Chapter Iv, Justifies Us in Concluding That in the Case of

micro-organisms matters go on in much the same way. These organisms, seized at the seat of inoculation by the phagocytes, are transported by these cells, in their peregrination through the organs, into the general circulation. The interpretation I have just given has been accepted by Deutsch.

This observer wished also to come to some conclusion as to the origin of the agglutinative property so well developed in the fluids of animals inoculated with the typhoid cocco-bacillus. He did not succeed in solving this question, but he was able to demonstrate the undoubted difference between this property and the protective power. The facts brought forward by Deutsch must, therefore, be ranged alongside the many others, reported on above, which demonstrate in the most conclusive fashion that these two powers of the body fluids are essentially distinct.

Such concordant results obtained by all investigators who have studied the origin of the protective power warrant the conclusion that it is the elements of the phagocytic organs, that is to say, the phagocytes themselves, which produce the protective substance. But it will be asked: Can we therefore accept the fixative substance or fixative as being derived from the same source? When the experiments I have just summarised were carried out the fixatives were not as yet sufficiently known and were confounded with the protective substances. Nevertheless, there can be no doubt as to what the answer to the question just put must be. In the account of the experiments of Pfeiffer and Marx we find very precise statements as to the granular transformation of the vibrios. Thus, they observed on several occasions that an extract of the spleen set up this transformation in a particularly distinct and rapid fashion at a period when the blood and serum, used in a much stronger dose, were incapable of producing the same effect. Now, as Pfeiffer’s phenomenon is a visible manifestation of the action of the specific fixative, it cannot be doubted that the spleen is really the principal seat of development of the fixative substance before it makes its appearance in the blood.

Before concluding this chapter we must review very briefly the principal phenomena associated with acquired immunity against micro-organisms. The extracellular destruction of these parasites takes place in the living animal under special conditions only, when the phagocytes suffer a temporary injury (phagolysis) and allow their microcytases to escape. These latter by no means represent attributes of the body fluids, as is even yet maintained by some writers. These soluble ferments are connected with the phagocytes and represent the ferments of intracellular digestion. The cytases undergo no modification during the process of immunisation and correspond to those which act in natural immunity.

The agglutinative substance often present in the normal fluids of the body becomes much more developed in those of immunised animals. It is truly humoral, as it circulates in the plasmas and passes into the fluid exudations and transudations. But the part played by it in immunity is very restricted.

The protective and fixative properties, most often closely connected with each other, are very markedly developed in an animal enjoying acquired immunity. They may act upon the micro-organisms which become permeated by the fixative substance, or upon the infected animal by stimulating its defensive reaction, but they are incapable of affecting the vitality or virulence of the micro-organism. The two properties (protective and fixative) reside in the fluids of the body, but they are functions of the cell products. The elements of the phagocytic organs (spleen, bone-marrow, lymphatic glands), or phagocytes, produce the specific protective and fixative substances which pass thence into the plasmas.

The phagocytic reaction is very general in acquired immunity. The phagocytes which have a very imperfect antimicrobial function or none at all, become, as the result of vaccination, much more active. They exhibit a very marked positive chemiotaxis and acquire the faculty of digesting micro-organisms in a greatly intensified degree. It is with the increase of this digestive power that we have connected the over-production by the phagocytes of the fixative and protective substances which are excreted in large quantities by these cells and pass into the fluids of the animal. As these substances are phagocytic products it may be readily conceived that in certain examples of acquired immunity the animal overcomes the micro-organisms without the protective substances being found in the fluids. It is sufficient that it is in the possession of the phagocytes, which may retain it within themselves and not throw it off into the circulation.

From this account it will be seen that the phenomena, in acquired immunity against micro-organisms, are merely a more or less stereotyped copy of those that are presented in the animal after the resorption of cells. There, also, we have intracellular digestion with over-production of specific fixatives, part of which are excreted and thus pass into the plasmas. In the resorption of cells there is also a double action of cytases and fixatives; but in this case the macrocytases intervene, whilst in the resorption of micro-organisms this function is performed by the microcytases. The fixatives in the two cases are very different from the point of view of their action, for they are specific; but the cells which act in their production belong, in both cases (resorption of animal cells and of micro-organisms), to the category of phagocytes.

It is often maintained that the theory I have just summarised is fundamentally opposed to the theory of side-chains or receptors formulated by Ehrlich. This view I cannot accept. Applied to acquired immunity against micro-organisms this theory may be summed up as follows. The micro-organisms, when inoculated in a non-lethal but immunising dose, combine with certain cells of the animal. The receptors of the micro-organisms find corresponding receptors in these cells, but, when once combined, the receptors of the cells become incapable of fulfilling their normal nutritive function. The cells, thus deprived of their receptors, reproduce such an enormous quantity of them that a portion is excreted into the surrounding medium and passes into the plasmas. These receptors, originating from cells, but which have become constituent parts of the body fluids, are nothing but the fixatives or intermediary bodies, or the amboceptors of Ehrlich. On a fresh arrival of the same micro-organisms, they meet with, in the fluid of the exudations, numerous amboceptors which combine with the corresponding receptors of the micro-organisms, without, however, destroying them or interfering with their vitality. As these amboceptors possess still a second affinity, that for the molecules of the cytases, or the “complements” of Ehrlich, the micro-organisms can be placed in contact with these soluble ferments. Without the intervention of the fixatives, the combination of the body of micro-organisms with the cytase can never take place, because the receptors of the micro-organisms are not adapted to those of the cytases. When the molecules of these ferments are found in the plasmas in a free state, they can be attacked by the corresponding group of the amboceptors.

