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ARTICLE
Year : 1957  |  Volume : 5  |  Issue : 2  |  Page : 23-50

Adenwalla oration - Immunological study of lens proteins


King Edward Memorial Hospital, Parel, Bombay, India

Date of Web Publication10-May-2008

Correspondence Address:
S N Cooper
King Edward Memorial Hospital, Parel, Bombay
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Cooper S N. Adenwalla oration - Immunological study of lens proteins. Indian J Ophthalmol 1957;5:23-50

How to cite this URL:
Cooper S N. Adenwalla oration - Immunological study of lens proteins. Indian J Ophthalmol [serial online] 1957 [cited 2020 May 28];5:23-50. Available from: http://www.ijo.in/text.asp?1957/5/2/23/40746

Table 1

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Table 1

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I express my deep gratitude to the All-India Ophthalmological Society for offering me to give this oration. To me, this oration, which goes by the name of the Adenwalla Oration is of deeper significance than to any other ophthalmologist, for Dinshaw Adenwalla in whose memory this fund was first started and then handed over to the All India Ophthalmological Society was a class-mate of mine, warming the same benches at the New High School of Bombay. He lost his life at the young age of 25 in a courageous attempt to save a drowning man off the shores at Juhu in the treacherous pre-monsoon sea. May the labour of my study I present today be judged worthy in memory of the life of a school-companion who met a hero's death, so untimely.

The subject I have selected for today's oration is a subject in which I have interested myself for nearly 20 years, and my views today on the subject are not the same sharp ones as at one time as those of an early enthusiast. They have suffered many disagreeable shocks and many sharp angles have been smoothed out. The importance of this subject perhaps has suffered considerably in these days of antihistamins, cortisone and antibiotics, yet in the pursuit of this study, a certain amount of clinical, therapeutic and experimental data has accumulated which I seek to present as of sufficient interest historically as well as therapeutically. I am not sorry for having nursed what is almost an obsession in my case, for I am accused of wearing allergy-tinted glasses. The use of these "glasses" has helped me to see more clearly into the underlying pathological process, perhaps a little more rationally, if not anything else. My hope is. the same tint suits you after what I have to say and you would like to wear it.

The clinical experimentation of this study has not been without its toll and some of the cases have been tragedies which may not have happened if we were not in pursuit of knowledge. We believe that that phase of initial clinical un­certainties is over and we are now in a position to present an approach to post­operative inflammations with a confidence greater than before.

Before I embark on my experiences it is necessary to simplify the present concepts about allergy and immunity which become confusing when it is said that allergy and immunity are parts of the same process. When any foreign matter is introduced into the system it reacts by producing anti-substances to protect itself against the intruder. The foreign matter is called antigen and the antisubstances antibodies. Excess of antibodies get lodged into tissues when they may be called tissue antibodies as opposed to circulating anti­bodies. The former persist even though the latter disappear.

When the same foreign matter is reintroduced into the system after a lapse of time (at least a week) the reaction that follows is called an anaphylactic (histamin-shock) reaction, and which can be of a very severe nature.

There are certain organs of the body that take up and house these anti­bodies more readily and are called "shock organs", the notable among them being the nasal mucous membrane, the respiratory passages, the skin and the EYE.

The whole phenomena can be compared to a desert warfare. A desert-fort is attacked by an enemy. If the attack is strong, or is on two or more fronts the fort will crumble before a chance is given for the defense to be built up. But if the attack is not so strong, the fort will send out messages for help, and soldiers will be brought on the same scene in sufficient numbers in about a week's time. Fighting will take place outside and inside the fort to neutralise the intruder. The brunt of the attack will be borne by one of the "shock-towers". The enemy then retreats. The fortress though damaged will be rendered immune to further attacks by the presence of soldiers outside the fort. [Figure - 1].

These soldiers, their work done, will gradually disappear from the scene, leaving a garrison behind in the "shock tower". Inside the tower the atmosphere is tense, because there is no knowing when the enemy will return. This tenseness causes bad tempers to prevail, and thus keeps the highly strung garrison in the damaged "shock-towers" in a state of sensitized activity. If the enemy returns, it thus finds a weakened fort. If the enemy is just strong enough to over-power the garrison only and get nearly destroyed in the attempt, the fighting will cease (a beneficial reaction) and the fort will be saved from further damage. If the enemy force is stronger on the other hand, now the enemy will occupy the fort and the confusion will restart. Once again soldiers will be summoned who will take about 1 or 2 days to arrive. Once again fighting will start and will only stop when both the opposing enemies are exhausted the fort will suffer propor­tionately to the intensity of the fighting and not on who wins the fight.

Nevertheless there is another danger, a danger of mutiny in the sensitized garrison of the damaged shock-tower.

Applying this analogy to the immune-allergic reaction of immunology in the case of the eyes, we can say that the two shock towers are the eyes, the opposing group of soldiers are the antigens and the antibodies, and the garrison, the anti­bodies inside the ocular tissues. Thus when an antigen, say from a tuberculous focus is first liberated into the circulation it induces antibodies against itself. These begin to accumulate and circulate in the blood and their presence in the form of haemagglutination tests are not detected till at least a week has passed. By this time the antibodies are to be found inside the eyes (shock towers) and thus both eyes get sensitized. About this time, if the eye is operated the reaction will be the more severe because the shock of a trauma is added to a sensitized organ.

If a second lot of the same antigen enters the sensitized eyes the fighting inside the eye begins in the form of an anaphylactic reaction which may continue till the antigen is neutralised. If the antigen is not neutralised the fighting continues and the eye is lost from an anaphylactic endophthalmitis. In this losing battle other debilitating factors, like focal sepsis, general debility, diabetes etc., act like "second fronts" in a warfare and contribute to the eventual collapse of the eye.

On the other hand, if the antigen is over-powered, the eye will become quiet but will remain in a sensitised state due to the presence of excess antibodies linked to the ocular tissues. The circulating antibodies will act as a protective umbrella (immunity) against further specific antigen action, and continue their protective action until such time as these antibodies fall below the immunizing level in the blood at the end of about nine months. Thus the "shocked" eye will continue to remain in a sensitised state, under a protective umbrella of general immunity over it, which will mask its hypersensitivity. The protective umbrella when removed the hypersensitivity of the eye will become manifest. This view explains why sensitivity develops in an organ when the antibody level in the serum drops below the minimum immunizing level although it does not disappear completely.

Hektoen (1923) was unable to produce precipitins in the rabbit by the injection of rabbit's lens proteins. However if the rabbit was previously rendered immune/ allergic to another protein, then specific precipitins could be obtained with the homologus (rabbits) lens protein. The amounts to mobilization of specific anti­bodies by a non-specific stimulus and is called an anamestic reaction.

Similarly in human beings it will not be possible to produce antibodies against human lens that is to produce sensitivity to one's own lens proteins unless another immune/allergic reaction has previously taken place from another structurally related antigen.

It is also possible to boost the antigenecity of an otherwise sluggish antigen by certain bacterial toxins (Burky 1934) and other adjuvants. (Freund and Bonanto, 1944). In phacoanaphylaxis therefore a septic or tuberculous focus of infection would particularly render the patient vulnerable to his own lens proteins which may not otherwise act as an antigenic force. This amounts more to a kind of mutiny in the analogy of the desert fortress described earlier. This mutiny will not take place unless the tempers run high to a breaking point due to internal conflicts in the garrison in the shock-tower. Now forces will be mobilized to check the activity of the mutineers and antibodies will be mobilized against lens antigen. Thus sepsis gives more chances for lens antigens to go undegraded into circulation to cause allergic responses, even without an operation as we find in certain cases of Morgagnian cataracts.

