Antitoxic serum. of air over the surface of the growth. Sometimes also the | is concerned, the anti-serum exerts its action either on the toxin virulence of a bacterium for a particular kind of animal becomes or on the bacterium itself; that is, its action is either antitoxic lessened on passing it through the body of one of another species. or anti-bacterial. The properties of these two kinds of serum Cultures of varying degree of virulence may be obtained by such may now be considered. methods, and immunity can be gradually increased by inoculation with vaccines of increasing virulence. The immunity may be made to reach a very high degree by ultimately using cultures of intensified virulence, this "supervirulent" character being usually attained by the method of passage already explained. A second method is by injection of the bacterium in the dead condition, whereby immunity against the living organism may be produced. Here manifestly the dose may be easily controlled, and may be gradually increased in successive inoculations. This method has a wide application. A third method is by injections of the separated toxins of a bacterium, the resulting immunity being not only against the toxin, but, so far as present knowledge shows, also against the living organism. In the development of toxin-immunity the doses, small at first, are gradually increased in successive inoculations; or, as in the case of very active toxins, the initial injections are made with toxin modified by heat or by the addition of various chemical substances. Immunity of the same nature can be acquired in the same way against snake and scorpion poisons, and against certain vegetable toxins, e.g. ricin, abrin, &c. The term "antitoxic" signifies that serum has the power of neutralizing the action of the toxin, as is shown by mixing them together outside the body and then injecting them into an animal. The antitoxic serum when injected previously to the toxin also confers immunity (passive) against it; when injected after the toxin it has within certain limits a curative action, though in this case its dose requires to be large. The antitoxic property is developed in a susceptible animal by successive and gradually increasing doses of the toxin. In the earlier experiments on smaller animals the potency of the toxin was modified for the first injections, but in preparing antitoxin for therapeutical purposes the toxin is used in its unaltered condition, the horse being the animal usually employed. The injections are made subcutaneously and afterwards intravenously; and, while the dose must be gradually increased, care must be taken that this is not done too quickly, otherwise the antitoxic power of the serum may fall and the health of the animal suffer. The serum of the animal is tested from time to time against a known amount of toxin, i.e. is standardized. The unit of antitoxin in Ehrlich's new standard is the amount requisite to antagonize 100 times the minimum lethal dose of a particular toxin to a guinea-pig of 250 grm. weight, the indication that the toxin has been antagonized being that a fatal result docs not follow within five days after the injection. In the case of diphtheria the antitoxic power of the serum may reach 800 units per cubic centimetre, or even more. The laws of antitoxin In order that the immunity may reach a high degree, either the bacterium in a very virulent state or a large dose of toxin must ultimately be used in the injections. In such cases the immunity is, to speak generally, specific, i.e. applies only to the bacterium or toxin used in its production. A certain degree of non-specific immunity or increased tissue resistance may be produced locally, e.g. in the peritoneum, by injections of non-production and action are not confined to bacterial toxins, but pathogenic organisms, peptone, nucleic acid and various other substances. In these cases the immunity is without specific character, and cannot be transferred to another animal. Lastly, in a few instances one organism has an antagonistic action to another; for example, the products of B. pyocyaneus have a certain protective action against B. anthracis. This method has, however, not yielded any important practical application. 2. Passive Immunity: Anti-sera.-The development of active immunity by the above methods is essentially the result of a reactive process on the part of the cells of the body, though as yet we know little of its real nature. It is, however, also accompanied by the appearance of certain bodies in the blood scrum of the animal treated, to which the name of anti-substances is given, and these have been the subject of extensive study. It is by means of them that immunity (passive) can be transferred to a fresh animal. The development of anti-substances is, however, not peculiar to bacteria, but occurs also when alien cells of various kinds, proteins, ferments, &c., are injected. In fact, organic molecules can be divided into two classes according as they give rise to anti-substances or fail to do so. Amongst the latter, the vegetable poisons of known constitution, alkaloids, glucosides, &c., are to be placed. The molecules which lead to the production of anti-substances are usually known as antigens, and each antigen has a specific combining affinity for its corresponding anti-substance, fitting