, a chain reaction ofstimulated emission is produced.One mirror reflects totally and theother partially, and the relativelysmall amount of light that is allowedto pass through the partially reflect-ing mirror produces the laser beam,either continuously or pulsed.

Lasers can have various effectson the target tissue depending on thewavelength and power used:

Thomas Kohnen

Johann Wolfgang Goethe

University, Frankfurt a.M.

10KargerGazette

Fig. 2. Posterior chamber intraocularlens implantation.a Posterior capsule opacification. b Nd:YAG laser posterior capsulotomyto open the posterior capsule.

Lasers in Eye Surgery

Fig. 1. Electromagnetic spectrum of lasers used in eye surgery.

Argon488-514 nm

Green HeNe543 nm

HeNe632 nm

Diode680 nm

Nd: YAG1064 nm

CO2

10,600 nm

400 nm 750 nm

Ultraviolet Visible light Infrared

ArF193 nm

KrF248 nm

XeCI308 nm

XeF351 nm

11KargerGazette

time and is currently in the devel-opmental stage. Three differentlasers are being used: neodymi-um:yttrium-aluminum-garnet (Nd:YAG) in the near-infrared energyrange with a 1.064-µm wavelength,erbium:yttrium-aluminum-garnet(Er:YAG) with a wavelength of 2.94µm, and yttrium-lithium-fluoride(picosecond laser). Each of theselasers holds great promise as a fu-ture clinical tool, but so far hardcataracts cannot be effectively re-moved and the surgical time neededto remove a standard cataract iscomparable with that of phaco-emulsification. Although manyophthalmologists believe that someform of laser technology will be thefuture of cataract surgery, its puta-tive advantages over standard ultra-sonic methods still remain to beproven. More research is necessaryto achieve safer and gentler cataractsurgery.

Neodymium: YAG Laser Secondary cataract formation

(or after-cataract) is a significantlate complication in people who un-

dergo extracapsular cataract extrac-tion, a procedure in which the sur-geon removes the lens nucleus man-ually or with phacoemulsification(see above). In both types of surgerythe posterior half of the capsule, theouter covering of the lens, is left be-hind. Following intraocular lens im-plantation, a formation of posteriorcapsular opacification (PCO) maydevelop (fig. 2a). The frequency ofPCO is age-related. Almost all chil-dren develop PCO after extracapsu-lar cataract extraction, whereas theincidence is much lower in adults.PCO decreases the visual acuity andtherefore significantly diminishesthe treatment success of cataractsurgery. Patients with PCO requireposterior capsulectomy, a proce-dure which removes the central part

of the posterior capsule and instant-ly improves vision. Nowaday thisopening of the posterior capsule(disruption of the posterior capsularbag membrane) is performed in afew seconds using an Nd:YAGlaser. The procedure can be carriedout on an out-patient basis at the slitlamp (fig. 2b). It has become thetreatment of choice and has re-stored the visual acuity of millionsof patients who were still unhappyafter cataract removal.

Laser Surgery for GlaucomaLasers play an important role in

modern-day treatment of glauco-ma, where their main use is to low-er intraocular pressure (IOP).

Argon Laser Trabeculoplasty Argon laser trabeculoplasty

(ALT) is a firmly established, well-tolerated procedure used to lowerIOP in various types of open-angleglaucoma. It is performed by plac-ing small, evenly spaced, nonpene-trating argon laser spots into the tra-becular meshwork of the angle in

the anterior chamber, which allowthe aqueous humor to drain. A peri-od of at least 4–6 weeks after ALT isrequired before the final result canbe evaluated. Results show thatALT has managed to control IOP in67–80% of eyes for 1 year, 35–50%for 5 years and 5–30% for 10 years.

Peripheral Laser Iridotomy In 1857, von Graefe introduced

surgical iridectomy for the treat-ment or prophylaxis of narrow-an-gle glaucoma. In 1956, Meyer-Schwickerath demonstrated that aniridectomy could be created with-out the need for an incision, usingxenon arc photocoagulation. Thismethod failed to gain popularity be-cause of frequently occurring lensand corneal opacities. However,

with modern lasers (argon andNd:YAG), laser iridotomy has nowessentially replaced surgical iridec-tomy in the vast majority of cases(fig. 3).