This is offered as an explanation to those who feel that it is not possible to get phacoanaphylaxis since it is not experimentally possible to produce lens anti­bodies to one's own lens proteins.

Extending the analogy to diagnosis. the strength of the defense outside and inside the fort will be assessed by sending a small test force into the field. The soldiers outside the fort will be lured out of their hide-outs and the number of the forces engaging this detail will disclose the strength of the enemy (serological tests). If the detail succeeds in reaching the fort, in case the field-forces do not offer resistance, then activity is sure to be aroused inside the fort (i.e. a focal reaction).

Extending this analogy into immunity we can say that if the enemy sends his forces in gradually increasing numbers, the fort defense will summon more and more forces for help and gradually a strong defense will be built up of seasoned warriors. In immunology we call that immunity. But if the invading forces are poured in more rapidly than the defense can cone with, the resistance will drop and the opposite effect (hypersensitivity with focal necrosis) will take place.

If the enemy brings in a double attack with another allergen. e.g. a focal infection or diabetes or any other debilitating factor, the chances work against the integrity of the "tower", as the antibody producing mechanism is over pressed with other antigens. This is offered as an explanation to those who contend that sepsis alone is the cause of so-called phacoanaphylaxis.

In this fight for survival it is assumed that communications are maintained and that is where complementary factors and hormones come into consideration of allergy and immunity. The value of such non-specific factors will be discussed later.

It will be seen that hypersensitivity and immunity are not two different pro­cesses but different results of the same process viz, an attempt to keep off the intruder and so there is only a narrow margin between the two. When general immunity is high tissue sensitivity may be present but is masked. When general immunity dwindles, tissue sensitivity becomes manifest. Thus during immunity, organ sensitivity may be normal or even higher than normal: in the so-called allergic state the organ is hypersensitive and so becomes vulnerable. In anaphy­laxis the resistance of the organ is sorely pressed and may collapse.

It can thus be seen that the crux of the problem is the organ itself, whether you take diagnosis, pathology or treatment, and not the circulating antibodies. For that reason it is the focal reaction that counts most in diagnois and treatment as we shall see later.

Hypersensitivity in the tissues is manifested clinically by a focal reaction in the shock organ when either (1) the same allergen is reintroduced into the system after an interval of at least a week, or (2) the focal resistance of the organ is lowered as by any form of trauma mechanical, bacterial, thermal or even emotional, or (3) another antigen is introduced into the system which eventually seeks to sensitize the same shock organ, the summated effect producing naturally a correspondingly severe reaction, as in a war on two fronts.

Serological tests are negative when the antibodies disappear from the blood if no more antigen is introduced, although the organ sensitivity may remain, and tests for organ sensitivity can be elicited. What is not appreciated is that all shock organs do not participate to an equal extent in the sensitivity. For example, the skin may not participate in the hypersensitivity that may develop in the nasal mucous membrane or the eye, e.g. asthma and urticaria, two of the clinical mani­festations of tissue hypersensitivity may not occur simultaneously.

Another fact which is not too well-known and which has been brought out so beautifully by Woods, Burky and Friedenwald (1940) is that when the eye and the skin have been both rendered hypersensitive to an antigen, the hypersensitivity may run parallel between these two shock organs, if the eye is not inflamed. But if the eye is inflamed, the ocular hypersensitivity runs much higher than dermal sensitivity, with the result that while trying to elicit a sizeable dermal reaction, the same amount of antigen may produce a severe focal reaction in the eye. We have seen this happen more than once in the case of the Mantoux test in cases of suspected ocular tuberculosis. and even in the case of phacoanaphylaxis when at one time we tried to elicit dermal positive tests in increasing strengths of the antigen for diagnosis of the condition.

Again what is not recognised at all, and this we present for the first time, is that focal reactions can be of a beneficial type. When we talk of a focal reaction in the eye we always seem to imagine a severe harmful reaction after injecting a test allergen like tuberculin into the skin: nevertheless such a reaction is com­pletely diagnostic. We have learnt to recognise another form, the beneficial form, which is perhaps as diagnostic as its counterpart the harmful focal reaction and and which is also therapeutically useful for which reason we call it our "therapeutic-diagnostic test".

There is yet another feature of this struggle to which attention must be drawn and which is called "organotropism". If one organ like the eye is sensitised its fellow organ is sensitised likewise, as we can imagine from the two towers of the fort, and even a mild trauma to this opposite organ may produce an anaphylactic reaction in that unaffected eye now. There is sufficient clinical proof in this connection.

Another important feature of allergy to remember is that if a hypersensitivity is established it is almost permanent, it never leaves the tissue entirely. It may return from time to time. It may betray itself even 20 years later. On the other hand immunity can never be permanently imparted.

Again it is necessary to remember that antibodies are specific and react only with the specific antigen.

Summarising some of the features of immune allergic reactions which are not sufficiently recognised we have to restate that:

(1) Different shock organs (or antibody-bearing organs) do not react to an equal extent to a given allergen.

(2) A shock organ that is inflamed and damaged from any cause but has participated in the hypersensitisation from an antigen will react more violently to the same test-antigen than another shock organ (skin for instance) which is also sensitised to the same antigen, but is not in a state of inflammation.

(3)A focal reaction can be of a beneficial nature if the strength of the test antigen is critically accurate (also see later p. 44) otherwise a focal reaction can be harmful.

(4)Organotropism, or induced hypersensitivity in the opposite analogous organ is a clinical fact.

(5)Immunity once established never remains permanent. When it dwindles it gives place to hypersensitivity in the tissues.

(6)Antibodies are specific to the antigen against which they are formed and so both immune and allergic reactions will take place only in the presence of corresponding antigen vs. antibody.

The picture I have painted may not be the true state of affairs, and perhaps is oversimplified, but nobody knows all about allergy (which literally means a strange condition) and immunity. I hope it clears the way for a more logical understanding of what is to follow. Our study has been made in two directions, laboratory and clinical.


  I. Laboratory Studies Top


Allergic and anaphylactic phenomena can be studied in three ways chemically, electrophoretically and immunologically. We have tried to study them in all the three ways.

Allergens are of two main varieties, bacterial and non-bacterial. Non­bacterial ones are again divided into two main groups, exogenous and endogenous. We are concerned with the endogenous group which are called organ specific proteins and which do not show species specificity. This means that the proteins of a certain organ of different species can produce similar antibodies and therefore not peculiar of their own species. The proteins of the lens produce antibodies which are called precipitins because a precipitate forms when the antigen is brought in contact with an antibody.

Uhlenhuth (1903) was the first to point out this fact in the case of the lens. If antibodies are induced in a rabbit against bovine lens, and if the serum of the rabbit containing these antibodies is now placed as a layer over a solution of lens extracts from different species of animals in separate test-tubes, in most instances a precipitin ring can be obtained at the junction of the two fluids.

A recent improvement in technique of demonstrating precipitin rings, which is called the gel-diffusion technique of Oudin (1947) has enabled us to identify several proteins each of which can produce a ring of its own. The number of rings represent the minimum number of common antigenic proteins between the two opposing preparations.