it as a lock does a key. The antigens, as already indicated, may occur in bacteria, cells, &c., or they may occur free in a fluid. Anti-substances may be arranged, as has been done by Ehrlich, into three main groups. In the first group, the anti-substance simply combines with the antigen, without, so far as we know, producing any change in it. The antitoxins are examples of this variety. In the second group, the anti-substance, in addition to combining with the antigen, produces some recognizable physical change in it; the precipitins and agglutinins may be mentioned as examples. In the third group, the anti-substance, after it has combined with the antigen, leads to the union of a third body called complement (alexine or cytase of French writers), which is present in normal serum. As a result of the union of the three substances, a dissolving or digestive action is often to be observed. This is the mode of action of the anti-substances in the case of a haemolytic or bacteriolytic serum. So far as bacterial immunity apply also to other vegetable and animal toxins, resembling them in constitution, viz. the vegetable toxalbumoses and the snake-venom group referred to above. Action of The production of antitoxin is one of the most striking facts of biological science, and two important questions with regard to it must next be considered, viz. how does the antitoxin act? and how is it formed within the body? Theo- antitoxin. retically there are two possible modes of action: antitoxin may act by means of the cells of the body, i.e. indirectly or physiologically; or it may act directly on the toxin, i.e. chemically or physically. The second view may now be said to be established, and, though the question cannot be fully discussed here, the chief grounds in support of a direct action may be given. (a) The action of antitoxin on toxin, as tested by neutralization effects, takes place more quickly in concentrated than in weak solutions, and more quickly at a warm (within certain limits) than at a cold temperature. (b) Antitoxin acts more powerfully when injected along with the toxin than when injected at the same time in another part of the body; if its action were on the tissue-cells one would expect that the site of injection would be immaterial. For example, the amount necessary to neutralize five times the lethal dose being determined, twenty times that amount will neutralize a hundred times the lethal dose. In the case of physiological antagonism of drugs this relationship does not hold. (c) It has been shown by C. J. Martin and Cherry, and by A. A. Kanthack and Cobbett, that in certain instances the toxin can be made to pass through a gelatine membrane, whereas the antitoxin cannot, its molecules being of larger size. If, however, toxin be mixed with antitoxin for some time, it can no longer be passed through, presumably because it has become combined with the antitoxin. Lastly it may be mentioned that when a toxin has some action which can be demonstrated in a test-tube experiment, for example, a dissolving action on red corpuscles, this action may be annulled by previously adding the antitoxin to toxin; in such a case the intervention of the living tissues is excluded. In view of the fact that antitoxin has a direct action on toxin, we may say that theoretically this may take place in one of two ways. It may produce a disintegration of the toxin molecule, or it may combine with it to produce a body whose combining affinities are satisfied. The latter view, first advocated by Ehrlich, harmonizes with the facts established with regard to toxic action and the behaviour of antitoxins, and may now be regarded as established. His view as to the dual composition of the toxin molecule has already been mentioned, and it is evident that if the haptophorous or combining group has its affinity satisfied by union with antitoxin, the toxin will no longer combine with living cells, and will thus be rendered harmless. One other important fact in support of what has been stated is that a toxin may have its toxic action diminished, and may still require the same amount of antitoxin as previously for neutralization. This is readily intelligible on the supposition that the toxophorous group is more labile than the haptophorous. There is, however, still dispute with regard to the exact nature of the union of toxin and antitoxin. Ehrlich's view is that the two substances form a firm combination like a strong acid and a base. He found, however, that if he took the largest amount of toxin which was just neutralized by a given amount of antitoxin, much more than a single dose of toxin had to be added before a single dose was left free. For example, if 100 doses of toxin were neutralized by a unit of antitoxin (v. supra) it might be that 125 doses would need to be added to the same amount of antitoxin before the mixture produced a fatal result when it was injected. This result, which is usually known now as the "Ehrlich phenomenon," was explained by him on the supposition that the "toxin" does not represent molecules which are all the same, but contains molecules of different degrees of combining affinity and of toxic action. Accordingly, the most actively toxic molecules will be neutralized first, and those which are left over, that is, uncombined with antitoxin, will