Let us compare the theory we have just sketched with that described further back. The micro-organisms, inoculated with a non-lethal but immunising dose, are, as we have seen, ingested by the phagocytes and afterwards digested within them. This intracellular digestion is followed by the over-production of the specific fixative, of which a part is excreted and passes into the plasmas. These are the results of the well-established experimental data described in this chapter. Ehrlich’s theory is in no way in opposition to this; it simply attempts to penetrate more deeply into the mechanism of the phenomena observed as taking place between the micro-organism and the cell. The act which we simply term intracellular digestion is divided by Ehrlich into its constituent parts. According to him there is a combination of the fixative, on the one hand, with the molecule of the micro-organism, on the other, with that of the soluble ferment or cytase. According to Ehrlich it is the amboceptors of the cells which become detached in order to furnish the fixative that circulates in the plasmas. For us there is simply an over-production of one of the two ferments of intracellular digestion, without defining more exactly what constituent part of this ferment passes into the circulation. The two theories may supplement each other but are in no way contradictory in principle. There is only a single important point wherein they do not accord. Ehrlich thinks that the cytases are always free in the body fluids and that the cells, in order to exert a digestive action on the micro-organisms, must previously seize their molecules by means of one of the groups of their amboceptors. We, on the contrary, have developed the idea that the cytases are only free in the animal during phagolysis and that under normal conditions the cytases remain closely bound up with the phagocytes. This statement is based upon a large number of well-established experimental facts and must therefore be accepted as proved. It does not, however, affect any fundamental principle of Ehrlich’s theory. On the other hand the bases of Ehrlich’s theory affect none of the main features of the theory I have developed. The doctrine which regards acquired immunity as a particular case of resorption may be reconciled with the conception of amboceptors. But it accords equally well with Bordet’s conception, according to which the fixatives act not as intermediary substances between the micro-organism and the cytase, but as substances which sensitise the micro-organisms for the penetration of the digestive ferment. This delicate question has not yet been definitely settled, but Bordet’s experiments described in Chapter IV are greatly in favour of this view.

Neisser and Wechsberg have tried to obtain some idea of the manner in which the fixatives act on the micro-organisms and have recorded a series of very interesting facts. They have shown that these substances only bring about the destruction of bacteria when they are in certain relations with the cytase. Mixtures of fixatives and cytases in which the former are found in excess not only do not kill the micro-organisms but even allow them to develop abundantly. To attain this result Neisser and Wechsberg mixed constant quantities of bacteria and normal serum containing cytase with variable quantities of the serum of immunised animals heated to 56° C. As we know, this specific serum, as the result of being thus heated, is deprived of its cytases, but may be readily made active again by the addition of normal, unheated serum. This paradoxical fact, demonstrated by Neisser and Wechsberg can, in their opinion, be explained only by Ehrlich’s theory of amboceptors. When these bodies with double affinities are found in too large quantity as regards the cytase, it may happen that one part only of those which combine with the receptors of the micro-organisms succeed in linking to themselves the molecules of the active ferment. The amboceptor being by itself incapable of destroying the micro-organism, can be injurious to it only on condition that it brings cytase. Consequently as the amount of this cytase is too small for the much larger number of amboceptors we can readily conceive that the micro-organisms may profit thereby and remain alive. This interpretation is certainly very ingenious, but nothing proves that it corresponds with the real state of things. Neisser and Wechsberg have themselves observed that the serum of the normal goat can also prevent the bactericidal action of the cytase. In this case, however, they suggest the intervention of an anticytase of this normal serum. The same explanation might perhaps serve also to explain the preventive action of the serum of immunised animals. We know that anticytases are found frequently enough in the various serums and that they undergo great variations, according to the conditions present in the animals furnishing the blood.

In any case, it is evident that the theory of receptors must in no way be regarded as the antithesis of the theory of phagocytosis. This latter quite retains its right to affirm that, in acquired immunity against micro-organisms, phagocytes play the most general and important part. They hold back the cytases which are capable of ridding the animal of micro-organisms from destroying them. It is further these same cells that produce and excrete the fixative and protective substances. The free fixatives may attack the micro-organisms in the body fluids but they are incapable of depriving them of life or even of virulence. The cytases, after escaping from the phagocytes, may certainly, in collaboration with the fixatives, destroy a certain number of the micro-organisms, but only in special cases met with, no doubt, but only rarely, under natural conditions. On the other hand, the phagocytes in the animal which enjoys acquired immunity constantly fulfil the function of seizing the micro-organisms and of submitting them in their interior to the combined action of fixatives and cytases.

Acquired immunity, like natural immunity against micro-organisms, presents merely special phases of intracellular digestion.