In this preparation [Figure - 2] bovine lens antigen is matched against bovine lens antiserum separated by an intervening portion of gel-agar. A number of lines are produced in the middle agar part, each line representing one protein in the lens which is capable of producing an antibody against itself. By counting the number of lines we can show that there are at least 7 separate proteins in this preparation, which are capable of producing a different antibody and so anti­genically distinct, as against Uhlenhuth and his collaborators who could get only a single ring in the test-tube preparation.

In another preparation [Figure - 3] which shows the horizontal separation method of Ouchterlony (1953), we have put in the central cup an antiserum produced in a rabbit against bovine lenses and have matched it against six different lens anti­gens from six different animals, which gives us an opportunity for comparison. Whereas it shows at least two common lines for all of them except for fish, the other lines are not similar and so although lenses from different species show at least two antigenic proteins which are similar, it does not show other similar antigenic proteins. The antiserum being induced against beef lenses, we find the maximum number of lines (about 15) against beef lenses. The most interest­ing feature is that fish lens does not produce any lines and so fish lens proteins are entirely different antigenically. This makes Uhlenhuth's statement and of those who have confirmed it a half truth. Part of the lens matter shows tissue specificity without species specificity, whereas part of it may show species speci­ficity. Immunologically speaking therefore, we can say that there are a number of species in which there are at least two proteins in their lenses which are im­munologically similar, and other proteins which are dissimilar. There are at least some species of animals in which these common proteins are either not existent or theft antigenecity is inhibited by other proteins. One such animal is the fish. Incidentally by this method it is not possible to pick out each of these rings and identify the protein.

This identification has been attempted by us in another way. It is possible to separate out the different proteins by a process called fractionalisation. There is a certain pH value for each protein at which it will precipitate out the most. This is called the iso-electric point of the protein. By simply changing the pH of the solution to the iso-electric point of that protein it is possible to separate out the protein. The methods have been described in detail by Allan Woods and Burky (1927).

The main antigenic protein of the lens. Alfa crystallin, and whole lens minus Alfa crystallin thus separated, have been studied electrophoretically, and reported by us. Their individual patterns can be compared with that of a mixture of lens proteins and so identified in the mixture, as can be seen from this [Figure - 4].

An electrophoretic study of the patterns of beef aqueous, vitreous, lens and serum by free electrophoresis have been carried out by Dr. S. S. Rao at the Halikine Institute. Bombay and the results have been jointly published by us Rao. Kulkarni and Cooper, Radhakrishnan (1955). A comparison shows that the pattern of the aqueous [Figure - 4] resembles that of the lens and that of the vitreous that of the serum. [Figure - 5].

At Dr. Rao's suggestion we have adopted the gel-diffusion technique for further immunological studies of the lens which have proved most interesting [Figure - 6]. In the first preparation in the centre cup we have the antiserum against the soluble part of beef lens which is matched against (1) its own antigen, that is the soluble part of the lens, (2) the whole, or soluble and insoluble parts of the lens, (3) beef aqueous, (4) vitreous. and (5) beef serum.

The interesting thing to note is that no lines are seen opposite the beef serum and very few lines are seen against the aqueous and vitreous whereas there are 17 lines against its own antigen. This means that there are no lens proteins circulating in the blood as also stated by Woods. Note also the few lines against aqueous and vitreous, which proves that there are small amounts of lens proteins ill the aqueous and vitreous.

In the next preparation [Figure - 7] the central cup contains antisera against the whole lens matched against the same antigens. There are slight differences between this and the previous one which are not of any clear significance.

The next preparation is interesting [Figure - 8]. The central cup contains antisera against beef aqueous. We can see the lines nicely spread-out in the case of the aqueous, vitreous and bovine serum. However (the single line pushed far towards the antiserum demands an explanation) the two forms of lens antigens (soluble and whole) put side by side act as a single but duplicated antigenic force and the single precipitin line is driven far into the territory of the antiserum. This shows up one fallacy of this technique and one immunological fact. When the antigen is too strong it drives its ring further towards the antiserum and so for a critical study it is best to have such a dilution of the antigen as would give rise to an even distribution of lines. The second point is that the maximum amount of antigen will he precipitated by a critical dilution, on either side of which the precipitate yield decreases, as will be later elaborated, when talking about the Therapeutic Test.

The next preparation [Figure - 9] of vitreous antiserum vs. the same five anti­gens shows the very poor band formation against lens proteins showing up the comparatively poor amount of lens proteins in the vitreous as compared with the aqueous.

A comparison can be made when the 4 preparations are viewed together.

1.This comparison shows that serum does not contain any proteins of the blood, on the other hand aqueous and vitreous have some proteins common with the serum as well as the lens.

2.One would expect that when, say, vitreous antigen faces the lens anti­serum and when lens antigen faces the vitreous antiserum one should get an equal number of precipitin lines. This however is not the case. The number of lines for a substance which is in the peripheral antigen cup shows the minimum number of proteins common with the substance in the central antisera cup. The number of lines opposite the substance in the central antiserum cup shows the number of proteins present in sufficient quantities to produce antisubstances and so capable of acting as antigens out of the common proteins. For example vitreous when in antigen positions shows 10 common proteins with soluble lens, and in the antisera position shows 0. This means that although vitreous contains at least 10 different lens proteins they are not in sufficient quantities to produce antibodies. There is however another explanation. Since vitreous contains a large number of blood proteins, the antiserum may be poor in antilens-antibodies, which are crowded out by the serum-proteins-"crowding-our phenomena. The aqueous. on the other hand contains at least 2 lens proteins in sufficient quantities to produce a fair amount of antibodies.

This is in conformity with our earlier observation, [Figure - 4],[Figure - 5] on electro­phoresis of aqueous and vitreous, where the aqueous pattern resembled the lens pattern and the vitreous one the serum pattern.

This leads us to the conclusion that lens proteins keep on escaping into the aqueous and vitreous. However when we match the whole bovine lens antiserum against bovine serum, we could not get any precipitin lines at all, which suggests that the escaped lens proteins in the aqueous are prevented from entering the circulation, which can either be mechanically prevented at the angle and then removed by phagocytosis from the iris, or these proteins are broken up by certain enzymes present in the aqueous. This suggests that lens proteins are not entirely entombed within the lens capsule but can migrate and do migrate out of its slightly permeable cage.

This is important because it offers an explanation for some forms of oplithalmitis which occur in the presence of a cataractous lens in which a dermal sensitivity can be obtained by an extract of the lens. This is particularly so in the case of Morgagnian cataracts. We know the existence of enzymes in the aqueous that can break up lens proteins. Lens proteins that escape into the anterior chamber are removed by these enzymes, and so do not enter the circula­tion in a natural form. With a deficient enzymatic action these lens proteins will find their way into circulation and may then sensitize the eye with subsequent events that follow hypersensitization. Nordmann (1954) however observes that substances with a heavy molecular weight only cannot permeate through the capsule.