have a weaker toxic action. This view has been assailed by Thorvald Madsen and S. A. Arrhenius, who hold that the union of toxin and antitoxin is comparatively loose, and belongs to the class of reversible actions, being comparable in fact with the union of a weak acid and base. If such were the condition there would always be a certain amount both of free toxin and of free antitoxin in the mixture, and in this case also considerably more than a dose of toxin would have to be added to a "neutral mixture" before the amount of free toxin was increased by a dose, that is, before the mixture becaine lethal. It may be stated that while in certain instances the union of toxin and antitoxin may be reversible, all the facts established cannot be explained on this simple hypothesis of reversible action. Still another view, advocated by Bordet, is that the union of toxin and antitoxin is rather of physical than of strictly chemical nature, and represents an interaction of colloidal substances, a sort of molecular deposition by which the smaller toxin molecule becomes entangled in the larger molecule of antitoxin. Sufficient has been said to show that the subject is one of great intricacy, and no simple statement with regard to it is as yet possible. We are probably safe in saying, however, that the molecules of a toxin are not identical but vary in the degree of their combining affinities, and also in their toxic action, and that, while in some cases the combination of anti-substances has been shown to be reversible, we are far from being able to say that this is a general law. Formation of antl toxio. The origin of antitoxin is of course merely a part of the general question regarding the production of anti-substances in general, as these all combine in the same way with their homologous substances and have the same character of specificity. As, however, most of the work has been done with regard to antitoxin production we may consider here the theoretical aspect of the subject. There are three chief possibilities: (a) that the antitoxin is a modification of the toxin; (b) that it is a substance normally present, but produced in excess under stimulation of the toxin; (c) that it is an entirely new product. The first of these, which would imply a process of a very remarkable nature, is disproved by what is observed after bleeding an animal whose blood contains antitoxin. In such a case it has been shown that, without the introduction of fresh toxin, new antitoxin appears, and therefore must be produced by the living tissues. The second theory is the more probable a priori, and if established removes the "Side chain" theory. necessity for the third. It is strongly supported by Ehrlich, who, in his so-called "side-chain " (Seitenkette) theory, explains antitoxin production as an instance of regeneration after loss. Living protoplasm, or in other words a biogen molecule, is regarded as consisting of a central atom group (Leistungskern), related to which are numerous secondary atom groups or sidechains, with unsatisfied chemical affinities. The side-chains constitute the means by which other molecules are added to the living molecule, e.g. in the process of nutrition. It is by means of such side-chains that toxin molecules are attached to the protoplasm, so that the living molecules are brought under the action of the toxophorous groups of the toxins. In antitoxin production this combination takes place, though not in sufficient amount to produce serious toxic symptoms. It is further supposed that the combination being of somewhat firm character, the side-chains thus combined are lost for the purposes of the cell and are therefore thrown off. By the introduction of fresh toxin the process is repeated and the regeneration of side-chains is increased. Ultimately the regeneration becomes an over-regeneration and free side-chains produced in excess are set free and appear in the blood as antitoxin molecules. In other words the substances, which when forming part of the cells fix the toxin to the cells, constitute antitoxin molecules when free in the serum. This theory, though not yet established, certainly affords the most satisfactory explanation at present available. In support of it there is the remarkable fact, discovered by A. Wassermann and Takaki in the case of tetanus, that there do exist in the nervous system molecules with combining affinity for the tetanus toxin. If, for example, the brain and spinal cord removed from an animal be bruised and brought into contact with tetanus toxin, a certain amount of the toxicity disappears, as shown by injecting the mixture into another animal. Further, these molecules in the nervous system present the same susceptibility to heat and other physical agencies as does tetanus antitoxin. There is therefore strong evidence that antitoxin molecules do exist as part of the living substance of nerve cells. It has, moreover, been found that the serum of various animals has a certain amount of antitoxic action, and thus the basis for antitoxin production, according to Ehrlich's theory, is afforded. The theory also supplies the explanation of the power which an animal possesses of producing various antitoxins, since this depends ultimately upon susceptibility to toxic action. The explanation is thus carried back to the complicated