Refractive SurgeryRefractive or vision correction

surgery includes techniques whichalter the eye’s focusing power bychanging its natural structures,

eliminating the need for glasses andcontact lenses. In the year 2000, al-most 2 million refractive proce-dures were carried out worldwide,the vast majority (>90%) being per-formed using laser technology.

ExcimerToday’s most advanced refrac-

tive surgical techniques are per-formed with the excimer (exciteddimers) laser. The development ofexcimer lasers began in 1975, wheninvestigators noted that under highpressure meta-stable rare gas atomsproduce unstable compounds.These compounds rapidly dissoci-ate to the ground energy state of theindividual molecules with the re-lease of an energetic ultraviolet pho-ton. These molecules can be in-

duced to produce light amplifica-tion by stimulated emission whenthey are excited by an electronbeam; the ArF (argon-fluorine)molecule emits light with a wave-length of 193 nm. At this wave-length corneal tissue can be re-moved with extreme precision –about 0.25 µm of corneal tissue isremoved with each pulse – and withminimal damage to the surroundingtissue (fig. 4). For myopic correc-tion central tissue has to be re-moved causing a flattening of thecornea; for hyperopic correctionperipheral tissue is ablated to causecentral steepening of the cornea,and for astigmatism an ellipticalshape is removed to make all merid-ians of the cornea equally steep orflat. Today, the two main tech-niques used to correct refractive er-rors by reshaping the cornea arephotorefractive keratectomy (PRK)and laser-assisted in situ ker-atomileusis (LASIK).

With PRK, the superficial layerof the cornea, the epithelium, is re-moved mechanically, and then aspecific amount of stromal tissue isablated using an excimer laser. Un-til the epithelium is healed, whichusually lasts 3–4 days, a protectivesoft contact lens can be placed onthe eye and corticosteroid eye dropsare administered for 3–6 months.Overall, the results for PRK havebeen acceptable and have im-proved with experience. Currently,PRK is in use for myopia of up to–6.0 dpt, for astigmatism, and forhyperopia of up to +5 dpt. Typicalcomplications are over- and under-correction, central scar formation(haze) and corneal infections. Thewound-healing process is prolongedand stability is mostly not achievedbefore 6 months.

The second technique, LASIK,is a combination of a lamellar cutinto the cornea and corneal stromalablation using the excimer laser.The lamellar cut is produced with amicrokeratome, cutting to a depthof about 120–160 µm, and leavingthe flap attached to the cornea by ahinge (fig. 5). Excimer laser ablationis performed after the flap has beenlifted up, leaving the stromal tissueof the cornea uncovered. After theablation the flap is folded back ontothe stromal bed, and within min-utes the flap is attached by internalcorneal forces and heals without su-tures. The healing process is muchfaster after LASIK and a visual acu-ity of 20/20 (1.0) uncorrected on thefirst postoperative day is not rare.Correction of myopia up to –10.0dpt, hyperopia up to +5.0 dpt and

astigmatism of up to –5.0 dpt is pos-sible and successful when all thecontraindications for this type ofprocedure (thin corneas, extremelylarge pupil diameter and cornealpathology) are taken into considera-tion. Currently, other lasers like pi-cosecond or femptosecond laser arebeing evaluated for their perfor-mance in intrastromal ablation orcorneal lamellar incisions. Newmethods which correct the aberra-tions of the whole optical system,e.g. wavefront aberroscopy, are alsobeing developed to increase the bestcorrected visual acuity of a humaneye following refractive surgery.

