Immunity in infective diseases

The problem of immunity in relation to infective diseases is one that not merely concerns general pathology but has a very important bearing on all branches of practical medicine, such as hygiene, surgery and the veterinary art. The prevention of disease by the production of an acquired immunity is daily assuming greater importance. With the object of arresting the multiplication and dissemination of morbific germs, we are seeking, by artificial means, to render individuals, who may come in contact with them, refractory to their pathogenic action. Patients who have just undergone a surgical operation and women in child-bed are frequently in danger of acquiring a post-operation disease or a puerperal affection; we are, therefore, striving to protect them by conferring upon them an artificial immunity.

The immunisation of animals useful to man is likewise a question of such great importance to agriculture and to industry as to have now become the object of legislation.

This question of immunity is, however, apart from its practical aspect, intimately connected with problems of pure theory. There can be no question that the marked pessimism developed during the century just closed was in a large measure prompted by the dread of disease and premature death, scourges against which humanity is as yet powerless. It is recognised that Byron and Leopardi, the great poets of pessimism, both suffered from congenital anomaly and from incurable disease and that these maladies cast a gloom over their poetry. Schopenhauer, the founder of the pessimistic school in modern philosophy, was noted for his exaggerated fear of disease.

During the greater part of the nineteenth century our knowledge as to immunity has been limited to certain practical methods, often efficacious it is true, but purely empirical, such as those employed in immunising man against small-pox and certain domestic animals against sheep-pox or pleuro-pneumonia.

So long as the nature of the viruses was unknown no really scientific study of their action or of immunity from them could be made. The revelation of the organised nature of the infective viruses opened up the way for these researches. This discovery, the outcome of the demonstration by Pasteur of the organised nature of the ferments, has enabled us to establish the part played by living agents in a great number of infective diseases, and, linked with the names of Davaine, Obermeyer, and above all with that of Robert Koch, it has very greatly advanced the study of susceptibility and of natural immunity in certain infections.

A considerable forward step was made with the discovery, by Pasteur and his collaborators Chamberland and Roux, that it was possible, in certain infective diseases, to confer immunity by means of micro-organisms which had had their virulence attenuated. Thanks to this discovery, science was now in a position to take up the thorough study of acquired immunity. The field of research was still further enlarged by the demonstration of the immunising power of the culture products of pathogenic micro-organisms and above all by the discovery that the blood of immunised animals is capable of conferring immunity upon susceptible animals.

Before taking up in detail the problem of immunity as it is revealed to us as a consequence of these discoveries, it is essential to cast a glance at infective and allied diseases as a whole and to indicate in what light we look upon them in view of the present state of our knowledge.

It has been definitely established that many infective diseases of man and animals are due to the invasion of small parasitic organisms, sometimes of animal nature (as in itch, trichinosis, malaria, Texas fever, nagana, or surra and the allied condition “dourine” in horses), sometimes belonging to the vegetable kingdom like the Moulds (aspergillosis), the Hyphomycetes (actinomycosis, Madura foot disease, bovine farcy) and the Yeasts (disease of the Daphniae, some pseudomyxomas and septicaemias, pseudolupus). But by far the greater number of infective diseases are due to the development in the organism of plants of the simplest structure, Bacteria. These Bacteria produce the gravest and most destructive infections, such as tuberculosis, bubonic plague, diphtheria, cholera, anthrax, the pneumonias, suppuration, erysipelas, tetanus, glanders, leprosy, &c. Among these bacteria some are too small to be resolved individually under the highest magnifying powers and can only be made out en masse. Such is the micro-organism of the contagious pleuro-pneumonia of cattle. To this minuteness of certain pathogenic Bacteria is very probably due the fact that in a considerable number of infections, amongst which are scarlatina, measles, rabies, syphilis, aphthous fever and small-pox, it has been impossible, up to the present, to recognise any specific micro-organisms.