constitution of biogen molecules in various living cells of the body. It may be added that in the case of all the other kinds of anti-substances, which are produced by a corresponding reaction, we have examples of the existence of traces of them in the blood scrum under normal conditions. We are, accordingly, justified in definitely concluding that their appearance in large amount in the blood, as the result of active immunization, represents an increased production of molecules which are already present in the body, either in a free condition in its fluids or as constituent elements of its cells. Antibacterial serum. In preparing anti-bacterial sera the lines of procedure correspond to those followed in the case of antitoxins, but the bacteria themselves in the living or dead condition or their maceration products are always used in the injections. Sometimes dead bacteria, living virulent bacteria, and living supervirulent bacteria, are used in succession, the object being to arrive ultimately at a high dosage, though the details vary in different instances. The serum of an animal thus actively immunized has powerful protective properties towards another animal, the amount necessary for protection being sometimes almost inconceivably small. As a rule it has no action on the corresponding toxin; i.e. is not antitoxic. In addition to the protective action, such a serum may possess activities which can be demonstrated outside the body. Of these the most important are (a) bacteriolytic or lysogenic action, (b) agglutinative action, and (c) opsonic action. The first of these, lysogenic or bacteriolytic action, consists in 2a the production of a change in the corresponding bacterium | found that this obtained in all cases where Pfeiffer's lysogenic whereby it becomes granular, swells up and ultimately may action could be demonstrated. Shortly afterwards Widal and undergo dissolution. Pfeiffer was the first to show also Grünbaum showed that the serum of patients suffering (a) Lyso that this occurred when the bacterium was injected from typhoid fever, even at an early stage of the disease, agglugenic action. into the peritoneal cavity of the animal immunized tinated the typhoid bacillus-a fact which laid the foundation of against it, and also when a little of the serum of serum diagnosis. A similar phenomenon has been demonstrated such an animal was injected with the bacterium into the peri- in the case of Malta fever, cholera, plague, infection with B. coli, toneum of a fresh, i.e. non-immunized animal. Metchnikoff and meat-poisoning" due to Gärtner's bacillus, and various other Bordet subsequently devised means by which a similar change infections. As regards the mode of action of agglutinins, Gruber could be produced in vitro, and analysed the conditions necessary and Durham considered that it consists in a change in the for its occurrence. It has been completely established that in envelopes of the bacteria, by which they swell up and become this phenomenon of lysogenesis there are two substances con- adhesive. The view has various facts in its support, but F. Kruse cerned, one specially developed or developed in excess, and the and C. Nicolle have found that if a bacterial culture be filtered other present in normal serum. The former (Immunkörper of germ-free, an agglutinating serum still produces some change Ehrlich, substance sensibilisatrice of Bordet) is the more stable, in it, so that particles suspended in it become gathered into resisting a temperature of 60° C., and though giving the specific clumps. E. Duclaux, for this reason, considers that agglutinins character to the reaction cannot act alone. The latter is ferment- are coagulative ferments. like and much more labile than the former, being readily destroyed at 60° C. It may be added that the protective power is not lost by exposure to the temperature mentioned, this apparently depending upon a specific anti-substance. Furthermore, lysogenic action is not confined to the case of bacteria but obtains also with other organized structures, e.g. red corpuscles (Bordet, Ehrlich and Morgenroth), leucocytes and spermatozoa (Metchnikoff). That is to say, if an animal be treated with injections of these bodies, its serum acquires the power of dissolving or of producing some disintegrative effect in them. The development of the immune body with specific combining affinity thus presents an analogy to antitoxin production, the difference being that in lysogenesis another substance is necessary to complete the process. It can be shown that in many cases when bacteria are injected the serum of the treated animal has no bacteriolytic effect, and still an immune body is present, which leads to the fixation of complement; in this case bacteriolysis does not occur, because the organism is not susceptible to the action of the complement. In all cases the important action is the binding of complement to the bacterium by means of the corresponding immune body; whether or not death of the bacterium occurs, will depend upon its susceptibility to the action of the particular complement, the latter acting like a toxin or digestive ferment. It is to be noted that in the process of immunization complement does not increase in amount; accordingly the immune serum comes to contain immune body much in excess of the