Laser Thermal KeratoplastyLaser thermal keratoplasty

(LTK) is a promising new techniquewhich uses laser energy to gentlyheat peripheral corneal tissue, pro-ducing a change in the cornea’s re-fractive power. 16 or 32 spots areplaced on the cornea in a symmetri-cal, circular fashion with high accu-racy (fig. 6). Absorbed laser light in-creases the temperature of waterand adjacent collagen fibrils, thuscausing them to contract. The re-sulting tension produces a steepen-ing of the anterior cornea over theoptical zone, which is intended tocorrect hyperopic refractive errors.Currently, two types of thermallasers are being used for hyperopicLTK: the holmium:yttrium alu-minum garnet (Ho:YAG) laser (fig.7) and the continuous-wave diodelaser. Laser energy is delivered byeither the noncontact or the contactmode. The procedure offers a solu-tion for people over 40 who requireglasses for reading, and correctionsof up to +3.0 dpt of hyperopia canbe achieved. In some patients, how-ever, the result is not permanentand retreatment might be neces-sary.

Pediatric Eye SurgeyA disease occurring in some pre-

mature babies is retinopathy of pre-maturity, which is the growth of ab-normal blood vessels in the retina,induced by an ischemic, avascularretina. Over time, this vessel growthmay produce a fibrous scar tissuewhich attaches to the retina andmay cause retinal detachment andeventually blindness. The hyperop-ic environment of the pretermneonate is directly linked to theseverity of disease. Standard treat-ment has been cryotherapy of theanterior avascular retina in the in-fant eyes that reach ‘thresholdretinopathy’. Recently, both argonand diode laser indirect ophthalmo-

Fig. 4. Precise removal of tissue(human hair) using the excimer laser.

Fig. 5. Lamellar cut of the corneausing a microkeratome for laser in situkeratomileusis with the excimer laser.

12KargerGazette

scope systems have been developedfor transpupillary peripheral retinalablation. Laser treatment is at leastas effective as cryotherapy if notmore so [4], and it is also easier toapply, especially for posterior dis-ease. Where available, lasers havelargely supplanted cryotherapy, ex-cept in cases of severe cloudy me-dia. Besides this main indication,retinoblastoma or posterior seg-ment diseases in children have beentreated using argon or YAG lasers.

Retinal SurgeryPhotocoagulation of the Posterior SegmentUsing topical anesthesia and a

contact lens, the laser light for pho-tocoagulation can be delivered intothe eye by a slit-lamp delivery sys-tem. Diseases or conditions which

are treatable by photocoagulationinclude diabetic proliferativeretinopathy (fig. 8), diabetic macu-lar edema, branch retinal vein oc-clusion, peripheral retinal andchoroidal neovascularization, idio-pathic central serous chorioretino-pathy, vascular anomalies, nonvas-cular tumors, and retinal breaks.The spot size is dependent on the lo-cation of the treatment: 50–200 µmfor macular photocoagulation,200–1,000 µm for peripheral retinalspots. Power and burn duration areinitially set according to desiredburn intensity, and the aimingbeam intensity is set to the lowestlevel that permits adequate beamvisualization. The retinal burn, oropacification, produced duringphotocoagulation is due to proteindenaturation in the outer retina [5].

Fig 6. Corneas with a circular ring of Ho:YAG laser spots for the treatment of hyperopia, whichleads to a central steepening of the cornea.

Fig 7. Laser thermal keratoplasty with the Ho:YAG laser.

Thomas Kohnen is associate profes-sor of ophthalmology (‘Privatdozent’) at the Johann Wolfgang Goethe Univer-sity in Frankfurt where he heads the De-partment of Refractive Surgery. SinceOctober 2000, he is also visiting associ-ate professor at the Cullen Eye Instituteat the Baylor College of Medicine inHouston, Texas. Dr. Kohnen is current-ly editing the book ‘Modern CataractSurgery Update’ to be published byKarger in the second half of 2001.

References1 Meyer-Schwickerath G: Develop-

ment of photocoagulation; inMarch WF (ed): OphthalmicLasers: A Second Generation. Tho-rofare, Slack, 1990, pp 13-19.

2 Ip M, Kim V, Puliafito CA: Basicprinciples of retinal surgery: Laserphotocoagulation; in Yanoff M,Duker J (eds): Ophthalmology.London, Mosby, 1999, 8.4.1.