In the next preparation beef lens antiserum in the centre is matched against incipient, unripe, ripe morgagnian and black cataract extracts, with beef soluble lens for comparison. [Figure - 10]. It shows the maximum number of lines for incipient and unripe cataracts (13 lines) as against the minimum of eight lines against Morgagnian lens. This would suggest that Morgagnian cataract may be the least antigenic. Clinically we have found that an unripe cataract with a burst capsule is definitely more phacoanaphylactic than any other lens. and Morgagnian perhaps the least, partly because unripe lens matter is more difficult to wash out and the Morgagnian lens matter the easiest. It may partly be due to the difference in the antigenic property of the two types of lenses. On the other hand it is mostly the Morgagnian lens which, as described above, causes lens anaphylaxis with the lens in situ, which therefore demands an immediate extraction of the Morgagnian lens.

The amino-acids of the lens and their immunological properties have been given attention by us in view of the fact that Agarwal has attributed immunological properties to cystin and has tried to establish its role in phacoanaphylaxis.In the first place, because of their small molecular weight aminoacids never can pro­duce precipitins by themselves: only large-sized protein molecules can do so. In any case with the gel-diffusion technique as you will see [Figure - 11], no bands could be obtained against bovine antiserum. In the second place amino-acids are break­down products of the lens proteins after autolysis.

The only explanation I can give to Dr. Agarwal is that the amino-acid by hanging on a larger protein molecule may so alter the molecule that it becomes antigenic which it was not so before. This is called a hapten action and may come only as a subconsideration of the main problem of hypersensitivity to the larger sized protein molecule of the lens, most commonly the Alpha and Beta crystallins, but cystin, biochemically speaking, by itself cannot give rise to an a anaphylactic reaction.

The chemical analysis of the different varieties of cataractous lenses was also carried out in our department with a view to ascertain the ratio between soluble and insoluble lens matter, in the hope that it may throw some confirmatory light on the immunologic and electrophoretic approaches to the same problem. However there has been such a wide variation in these ratios in different lenses of the same types that it has not been possible to bring any order out of the results. All that can be ascertained was that average ratio of soluble to insoluble lens was 0.54 in the case of unripe cataract, 0.4 in the case of morgagnian cataract. This would suggest that as the cataract progresses, more and more lens proteins become insoluble in nature.

A comparative study of the chemical analysis and electrophorectic patterns of the proteins of ox lenses have shown that the four chemically distinct proteins of the lens, (albumin, nucleoprotein, mucoprotein and phosphoprotein) cannot be identified electrophoretically- pirie and van heyningen(1956). On the other hand in the electrophoretically separated ox-lens proteins, the fastest moving fraction has been recognised as the immunologically distinct Alpha crystalline-Francois Rabaey and Wieme(1953)

An electrophorectic study of the different cataractous human lenses by paper electrophoresis was carried out by us with the hope to ascertain the quantity of the three main antigenic proteins of the lens, viz.alpha, beta and gama. As opposed to bovine lenses, it is extremely difficult to run an electrophorectic pattern of the human lens. In the case of human lenses a diffuse homogeneous pattern is obtained which is of no use for analytical purposes. This peculiar characteristics of human lenses in electrophoresis has been also observed by Francois, Wieme, Rabaey and Neetans (1953). This may be due to greater homogenety in the mixture of the lens proteins of human lenses. It is not surprising that analysis of proteins by different methods give different results. Thus chemically four proteins are recognized, electrophoretically 3 and by immuno-chemistry as many as 17 to 18.

The best guide therefore appears to be the gel-diffusion technique and the conclusions have already been stated, namely all cataractous lenses appear to have more or less similar antigenic characteristics. It is mostly the inability of the unripe cortex to be washed out as opposed to that of a ripe or Morgagnian cataract that makes the cortex of the unripe cataract more phacoanaphylactic than the other varieties, that is when the capsule has burst while removing an unripe cataract intracapsularly.


  II Clinical Studies Top


Our interest in the immunology of lens proteins began during my studentship abroad (1928-30) with a conflict of views on the nature of uveitis of undetermined origin between two schools-the English school then emphasising the role of infected teeth and the Viennese one emphasising the role of a healed or latent tuberculous focus.

The first case on which I tried to evaluate this point ended in a disaster. It was a case of detachment of the retina in a lady who had nursed her tuberculous husband for a number of years. Detachment surgery was not so popular then and I sought to apply the theory of focal infection in her and I thought of using tuberculin. I did a Mantaux on her and the next day her eye was in a terrific state with dendritic keratitis. I took the help of the then Professor of Pathology, late Dr. Dhayagude. He suggested that this may be a focal reaction and advised me to use a 1/1.000,000 dilution of old tuberculin, and to my surprise it brought about immediate amelioration of the condition but the eye could not be saved of its detachment. My interest in tuberculin therapy had taken root.

The second case, I have cited many times previously. He had developed severe iridocyclitis after needling of an after-cataract. No improvement had resulted by every possible form of treatment then, and he sought my advice as the eye was to be enucleated. A desperate last minute trial with tuberculin after the experience of the previous case, brought an immediate relief of symptoms, so much so that the patient attributed the "cooling" effect he experienced in his eye the next day, to a plate of ice-cream he had after he left me.

He was followed by similar experiences where the very first injection seemed to produce a very beneficial effect on the patient within 18 hours of its administration. This enabled us to establish a 'therapeutic test' for allergic con­ditions which I shall describe later. It also made me feel that all post-operative inflammations were due to a hypersensitivity to tuberculin. However a few cases did not respond.

This turned our suspicion in the direction of lens proteins as antigenic factors in post-operative inflammations. A preliminary study on the lines of Woods and Burkey gave a very encouraging response.

The Indian Council of Medical Research granted us an inquiry on this problem.

Our results have been published in our reports to the Indian Council of Medical Research for four successive years 1948-51. Briefly we prepared lens extracts from the soluble parts of the lens according to the method of Woods and Burkey, of different dilutions. We soon realised that if the extract was admi­nistered in the dosage of 0.1 cc. of a dilution of 1 in 10.000, it produced in some of the cases of post-operative uveitis a beneficial focal and general reaction of the same dramatic nature as in the case of tuberculin mentioned earlier. For example, a case of lamellar cataract was operated over 20 years ago. The second eye after operation never became perfectly quiet and was "flaring up" from time to time. The first test-dose not only produced a considerable improvement in the condition of the eye the next day but he asked me whether I had given him an injection of morphia because he felt so "light in the head" that he felt sleepy the whole day and slept better for that night than lie had done before for many nights.

Now, an attempt to bring about immunization with increased concentration of the antigen brought on a series of unpalatable experiences which culminated in the case of a lady which we have recorded previously. Cooper and Lakhani, where after bringing about an amelioration of the ocular condition of a severe post-operative uveitis with lens therapy, we sought to immunise her with increas­ing doses of the lens proteins prior to the operation on the second eye. About four days after the operation on the second eve, which was a flawless intra­capsular one, she developed a severe uveitis which ultimately ended in total blind­ness. This case shook all my enthusiasm for a therapeutic procedure I was nursing for permanent adoption. but the seed of lens anaphylaxis had taken too deep a root in my imagination

In two other cases we found that after an initial improvement the eye con­dition became worse on continuing treatment. Evidently there was something wrong in our technique.

At first we were inclined to attribute these disagreeable experiences to irregular injections. What surprised us most was that when we did the precipitin test, in sonic of these the precipitin tests were positive, in others they were negative, this confusion has now been cleared. realising that it is possible for the circulating antibodies to be above or below the precipitin producing level in the presence of a hypersensitized shock-organ as explained earlier.