amount of complement necessary to complete its action. An important point with regard to the therapeutic application of an anti-bacterial serum, is that when the serum is kept in vitro the complement rapidly disappears, and accordingly the complement necessary for the production of the bactericidal action must be supplied by the blood of the patient treated. This latter complement may not suit the immune body, that is, may not be fixed to the bacterium by means of it, or if the latter event does occur, may fail to bring about the death of the bacteria. These circumstances serve, in part at least, to explain the fact that the success attending the use of anti-bacterial sera has been much inferior to that in the case of antitoxic sera. tination. Another property which may be possessed by an anti-bacterial serum is that of agglutination. By this is meant the aggregation into clumps of the bacteria uniformly distributed (b) Aggiu- in an indifferent fluid; if the bacterium is motile its movement is arrested during the process. The process is of course observed by means of the microscope, but the clumps soon settle in the fluid and ultimately form a sediment, leaving the upper part clear. This change, visible to the naked eye, is called sedimentation. B. J. A. Charrin and G. E. H. Roger first showed in the case of B. pyocyaneus that when a small quantity of the homologous serum (i.e. the serum of an animal immunized against the bacterium) was added to a fluid culture of this bacillus, growth formed a sediment instead of a uniform turbidity. Gruber and Durham showed that sedimentation occurred when a small quantity of the homologous serum was added to an emulsion of the bacterium in a small test-tube, and The phenomenon of agglutination depends essentially on the union of molecules in the bacteria-the agglutinogens-with the corresponding agglutinins, but another essential is the presence of a certain amount of salts in the fluid, as it can be shown that when agglutinated masses of bacteria are washed salt-free the clumps become resolved. The fact that agglutinins appear in the body at an early stage in a disease has been taken by some observers as indicating that they have nothing to do with immunity, their development being spoken of as a reaction of infection. This conclusion is not justified, as we must suppose that the process of immunization begins to be developed at an early period in the disease, that it gradually increases, and ultimately results in cure. It should also be stated that agglutinins are used up in the process of agglutination, apparently combining with some element of the bacterial structure. view of all the facts it must be admitted that the agglutinins and immune bodies are the result of corresponding reactive processes, and are probably related to one another. The development of all antagonistic substances which confer the special character on antimicrobic sera, as well as antitoxins, may be expressed as the formation of bodies with specific combining affinity for the organic substance introduced into the systemtoxin, bacterium, red corpuscle, &c., as the case may be. The bacterium, being a complex organic substance, may thus give rise to more than one antagonistic or combining substance, In By opsonic action is meant the effect which a scrum has on bacteria in making them more susceptible to phagocytosis by the white corpuscles of the blood (q.v.). Such an effect (c) Opsonic a particular bacterium had a special action in bringing about phagocytosis of that organism, and it had been found that this property was retained when the serum was heated at 55° C. It is now generally admitted that at least two distinct classes of substances are concerned in sonic action, that thermostable immune opsonins are developed as a result of active immunization and these possess the specific properties of anti-substances in general, that is, act only on the corresponding bacterium. On the contrary the labile opsonins of normal serum have a comparatively general action on different organisms. It is quite evident that the specific immune-opsonins may play a very important part in the phenomena of immunity, as by their means the organisms are taken up more actively by the phagocytic cells, and thereafter may undergo rapid disintegration. The opsonic action of the serum has been employed by Sir A. Wright and his co-workers to control the treatment of bacterial infections by vaccines; that is, by injections of varying amounts of a dead culture of the corresponding bacterium. The object in such treatment is to raise the opsonic index of the serum, this being taken as an indication of increased immunity. The effect of the injection of a small quantity of vaccine is usually to produce an increase in the opsonic index within a few days. If then an additional quantity of vaccine be injected there occurs a fall in the opsonic index (negative phase) which, however, is followed later by a rise to a higher level than before. If the amounts of vaccine used and the times of the injection are suitably chosen, there may thus be produced by a series of steps a rise of the opsonic index to a high level. One of the chief objects in registering the opsonic power in such cases is to avoid the introduction of additional vaccine when the opsonic index is low, that is, during the