3 Thall EH: Principles of lasers; inYanoff M, Duker J (eds): Ophthal-mology. London, Mosby, 1999,2.5.1.

4 Laser Retinopathy of PrematurityStudy Group: Laser therapy forretinopathy of prematurity. ArchOphthalmol 1994;112:154-156.

5 Bloom SM, Brucker AJ: LaserSurgery of the Posterior Segment,ed 2. Philadelphia, Lippincott-Raven, 1997.

6 Treatment of Age-Related MacularDegeneration with PhotodynamicTherapy (TAP) Study Group: Pho-todynamic therapy of subfovealchoroidal neovascularization inage-related macular degenerationwith verteporfin. Arch Ophthalmol1999;117:1329-1345.

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Photodynamic TherapyAge-related macular degenera-

tion is a major cause of severe vi-sion loss in people older than 65years in North America and Eu-rope. Loss of visual acuity resultsfrom choroidal neovascularization(CNV). The standard treatment forchoroidal membranes involves pho-tocoagulation with a hot laser,which inevitably destroys the adja-cent and overlying normal retina.Now a new treatment method for CNV is available – photody-namic therapy with verteporfin (Vi-sudyneTM) – that can minimize dam-age to the surrounding viable retinaltissue. In this treatment, 15 min af-ter the verteporfin has been injectedintravenously, the drug is activatedby delivering a cold laser light (at689 nm) over 80 s, using a spot size

with a diameter 1,000 µm largerthan the greatest linear dimensionof the CNV lesion. A recent com-parative, placebo-controlled studyhas recommended verteporfin ther-apy for the treatment of patientswith predominately classicCNV resulting from age-re-lated macular degenera-tion [6].

ConclusionLasers have brought

about a revolution inophthalmic surgery: Ow-ing to their precision andnoninvasive nature, theactual surgery can be per-formed on an outpatient ba-sis in a matter of minutes, withlittle or no pain or discomfort.Recovery time after treatment isshort as there are no large incisionsto heal and postoperative complica-tions, e.g. inflammation and infec-tion, are reduced substantially. To-day, almost 40 years after the ad-vent of the laser, medical laser tech-nology continues to evolve rapidlyand ophthalmologists continue toexplore new applications for thistool, whose possibilities for savingand sharpening vision seem to beunlimited.

Fig 8. Argon laser panretinal photocoagulation for the treatment ofproliferative diabetic retinopathy.

Look no further ...

... for the latest in ophthalmology.

You’ll find it on the Karger Website:

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EditorJ.W. StreileinBoston, MA

Immune Responseand the Eye

A.S. Berger, St. Louis, MOP.W. Chen, Boston, MAL.V. Del Priore, Newark, NJJ.V. Forrester, AberdeenR.L. Hendricks, Pittsburgh, PAH.J. Kaplan, St. Louis, MOA. Keane-Myers, Boston, MAB.R. Ksander, Boston, MAG. Liu, Boston, MAM.T. Magone, Bethesda, MDP.G. McMenamin, NedlandsD. Miyazaki, Boston, MAJ.Y. Niederkorn, Dallas, TXY. Ohashi, EhimeS.J. Ono, Boston, MAJ.W. Streilein, Boston, MAA.Tai, Boston, MAA.W.Taylor, Boston, MAT.H.Tezel, St. Louis, MOS.M. Whitcup, Bethesda,

215 t 1 t 01

33 t1 t 01

Developments in Ophthalmol-ogyEditor: W. Behrens-BaumannVol. 32

Mycosis of theEye and Its Adnexa

W. Behrens-Baumann

Developments in Ophthalmol-ogyEditor: W. Behrens-BaumannVol. 30

Immuno-OphthalmologyEditors

U.PleyerM.ZierhutW.Behrens-Baumann

Developments in Ophthalmol-ogyEditor: W. Behrens-BaumannVol. 31

ABC

Uveitis UpdateEditor

D. BenEzra

Apollo, god of light,

music and the arts, medicine,

reason and archery.

Plaster cast of a marble

bust in the British Museum,

London:

Roman copy of a Greek

sculpture dating from

around 470 BC

(Skulpturhalle Basel,

Switzerland;

photo by G.Schmid).