Now we have come to realise that if the dose is stronger or the antigen is given for too long a time one may actually sensitize the eye instead of desensitizing and after a modification of our technique, these adverse experiences have ceased.

Phacoanaphylaxis

We have cone to recognise anaphylaxis after ocular sensitivity to lens proteins. as occurring at three distinct periods after the operation.

1. Soon after the operation as when the second eye is operated, in which case we assume that the eye is already sensitised.

2. About the seventh day after the operation when time is given for the sensitivity to develop in the eyes after the liberation of lens proteins from their position inside the capsule.

3. Some months after the operation when the circulating antibodies are removed from the circulation and thus the protective umbrella for the shock organ is removed.

In addition to these there is a chronic variety which persists for months together, does not yield to all the known methods of attack and will only yield to a therapeutic test dose of lens antigen.

Our clinical experience is too wide to be presented in a single address as of today. We shall therefore deal with certain immunological problems that have been suggested in post-operative uvetis and have been answered by clinical and laboratory experience. For example.

(1) Is the post-operative reaction toxic or allergic in nature.

(2) What are the clinical features of such inflammations.

(3) Which types of lenses produce stronger allergic reaction? We have already answered that in the first page.

(4) In which type of patients we get stronger allergic reactions.?

(5) Which would be the best type of lens extract for diagnostic and therapeutic purposes.

(6) Which diagnostic test is most reliable.

(7) What is the technique of desensitisation?

(8) Which would be the way to standardise lens proteins and perhaps many others?

The first question has already been dealt with in a previous paper (Cooper and lakhani 1948) as also previously by Woods and Burkey(1933), Verhoeff and Lemoin(1922).


  Clinical Features Top


Our previous clinical experiences we have already stated before this society Cooper, Lakhani and Jhaveri(1948). Our views on the subject have undergone quite some changes since then.

The first clinical feature, which is rather characteristic of this condition or perhaps of any anaphylactic condition in the eye is hyphema. Ordinarily a traumatic type of hyphema should disappear from the anterior chamber of the eye in two or three days if the normal scavenging mechanism in the eye is func­tioning. In the anaphylactic state, this absorption does not take place and the hyphema keeps on recurring, which accounts for its non-disappearance for a long time.

Another peculiarity of this hyphema is that it usually takes place on about the seventh day of operation, i.e. when the patient is about to go home, in the early hours of the morning when he is suddenly aroused from his sleep by acute pain. He stoutly denies any history of trauma during sleep. This haemorrhage does not disappear readily, but one injection of a therapeutic test-dose will bring about a considerable improvement in the clinical condition, if the test allergen is correct and the dose critical as we shall describe presently. The history and the therapeutic reaction are too characteristic and met with too frequently to be just coincidental.

The second feature is an aseptic hypopyon formation. This occurs when an eye is operated upon a second time particularly to tackle a complication. For example if a cataract is removed extracapsularly, intentionally or unintentionally. i.e. after a capsule-break and say an iris prolapse takes place later. Let us say the excision is delayed for 8 days or more. After the excision a severe post­operative anaphylactic reaction takes place with pus formation in the anterior chamber which may be mistaken for suppuration, but the wound edges are clean. No amount of antibiotics and cortison is going to remove the pus. However one therapeutic test-dose may give the answer to the nature of the inflammation and its treatment. This is the particular type which we have come across in frequency second to hyphema. There is no time and no need to elicit a precipitin test or a dermal test. We have a number of such cases on our records, two of our own and at least six from other quarters.

The third type is an obstinate chronic irido cyclitis of a moderate degree which will only yield to the same therapeutic test-dose.

I may add, that even after a dramatic improvement as mentioned above One must remember:

1.That any form of the anaphylactic reactions described may recur as reminders of the fact: hypersensitivity once, hypersensitivity always.

2. An attempt at permanent desensitization may end in disaster, - immunity gives place to hypersensitivity.

3. The late history in a certain number of such cases is a non-congestive form of glaucoma. A careful watch over the tension and cyclodiathermy when the tension rises offer the only means of then saving a losing battle.

This bring us to five clinical lessons we have learnt particularly in extra capsular operations.

1.Intracapsular operations are less inflammation producing than extracapsular

2.A needling operation or a second discission in congenial cataracts may be more damaging to the eye than the first operation, particularly on the second eye.

3.Operations on the second eye show greater post-operative inflammation and take a longer post-operative time to clear.

4.In sympathetic ophthalmia the sympathising eye often ends up with a worse result than the exciting eye.

5. If it is necessary to operate on both the eyes at short intervals, it is better to operate on both the eyes at the same time, if an extracapsular operation is con­sidered than to operate at intervals of a week to a fortnight. It is best to operate intra-capsularly when operation on both the eyes at the same time is considered.

These facts can be illustrated by individual instances, of which we have many, and comparative clinical studies.

One other clinical fact which has emerged from our comparative studies is, traumatic cataracts somehow are non-phacoanaphylactogenic. Here the post­operative course after extraction is singularly uneventful.


  Types of Patients Getting Phacoanaphylaxis Top


The most dangerous cases are those where an extracapsular operation is done in one eye, where a rather stronger degree of post-operative reaction has occurred. This is followed by an operation on the other eye, a week to 15 days later. In this eye an attempt to remove an unripe cataract intracapsularly ends in a ruptured capsule. This is the extreme case, immunologically speaking dangerous. To this there can be additional contributory factors, such as this:

(1 ) focal sepsis, (2) debilitating disease like diabetes, (3) not so clean an ope­ration or an operation that has taken a longer time, (4) a complication during and after an operation and (5) hormonal insufficiency.

Thus in the first type of anaphylaxis cited on p. 38, if one of the contributory factors has already weakened the defence mechanism, and if the eye is already sensitized to any antigen e.g. the toxins from a septic or tuberculous focus then the trauma of the operation above precipitutes an anaphylactic reaction almost immediately, especially if the operation is not so clean.

On the other hand, if no type of hypersensitivity is already induced, then when an extracapsular operation is done, a latent period of about a week must elapse before hypersensitivity is induced in the same as well as the opposite eye. Hyphema of the seventh day, described earlier, can be a clinical manifestation of such an anaphylaxis.

The opposite eye, sensitized by organotropism as described earlier, when operated within a fortnight of the first operation is in a state of maximum hyper­sensitization when the trauma of the operation is inflicted on it, which can be responsible for the precipitation of an anaphylactic type of reaction. This is ren­dered further dangerous if the operation results in a burst capsule, especially if the lens is unripe and the lens matter difficult to wash away, as then a great lot of antigen will be liberated which can produce a harmful focal reaction.

We do not say that in every post-operative reaction it is the same story every time. An anaphylactic reaction has several contributory factors and so the mani­festations will vary in severity. While assessing therefore a post-operative reaction it is necessary to consider the possible contribution of each of these factors. Only one must not forget the role of hypersensitivity induced in the same and opposite eyes by lens matter, particularly from the not-so-easily washable lens matter of an unripe cataract in the case of a burst capsule.

The following modifications of Rich's equation will help to visualise the probable nature of such an inflammation. [Figure - 13]

Contributory factors may be another allergen. tissue damage or a debilitating disease. Inhibiting factor is cortisone or any other unidentified substance which we may call a complement, lack of which will add to the inflammation.