negative phase, as if this were done a further diminution of the opsonic action might result. The principle in such treatment by means of vaccines is to stimulate the general production of anti-substances throughout the body, so that these may be carried to the sites of bacterial growth, and aid the destruction of the organisms by means of the cells of the tissues. A large number of favourable results obtained by such treatment controlled by the observation of the opsonic index have already been published, but it would be unwise at present to offer a decided opinion as to the ultimate value of the method. | with regard to anti-bacterial sera, the presence of phagocytosis cannot be regarded as the essence of immunity, but rather the evidence of its existence. The increased ingestion of bacteria in active immunity would seem to depend upon the presence of immune opsonins in the serum. These, as already explained, are true anti-substances. Thus the apparent increased activity of the leucocytes is due to a preliminary effect of the opsonins on the bacteria. We have no distinct proof that there occurs in active immunity any education of the phagocytes, in Metchnikoff's sense, that is, any increase of the inherent ingestive or digestive activity of these cells. There is some evidence that in certain cases anti-substances may act upon the leucocytes, and to these the name of "stimulins" has been given. We cannot, however, say that these play an important part in immunity, and even if it were so, the essential factor would be the development of the substances which act in this way. While in immunity there probably occurs no marked change in the leucocytes themselves, it must be admitted that the increased destruction of bacteria by these cells is of the highest importance. This, as already pointed out, depends upon the increase of opsonins, though it is also to be noted that in many infective conditions there is another factor present, namely a leucocytosis, that is, an increase of the leucocytes in the blood, and the defensive powers of the body are thereby increased. Evidence has been brought forward within recent years that the leucocytes may constitute an important source of the antagonistic substances which appear in the serum. Much of such evidence possesses considerable weight, and seeing that these cells possess active digestive powers it is by no means improbable that substances with corresponding properties may be set free by them. To ascribe such powers to them exclusively is, however, not justifiable. Probably the lining endothelium of the blood-vessels as well as other tissues of the body participate in the production of anti-substances. The subject of artificial immunity has occupied a large proportion of bacteriological literature within recent years, and our endeavour has been mainly to indicate the general Natural laws which are in process of evolution. When the immunity. facts of natural immunity are examined, we find that no single explanation is possible. Natural immunity against toxins must be taken into account, and, if Ehrlich's view with regard to toxic action be correct, this may depend upon either the absence of chemical affinity of the living moiccules of the tissues for the toxic molecule, or upon insensitiveness to the action of the toxophorous group. It has been shown with regard to the former, for example, that the nervous system of the fowl, which possesses immunity against tetanus toxin, has little combining affinity for it. The non-sensitiveness of a cell to a toxic body when brought into immediate relationship cannot, however, be explained further than by saying that the disintegrative changes which underlie symptoms of poisoning are not brought about. Then as regards natural powers of destroying bacteria, phagocytosis aided by chemiotaxis plays a part, and it can be understood that an animal whose phagocytes are attracted by a particular bacterium will have an advantage over one in which this action is absent. Variations in chemiotaxis towards different organisms probably depend in natural conditions, as well as in active immunity, upon the opsonic content of the serum. Whether bacteria will be destroyed or not after they have been ingested by the leucocytes will depend upon the digestive powers of.the latter, and these probably vary in different species of animals. The blood serum has a direct bactericidal action on certain bacteria, as tested outside the body, and this also varies in differto the anthrax bacillus at first gave the hope that it might explain variations in natural immunity. Thus the serum of the white rat, which is immune to anthrax, kills the bacillus; whereas the serum of the guinea-pig, which is susceptible, has no such effect. Further observations, however, showed that this does not hold as a general law. The serum of the susceptible rabbit, for example, is bactericidal to this organism, whilst the serum of the immune dog is not. In the case of the latter animal the serum Active immunity has thus been shown to be associated with the presence of certain anti-substances in the serum. After these substances have disappeared, however, as they always do in the course of time, the animal still possesses immunity for a varying period. This apparently depends upon some alteration in the cells of the body, but