It is probable that we shall succeed in discovering parasites, not only in the diseases I have just cited, which present the characters of infective and virulent diseases, but also in diseases of entirely different types. In spite of the failure of various attempts to demonstrate the parasite of malignant tumours, it may be hoped that, with improvement in scientific methods, such a parasite will be unequivocally demonstrated. In many other conditions which are at present considered as not dependent on micro-organisms, an intimate connection with such organisms will probably be established. Such are the atrophic diseases and certain diseases of nutrition in which the parasites, without playing a direct or immediate rôle, act by means of their products, or by the changes which they set up in the affected organism. To give an idea of this possibility it will be useful to cast a glance at the various modes of action of the numerous etiological agents in infective diseases. The parasites which produce them have, as a common feature, their small dimensions; they can only be recognised with precision by the employment of high powers of the microscope. They are likewise distinguished by a great variability, which is not astonishing, since among infective agents are found on the one hand animals of high structure (such as the Acari of itch) and on the other plants of the simplest character such as the Gonococci or the various Cocco-bacilli.

The Acari are capable of perforating the epidermis by the mechanical action of their feet and mouth-parts. They excavate channels in the skin and thus provoke the irritation so characteristic of itch. The larvae of the Trichinae in like manner produce marked lesions by the mere mechanical act of penetration and migration in the striped fibre of muscular tissue. In human trichinosis, however, the disease picture is more complicated than in itch and leads us to assume that there is some additional action of the excreta of the larvae in the production both of the febrile state and of certain general phenomena. In the nagana disease (transmitted by the Tsetse fly) there is equal reason to admit the preponderating rôle of the mechanical action of the flagellated parasite (Trypanosoma) which obstructs the vessels of the nervous centres.

In the diseases which are set up by Fungi, such as ringworm and aspergillosis, the purely mechanical element still appears to play the more important part. Even certain of the bacterial infections manifest this same character. Thus, there is no doubt that in chronic tuberculosis in the guinea-pig, Koch’s bacillus brings about a substitution of tuberculous elements for the normal tissues, and this to such a degree that, at the termination of the disease, there may remain merely traces of the liver and of the lungs, and the animal dies for want of these organs, whose normal action is no longer possible. In the tuberculous guinea-pig the phenomenon of intoxication by the bacillary poisons plays but a secondary rôle; yet there are examples of tuberculosis (as in acute miliary tuberculosis in man or experimental tuberculosis in cattle, obtained by Nocard’s method of inoculation into the milk ducts), where the poisoning assumes much greater importance.

Among the bacterial diseases of man, leprosy may be cited as one in which the intoxication is relegated to a subsidiary position, yielding place to the mechanical substitution of the specific granuloma for the normal tissues. It is only in the acute leprous exacerbations that we perceive any signs of intoxication by the products of the leprosy bacillus.

All the instances cited, however, constitute but a feeble minority which is completely thrown into the shade in the presence of very numerous infections in which the toxic element dominates the situation. Even in carbuncular diseases an exact analysis of their morbid phenomena has compelled us to recognise the marked influence of the poison produced by the bacterium. The majority of the micro-organisms act as poisoners which introduce themselves into the organism where they can secrete toxins capable of provoking general disorders of very diverse natures. Indeed in infective diseases a whole gamut of very remarkable variations is produced. Thus many of the micro-organisms capable of setting up septicaemias must multiply abundantly in the organism and be distributed in the blood, before they can produce a general morbid condition. The spirillum of human recurrent fever is an example of this. It multiplies for some days and produces several generations without provoking the least malaise; then, however, their appearance in the blood suddenly produces intense fever and constitutional phenomena of the most pronounced character.

On the other hand there are certain bacteria which are distinguished by a very much feebler reproductive power, but a more marked toxic activity. Incapable of spreading through the organism, these bacteria remain localised at the point of entrance, where they secrete their poisons and thus frequently set up a fatal intoxication. Some of these bacteria, such as the bacilli of tetanus and of diphtheria, penetrate more or less deeply into the living tissues of the affected animal. Others can manifest their toxic action so to speak at a distance or by simple contact with the living elements. Into this category comes the organism of Asiatic cholera. Koch’s vibrio, once established in the intestine, there secretes its poison; this, absorbed by the apparently intact intestinal mucous membrane, sets up a fell disease, purely toxic in character. It is probable that in the case of those intestinal diseases whose etiology is still unknown, such as infantile choleras, the poisoning by the products of micro-organisms constitutes the essential phenomenon. The micro-organisms do not make their way into the blood or tissues; they remain in the contents of the intestine and thence set up their deadly intoxication.