As previously stated Hektoen was unable to produce precipitins in rabbits to homologus lens unless the rabbits were rendered immune allergic to another antigen. This shows the importance of considering the role of contributing factors in the overall picture of phacoanaphylaxis.


  Diagnostic Tests Top


Before we evaluate let us premise that recovery of precipitins from the blood and positive hemagglutination tests have proved that the nature of some of the post-operative inflammatory reactions are of a phacoanaphylactic type.

Secondly, we must think of a hypersensitive eye under the cover of a protec­tive umbrella of circulating antibodies, just like having two or more substances under a cover e.g. cheese and milk under a common cover. To diagnose what is underneath the cover we can smell the cover, or the milk or the cheese itself. If the cover and/or the milk smell of the cheese, the odour of which may have per­meated into these substances, we may surmise that there is cheese underneath the cover. If the cover and the milk do not smell of cheese, because either the odour of the cheese has not permeated to these substances or has disappeared as the cheese becomes stale, the only way to find out whether there is cheese or not is to smell the cheese itself. The cheese can be smelt from a distance when one can get just a pleasant smell of it. or it can be smelt at a close range when the pungent odour will make one's face turn away. In any case the infallible test is to smell the cheese itself. Thus diagnostic tests are of three types. (1) to "smell" the protective cover, or blood sensitivity tests, like haemagglutination in immunology. (2) to "smell" the other substances under a common cover, i.e. organ-sensitivity tests like dermal sensitivity test, and (3) to smell the thing itself i.e specific organsensitivity test i.e. the focal reaction tests of immunology.

1. Blood or serological tests give an idea of the protective umbrella of immunity. A more intelligent idea of the possible state of things can be had if the serological test is read along with the clinical condition present. Thus:- -

It can thus be seen that an ocular inflammation in spite of the presence of antibodies in the blood as in 4 and 4a in the table may mean:

(1) Failure of antigen to unite with the antibodies in the eye due to lack of a hormone or a non-specific complement or due to local damage to the tissues.

(2) Excess antibody formation with sensitization of the eye.

(3) Diminished immunity which also leads to hypersensitization of the tissues.

(4) Inflammation due to some other allergen as a contributory cause e.g. a focus of infection, or uvea from a prolapsed iris along with hyper­sensitization of the eye to lens.

An ocular inflammation with a negative serological test does not necessarily mean an absence of hypersensitization of the eye to lens for,

(1) the circulation antibodies may diminish below the precipitin-positive-test levels, leaving the eye in a hypersensitized state which may then react to any form of trauma, or

(2) antibodies may have been prevented from forming in an amount sufficient to be detected serologically.

A quiet eye with a positive serological test as in 3 and 3a in the table does not necessarily mean an immune state of affairs, for a hypersensitized eye may be unmasked later when the protective immune umbrella disappears.

In addition to the difficulties of interpretation there are other practical difficulties about the test e.g. critical dilution to elicit the test as described later.

2.The dermal sensitivity test is for testing the sensitivity of the skin as a shock organ. It is the easiest of all tests for determining hyper­sensitivity. Since all shock-organs do not have the same sensitivity, if the dermal test is positive it only means that the skin as a shock organ is sensitized. On the other hand if it is negative it does not mean that the eye is not sensitized, for in the analogy described previously, the "cheese" may have become stale or the odour of the "cheese" may not have permeated to the "milk". The real usefulness of dermal sensitivity comes when a selective sensitivity between Alpha and Beta has to be assessed in those cases where a sensitivity to Beta alone may have taken place. Again a word of warning-no attempt should be made to elicit a sizeable dermal reaction in the presence of an inflamed eye, with increasing doses of the lens antigen, lest the ocular condition may flare up with a harmful type of focal reaction.

3.So the only test which can be absolutely reliable can be directed to the affected shock-organ, (smelling the cheese itself) I mean the focal reaction in the eye. Fortunately we have realised that a focal reaction can be of a beneficial kind if the therapeutic test-dose is correct (smelling the cheese from a distance) as described earlier. We have relied upon this test for a number of years but have hesitated to declare it because there appeared to be no explanation. no rationale.

Assuming to be correct what is stated about the critical dilutions in the next paragraph, if the amount of antigen introduced for the test is just sufficient to react with all the antibodies hooked to the tissues, the antibodies will be rendered inert. The dermal reaction may not take place. at the same time a beneficial focal reaction may take place along with the dramatic relief of ocular condition as des­cribed. Any attempt to elicit a sizeable dermal reaction will therefore need a progressively stronger solution of the antigen and will thus cause a progressively increasing danger of setting up a harmful focal reaction.

With precipitin and haemagglutination tests now we have appreciated that the precipitate formation between antigen and antibody and the agglutination tests show a peculiar characteristic. Contrary to expectation the strongest solution of an antigen does not cause the maximum precipitation. The maximum precipita­tion is caused by a critical dilution; anything stronger or weaker will cause a diminishing precipitate. This is known as the zone-phenomenon.

For example in five test-tubes lens antiserum is matched against different dilutions of the antigen. the maximum precipitate is given by a dilution of I /1000 of the antigen. This is the critical dilution of the antigen for a maximum precipitate when matched against a given antiserum. Dilutions of 1/10, 1/100 and of 1/10,000 and 1/100,000 produce precipitates in a diminishing degree on either side of the critical dilution of 1/1.000 in this case.

Similarly for haemagglutination, we found a maximum agglutination with a critical dilution of the antiserum, which was 1/256.

Now perhaps we can find some rationale in our therapeutic test, and also an explanation for those early disappointing adverse reactions we described. When the antigen is introduced in quantities just so much that the tissue antibodies are all precipitated, the soldiers on both the sides are neutralised, the struggle comes to an end with no hard feelings, and a beneficial focal reaction takes place, which is at once diagnostic and therapeutic. By trial and error we have found that 0.1 cc. of a 1/10,000 dilution of lens extract is ordinarily beneficial, and this we call the first therapeutic test-dose. It works out to .01mg, of soluble lens matter per dose.

Our routine is as follows:0.1cc of a 1/10.000 solution is injected intradermally. If within 18 hours no beneficial reaction occurs we inject 0.2 cc. of the same solution after 2 days. If no improvement takes place we inject 0.4 cc. of the same after 2 more days. If no improvement takes place we consider the test negative. If improvement takes place the test is positive and the same dilution and dose are maintained for subsequent therapeutic purposes. When we say improvement, it has got to be from 25 to 50% and within 18 to 24 hours. If the dose is critical, in some instances the relief is so great, that the patient sleeps very well for the first time in a number of months. This is so characteristic that we inquire of the patient as to how he slept, the first night after the test-dose. Naturally one cannot hit off the critical dose every time but we can hope to achieve an approximately critical dose.

So far we have adjudged our dose empirically as stated above. We have only recently been successful with the haemagglutination test, which holds out promise for future research and we hope to adjudge the critical dose from the result of this test.


  Treatment Top


Being now established as an anaphylactic condition, the key for treatment must be a specific key as we premised that the antigen antibody reaction is specific.

I am not much concerned with the local treatment, because the ocular con­dition is again a sick eye in a sick person, and so we shall treat the person, which is more important.

There are 3 ways in which this can be done.