its exact nature is not known. The destruction of bacteria by direct cellular agency both in natural and acquired immunity must not be overlooked. The behaviour of certain cells, especially leucocytes, Phagun cytosis. in infective conditions led Metchnikoff to place great importance on phagocytosis. In this process there are two factors concerned, viz. the ingestion of bacteria by the cells, and the subsequent intracellular digestion. If either of these is wanting or interfered with, phagocytosis will necessarily fail as a means of defence. As regards the former, leucocytes are guided chiefly by chemiotaxis, i.e. by sensitiveness to chemical substances in their surroundings-a property which is not peculiar to them but is possessed by various unicellular organisms, including motile bacteria. When the cell moves from a less to a greater degree of concentration, i.e. towards the focus of production, the chemiotaxis is termed positive; when the converse obtains, negative. This apparently purposive movement has been pointed out by M. Verworn to depend upon stimula-ent animals. Observations made on this property with respect tion to contraction or the reverse. Metchnikoff showed that in animals immune to a given organism phagocytosis is present, whereas in susceptible animals it is deficient or absent. He also showed that the development of artificial immunity is attended by the appearance of phagocytosis; also, when an anti-serum is injected into an animal, the phagocytes which formerly were indifferent might move towards and destroy the bacteria. In the light of all the facts, however, especially those contains an opsonin which leads to phagocytosis of the bacillus, | snake into kings of Iran who fight with the Turanians. Many and the latter is then destroyed by the leucocytes. It is quite evident that bactericidal action as tested in vitro outside the body does not correspond to the degree of immunity possessed by the animal under natural conditions. We may say, however, that there are several factors concerned in natural immunity, of which the most important may be said to be the three following, viz, variations in the bactericidal action of the serum in vivo, variations in the chemiotactic or opsonic properties of the serum in vivo, and variations in the digestive properties of the leucocytes of the particular animal. It is thus evident that the explanation of natural immunity in any given instance may be a matter of difficulty and much complexity. AUTHORITIES.-Bacteriological literature has become so extensive that it is impossible to give here references to original articles, even the more important. A number of these, giving an account of classical researches, were translated from French and German, and published by the New Sydenham Society under the title Microparasites in Disease: Selected Essays, in 1886. The following list contains some of the more important books published within recent years. Abbott, Principles of Bacteriology (7th ed., London, 1905); Crookshank, Bacteriology and Infective Diseases (with bibliography, 4th ed., London, 1896); Duclaux, Traité de microbiologie (Paris, 1899-1900); Eyre, Bacteriological Technique (Philadelphia and London, 1902); Flügge, Die Mikroorganismen (3rd ed., Leipzig. 1896); Fischer, Vorlesungen über Bakterien (2nd ed., Jena, 1902); Günther, Einführung in das Studium der Bakteriologie (6th ed., Leipzig, 1906); Hewlett, Manual of Bacteriology (2nd ed., London, 1902); Hueppe, Principles of Bacteriology (translation, London, 1899); Klein, Micro-organisms and Disease (3rd ed., London, 1896); Kolle and Wassermann, Handbuch der pathogenen Mikroorganismen (Jena, 1904) (supplements are still being published; this is the most important work on the subject); Löffler. Vorlesungen über die geschichtliche Entwickelung der Lehre von der Bacterien (Leipzig, 1887); M'Farland, Text-book upon the Pathogenic Bacteria (5th ed., London, 1906); Muir and Ritchie, Manual of Bacteriology (with bibliography, 4th ed., Edin. and Lond., 1998); Park, Pathogenic Micro-organisms (London, 1906); Sternberg, Manual of Bacteriology (with full bibliography, 2nd ed., New York, 1896); Woodhead, Bacteria and their products (with bibliography, London, 1891). The bacteriology of the infective diseases (with bibliography) is fully given in the System of Medicine, edited by Clifford Allbutt, (2nd ed., London, 1907). For references consult Centralbl. für Bakter. u. Parasitenk. (Jena); also Index Medicus. The most important works on immunity are: Ehrlich, Studies in Immunity (English translation, New York, 1906), and Metchnikoff, Immunity in Infective Diseases (English translation, Cambridge, 1905). (R. M.