1. Non-specific measures.

2. Use of hormones.

3. Specific measures.

The rationale of milk injections and non-specific foreign proteins can be gathered from the fact that slight reactions to one protein will temporarily inhibit any tendency to reaction to others. This may be due to the "crowding out" of a beginning (lesser) specific lens antibody production. Such a factor would act indirectly in any antigen-antibody reaction. Thus a non-specific protein may act as a reaction blocking agent but not a reaction forming or breaking agent, if it is used as a prophylactic measure, that is in cataract surgery, soon after the operation.

In our clinical experience, we do confess, that sometimes when the use of supposedly specific antigens for our therapeutic test is not working so well, a single milk injection between two injections of the lens antigen produces the desired effect. In this respect, non-specific proteins may act just like catalysing agents in chemistry which hasten clinical reactions. In immuno-chemistry there­fore, non-specific proteins may also act as catalysing agents accelerating the bene­ficial result of mutual antigen-antibody neutralization. However, milk may have cross-reacting proteins with lens, since milk is known to give cross reaction with serum. We have tried to find this out by the gel-diffusion techniques and we find that there is one precipitin hand common to milk and lens. The common protein may thus have a specific action in addition.

Lately cortisone has come under the limelight of such anaphylactic reactions, and undoubtedly it is a formidable weapon in our hands in combating antigen antibody reactions of the harmful type. It acts as an anti-inflammatory factor and is supposed to block the antigen-antibody reaction of anaphylaxis. It is not a link in the antigen-antibody reactions, as we can get beneficial reactions even without the help of cortisone. Arguing that it blocks the antigen-antibody reaction, it may block the reaction of the beneficial kind and so may not be used when we seek the antigen-antibody reaction of the beneficial type.

Thus milk and cortisone may block excess antibody production and may help to prevent hypersensitization.

Other hormones, particularly the gonadotropic hormones help in closing the link between specific antigen-antibody reactions of the beneficial type, because we have seen in some cases when the specific beneficial reaction is not Shaping espe­cially in old people, testosterone or leutocyclin seem to bring about that reaction.

Our latest case came under observation several months after an uneventful operation in which the wound got opened up on removing the stitch, resulting in a prolapse. After months of treatment with cortison and non-specific measures the eye was considered for enucleation. It was at this stage we saw her for the first time and gave her two injections of uveal suspension which produced a com­plete change in her ocular condition, for the better. When such experiences are repeated in several cases one's faith in specific antigen-antibody reactions for diagnostic and therapeutic purposes gets established provided the dose is correct.

This is called the lock and key phenomenon. The lock is the antibody, the key is the antigen. To turn the key it must have a handle (complement) and a hand with energy to turn the key (hormones). It is only when these four requirements are fulfilled in their correct proportions that the key can be turned smoothly. As can be seen from the diagram. if one of the factors is lacking it will prevent the antigen antibody union.[Figure - 12]

If the lock is cheap, only the hand, the energy and piece of bent wire or a cheap key will be necessary to work it, but the lock of antigen/antibody reaction is like the lock of a safe requiring a specific key or a secret combination to work it.

Those cases which improve only with the hormones, it is the "hand" that is missing. Similarly non-specific proteins like milk when they improve the condi­tion may be supplying that catalysing "handle" (complement) that may be lacking. However milk and cortison may block excess antibody production and may help to prevent hypersensitization.

Excess antibodies in the eye, can be neutralised only with the specific antigen which is the specific "key" to our safe. The specificity is so marked in some cases, that a selective desensitization with Alpha or Betacrystalline may be required. However, it will require the "hand - and the "energy" to turn the "key" and so even the specific antigen will not work in the absence of the hormones and a compliment. In a long series of records we have 3cases in which Beta-crystalline alone could bring about an improvement in a post-operative inflamma­tion. Although Woods and Burkey (1927) have incriminated only Alpha­crystallin with active immunological reactions on certain experimental grounds, we feel after a long clinical experience that in exceptional cases it is possible to manifest a selective hypersensitivity to Beta-crystallin.

Why should lens antigen work when given parenterally only in certain mini­mal doses in the presence of so much lens matter in the eye is still shrouded in mystery. Perhaps the lens matter remaining inside the eye is so disorganised that it loses its antigenecity and acts only as an activating agent of inflammation.

It should be remembered that if more antigen is used than required to neutralise the existing tissue antibodies, the ocular hypersensitivity will persist or increase as new tissue antibodies are formed and the inflammation may continue or get worse. Similarly I am convinced that any attempt to confer permanent immunity by gradually increasing doses of antigen is a dangerous procedure. We must be satisfied with controlling the harmful ocular reaction whenever it takes place by attempting to desensitize the eyes and keep them regularly de­sensitized from time to time and not immunise them. Our earlier disappointments were due to a wrong concept of immunology, that immunity can be conferred by progressively increasing doses of the antigen. Beyond a certain limit of immunity. the shock-organ, the eye in our case, reacts by developing higher sensitivity and permanent immunity can almost never be conferred.

This we learnt when at one time we attempted to produce blanket immunity to lens by giving a few injections of lens proteins prior to an extracapsular lens extraction. We lost six of the nine eyes in which this was attempted - a lesson learnt at great cost. Since then we have confined the use of lens proteins only in those cases which have developed a post-operative inflammation.

It is customary to find patients well improved with specific immuno-therapy, with or without cortison and non-specific protein therapy, to come back after 3 to 12 months with a recurrence of the inflammation in some form. After achieving initial desensitization of the eye therefore, by about 6 weekly or bi-weekly injec­tions, the time interval may be increased to a fortnight, month, 3 months or 6 months depending upon the rapidity with which symptoms of recurrence take place.

In this connection the case of one Mrs. Chucko is instructive. She was operated 24 years back for a "cataract after child-birth" in the right eye. In all probability it was a cyclitic cataract and the chronic inflammation in the eye never left her for all these years. She had a miraculous improvement only with de­sensitizing injections of lens. However, her inflammation (a uveitis with hypopyon) kept on recurring every two months and every time her ocular condition improved with the first therapeutic dose of lens injections. She has now been controlled satisfactorily by a single monthly injection of lens protein which she does not dare to miss taking now.

Finally, in these days of intracapsular surgery, cortison and antibodies we definitely come across lesser cases of this nature than what we used to do before. lntracapsular surgery removes altogether the chances of developing ocular hyper­sensitivity to lens. In extracapsular surgery and in cases of burst capsule while doing intracapsular surgery, the chances are further minimised by an early use of milk injection or/and cortison as reaction blocking agents with less chances of excess antibody production and consequently lesser chances of sensitizing the eye to lens antibodies. Routine use of antibiotics previous to the operation and after removes perhaps the main contributing factor, sepsis from within.

But capsules will keep on bursting, contributing factors from viral, parasitic and other infections non-sensitive to the available antibiotics will remain, and cortison may not act, as described previously, in some cases. The lock will have to be turned only by the specific key then the lens antigen. A lessor incidence of such inflammations today may make us unmindful of this danger in exceptional cases. So I am warning: Do not kid yourself into believing when post-operative inflammation does not yield to treatment, that the "infection" is of such a nature that cortisone and antibiotics are of no avail. A single diagnostic therapeutic dose may agreeably put you wise on the anaphylactic nature of such resistant cases. In India, where extracapsular surgery is still practised widely the incidence is perhaps higher than in Europe and the Americas. With the advent of Ridley's operation, extracapsular surgery has come into vogue again. It is a pity that post-operative inflammations after the acrylic implant are attributed to the acrylic and not con­sidered in terms of phacoanaphylaxis at all, even at the cost of giving up this im­portant advance in surgery as a bad job. It is necessary to keep a vial of a solution of lens proteins 0.01% at hand. It keeps well even for a year or more if stored in a cool dark place. It should be commercially available in this strength. If anyone is interested, we can supply him with the dilution, free of cost, with a promise to inform us the result of its use.