*) modern authors have attempted to make history out of these stories, and have created an old Bactrian empire of great extent, the kings of which had won great victories over the Turanians. But this historical aspect of the myth is of late origin: it is nothing but a reflex of the great Iranian empire founded by the Achaemenids and restored by the Sassanids. The only historical fact which we can learn from the Iranian tradition is that the contrast and the feud between the peasants of Iran and the nomads of Turan was as great in old times as it is now: it is indeed based upon the natural geographical conditions, and is therefore eternal. But a great Bactrian empire certainly never existed; the Bactrians and their neighbours were in old times ruled by petty local kings, one of whom was Vishtaspa, the protector of Zoroaster. Ctesias in his history of the Assyrian empire (Diodor. Sic. ii. 6 ff.) narrates a war waged by Ninus and Semiram, against the king of Bactria (whom some later authors, e.g. Justin i. 1, call Zoroaster). But the whole Assyrian history of Ctesias is nothing but a fantastic fiction; from the Assyrian inscriptions we know that the Assyrians never entered the eastern parts of Iran. Whether Bactria formed part of the Median empire, we do not know; but it was subjugated by Cyrus and from then formed defeated Darius JII., his murderer Bessus, the satrap of Bactria, one of the satrapies of the Persian empire. When Alexander had But Bactria tried to organize a national resistance in the east. was conquered by Alexander without much difficulty; it was only farther in the north, beyond the Oxus, in Sogdiana, that he met with strong resistance. Bactria became a province of the Macedonian empire, and soon came under the rule of Seleucus, king of Asia (see SELEUCID DYNASTY and HELLENISM). The Macedonians (and especially Seleucus I. and his son Antiochus L.) founded a great many Greek towns in castern Iran, and the Greek language became for some time dominant there. The many difficulties against which the Seleucid kings had to fight and the attacks of Ptolemy II., gave to Diodotus, satrap of Bactria, the opportunity of making himself independent (about 255 B.C.) and of conquering Sogdiana. He was the founder of the GraecoBactrian kingdom. Diodotus and his successors were able to maintain themselves against the attacks of the Seleucids; and when Antiochus III., "the Great," had been defeated by the BACTRIA (Bactriana), the ancient name of the country Romans (190 B.C.), the Bactrian king Euthydemus and his son between the range of the Hindu Kush (Paropamisus) and the Demetrius crossed the Hindu Kush and began the conquest of Oxus (Amu Darya), with the capital Bactra (now Balkh); in the eastern Iran and the Indus valley. For a short time they wielded Persian inscriptions Bakhtri. It is a mountainous country with great power; a great Greek empire seemed to have arisen far in a moderate climate. Water is abundant and the land is very the East. But this empire was torn by internal dissensions and fertile. Bactria was the home of one of the Iranian tribes (see continual usurpations. When Demetrius advanced far into India PERSIA: Ancient History). Modern authors have often used the one of his generals, Eucratides, made himself king of Bactria, name in a wider sense, as the designation of the whole eastern and soon in every province there arose new usurpers, who propart of Iran. As there can be scarcely any doubt that it was in claimed themselves kings and fought one against the other. these regions, where the fertile soil of the mountainous country is Most of them we know only by their coins, a great many of which everywhere surrounded and limited by the Turanian desert, that are found in Afghanistan and India. By these wars the dominant the prophet Zoroaster preached and gained his first adherents, position of the Greeks was undermined even more quickly than and that his religion spread from here over the western parts of would otherwise have been the case. After Demetrius and Iran, the sacred language in which the Avesta, the holy book of Eucratides, the kings abandoned the Attic standard of coinage Zoroastrianism, is written, has often been called "old Bactrian." and introduced a native standard; at the same time the native But there is no reason for this extensive use of the name, and the language came into use by the side of the Greek. On the coins term "old Bactrian " is, therefore, at present completely aban- struck in India, the well-known Indian alphabet (called Brahmi doned by scholars. Still less foundation exists for the belief, once by the Indians, the older form of the Devanagari) is used; on the widely spread, that Bactria was the cradle of the Indo-Euro- coins struck in Afghanistan and in the Punjab the Kharoshthi pean race; it was based on the supposition that the nations of alphabet, which is derived directly from the Aramaic and was in Europe had immigrated from Asia, and that the Aryan languages common use in the western parts of India, as is shown by one (Indian and Iranian) stood nearest to the original language of of the inscriptions of Asoka and by the recent discovery of the Indo-Europeans. It is now acknowledged by all linguists many fragments of Indian manuscripts, written in Kharoshthi, that this supposition is quite wrong, and that the Aryans prob-in eastern Turkestan (formerly this alphabet has been called ably came from Europe. The castern part of Iran seems to Arianic or Bactrian Pali; the true name is derived from Indian have been the region where the Aryans lived as long as they sources). formed one people, and whence they separated into Indians and Iranians. The weakness of the Graeco-Bactrian kingdoms was shown by their sudden and complete overthrow. In the west the Arsacid empire had risen, and Mithradates 1. and Phraates II, began to conquer some of their western districts, especially Areia (Herat). But in the north a new race appeared, Mongolian tribes, called |