  Conclusion Top


After listening to these experiences and the discussions in this matter some of you may recollect a few of your cases to which such discussion is applicable. Perhaps some may feel that no such case has ever come his way. Others may say that he always gives a milk injection or cortison in these cases and such cases come round under this treatment. Still others feel that sepsis is at the root of such inflammations and there is no such thing as phacoanphylaxis.

To those who feel that such a post-operative condition does not exist I may say that a certain type of clinical experience often flows one way to the happy or unhappy lot of one observer for some unexplicable reason. From the number of cases we have had of this kind from other Quarters than ours, I feel that every ophthalmologist must be having experience of at least one such case, where the usual remedies, even cortison has not worked, and the eye goes on to a blinding endophthalmitis. Perhaps they are wrongly diagnosed as cases of infective conditions. Perhaps such cases have come my way more than in the case of others and so this study, I hope, will help them to tackle a similar case either of their own doing or that of somebody else's.

To the second lot who pin their faith in non-specific therapy and cortison I have to say that this approach, though convenient, is not conducive of a proper understanding of the type of this post-operative inflammation. Why non-specific therapy ? Why cortison ? Why and how do these remedies act ? What about those cases who do not improve and may seek refuge elsewhere ? These are the questions that have to be asked and answered, and not be content that somehow such cases have not done them in the eye. For my part I have learnt to turn these misfortunes into fortunate misfortunes in an attempt to clear the mist that shrouds the problem of the so-called idiopathic post-operative uveitis and endophthalmitis.

To the third lot (especially continental surgeons) who feel that sepsis is at the root of such inflammations I have to ask them to look at the subject in a broader light and consider sepsis as one of the contributing causes as explained in the equation on p. 41. I do not deny the role of sepsis, particularly internal sepsis but I should not be denied the role of ocular sensitivity to lens in the overall picture.


  Summary Top


1. A simplified concept of the immune/allergic reactions in immunity and anaphylaxis is presented, particularly stressing the development of hypersensitivity in shock-organs.

2. A comparative immunological study of lens proteins of different species of animals and different types of cataractous lenses by Ouchterloni's method of horizontal separation of precipitin bands is presented with discussion on their practical and clinical significance. This is supplemented by chemical and electro­phoretic studies.

3.A similar study is presented with antisera prepared from beef lens aqueous, and vitreous against antigens of beef lens, aqueous, vitreous and bovine serum to show the presence of lens proteins in the aqueous and their complete absence from serum and relatively from the vitreous. This is studied in conjunc­tion with electrophoretic studies.

4. A clinical study of phacoanaphylaxis is presented stressing the possibili­ties and rationale of a new "therapeutic test" for diagnosis and treatment on the assumption that after an intradermal test a focal reaction can be beneficial if the test-dose is critically correct.


  Acknowledgements Top


I must first express my deep gratitude to Dr. S. S. Rao and Dr. Hazra of the Haffkine Institute. Bombay, for their invaluable help in biochemical processes of which I knew little then, without whose help the biochemical study could never have been possible.

I take this opportunity to thank my special biochemical assistants through the last nine years, Mr. Chakravarthy, Mr. Ranakrishna. Miss Nadkarni, and Miss Pramode Bhatia.

I thank sincerely the Indian Council of Medical Research for sanctioning an inquiry on this subject for three years and to the King. Edward Memorial Hospital and Seth G. S. Medical College Research Society under whose auspices. the inquiry is being continued.

I take this opportunity to thank the various ophthalmologists who have used the antigen prepared by us and communicated their results.

The various writings of Alan Woods of Baltimore on the subject of allergy have been my greatest source of inspiration to pursue this subject clinically and experimentally.[21]

 
  References Top

1.
Agarwal. L. (1954), Ophthalmologica, 128, 352.  Back to cited text no. 1
    
2.
Burky, E. L. (1934), Arch. of Ophthal. 12, 536.  Back to cited text no. 2
    
3.
Burky, E. L. and Woods, A. C. (1931) Arch. Ophth. 6, 548.  Back to cited text no. 3
    
4.
Cooper, S. N. and Lakhani, K. G. (1948) Indian Physician. 7, 70.  Back to cited text no. 4
    
5.
Cooper. S. N. Lakhani. K. G. and Jhaveri, B. M. (1948) Proc. All-India Ophthal. Soc. 9, 35.  Back to cited text no. 5
    
6.
Francois, J.. Rabaey, M. and Wisme, R. (1954), Bull. Soc. Franc d'Ophthal. 26.  Back to cited text no. 6
    
7.
Francois, J.. Wieme. R.. Rabaey, M. and Neetens, A. (1953) Soc. Beige d'Ophth 104. 2  Back to cited text no. 7
    
8.
Freund, J. and Bananto, M. V. (1944) J. lmmunol. 48. 325.  Back to cited text no. 8
    
9.
Hektcen, L. (1923) Amer. J. Ophthal. 6, 276.  Back to cited text no. 9
    
10.
Hektoen, L. and Schulhof. K., (1924) J. Infect. Dis. 34, 433.  Back to cited text no. 10
    
11.
Nordmann, J. (1954). Biologic du Cristallin. Report to the French Ophthalmo Society, Masson et Cie., Paris, p. 255.  Back to cited text no. 11
    
12.
Ouchterlony. 0. (1953). Sixth internal. Cong. Microbiol. 2, 140.  Back to cited text no. 12
    
13.
Oudin (1947), Bull. Soc. Chim. Biol. (Paris). 29, 140.  Back to cited text no. 13
    
14.
Pirie, A. and van Heyningen (1956) Biochemistry of the Eye. Blackwall Scientific Publications, Oxford, p. 5.  Back to cited text no. 14
    
15.
Rao. S. S. Kulkarni, M. E., and Cooper, S. N., Radhakrishnan, M. R. (1955) Brit. J. Ophthal. 39, 165-167.  Back to cited text no. 15
    
16.
Tronche, P. (1955), Contribution a l'etude des Proteines du Crystallin, Paul Vallier, Cermont-Ferrand.  Back to cited text no. 16
    
17.
Uhlenhuth P(1903) quoted from 17,p.54.  Back to cited text no. 17
    
18.
Verhoeff,F .H and Lemoine A.N (1922),Tr . Internat Congress Ophth,Washington p 234.  Back to cited text no. 18
    
19.
Woods A.C Burky, E L and Friedenwald J.S (1940),Arch of Ophthal,23,355.  Back to cited text no. 19
    
20.
Woods A.C and Burky E.L (1927) J.A.M.A 89,102.  Back to cited text no. 20
    
21.
Woods A.C(1933), Allergy and Immunity in Ophthalmology, The johns Hopkins Press,Baltimore, p 61.  Back to cited text no. 21
    


    Figures

  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12], [Figure - 13]
 
 
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