Instances do exist in which the pathogenic micro-organism disappears from the body, leaving there a toxin which, alone, is responsible for death. Thus in the spirillar septicaemia of geese, the birds die at a stage when not a single living spirillum can be found in the body. The poisoners have been destroyed before the toxin produced by them had completed its work. In other instances, e.g. typhoid fever of the horse, the specific micro-organism likewise disappears before the death of the animal; but at the period when the poison of this bacterium finishes its fatal work, there is a secondary invasion of other micro-organisms which have nothing to do with the typhoid fever proper of the horse.

This great variability in the action of the different pathogenic agents is still further increased through the differing relations between the parasites and the affected organism. Certain micro-organisms are capable of producing a typical disease, whatever may be the mode and seat of invasion of the organism. But these are comparatively few in number. The bacillus of tuberculosis belongs to this minority. Whether it enters subcutaneously, by the eye or by the respiratory, digestive or genito-urinary passages, it invariably produces tubercular lesions more or less grave and more or less capable of generalisation. On the other hand, a very large number of micro-organisms only exert their pathogenic action when they invade the organism at definite points. The anthrax bacillus, when introduced through the slightest lesion of the skin or of the mucous membranes, produces in man, and in a large number of mammals, a very grave and usually fatal disease; when absorbed in the vegetative state with food, it is almost always innocuous. With the cholera vibrio we have an exactly opposite condition of affairs. When inoculated, even in large numbers, below the skin in the human subject, it rapidly disappears, producing merely insignificant disturbances; but when the same vibrio is introduced into the digestive canal it develops and produces Asiatic cholera, a disease so often terminating in death.

All these variations and peculiarities associated with the nature of infective agents are of great importance from the point of view of immunity.

Do diseases come from without or do their causes arise within the organism? is a pressing question, long discussed by pathologists. Those who have discovered most of the pathogenic micro-organisms have ranged themselves on the side of the former hypothesis. For the majority of them the essential etiological factor in the causation of infective diseases consists in the invasion of the patient by the pathogenic micro-organism from the outer world. This theory is in perfect harmony with many of the admitted facts of epidemiology, according to which the viruses of the most deadly epidemic diseases, such as Asiatic cholera, yellow fever, and bubonic plague, must be imported into a country previously free from the disease before an epidemic can be developed. In anthrax and trichinosis it is recognised that the parasites must come from without. Hence, in the study of pathogenic micro-organisms one always follows the rule that it is essential to find the specific micro-organism in all cases of the disease in question and to prove its absence in healthy individuals or in those who are affected with other diseases. Thus, Koch^[1], in his classical researches on Asiatic cholera, insisted on the fact that the cholera vibrio was always found in cases of this disease but never in healthy persons. Almost simultaneously Loeffler^[2], in the course of his work on the etiology of diphtheria, demonstrated the presence of a specific bacillus not only in a large number of cases of this disease but also in the throat of a healthy child; and this fact at first prevented him from accepting this bacillus as the real cause of diphtheria.

This view accepted by two such eminent bacteriologists cannot however be maintained. It is impossible to assume that each time that a pathogenic micro-organism makes its way into a susceptible species its presence must inevitably be followed by the production of the specific disease. Although the discovery by Loeffler of the diphtheria bacillus in the throat of healthy individuals has repeatedly been confirmed, it is impossible to doubt the etiological rôle of this organism in diphtheria. Moreover, it has been established that Koch’s vibrio, although undoubtedly the etiological factor in the production of Asiatic cholera, has nevertheless been recognised in the digestive canal of perfectly healthy persons.

As soon as he is born, man becomes the habitat of a very rich microbial flora. The skin, the mucous membranes, and the gastrointestinal contents become stocked with such a flora, but a very small number of these micro-organisms have up to the present been recognised or described. The buccal cavity, the stomach, the intestines and the genital organs offer a feeding ground for Bacteria and inferior Fungi of various kinds. For long it was thought that in healthy individuals all these micro-organisms were inoffensive and sometimes even useful. It was supposed that when an infective malady was set up a specific pathogenic micro-organism was added to this benign flora. Exact bacteriological researches have, however, clearly demonstrated that as a matter of fact the varied vegetation in healthy persons often includes representatives of noxious species of bacteria. Besides the diphtheria bacillus and the cholera vibrio, which have repeatedly been found in a virulent form in perfectly healthy individuals, it has been demonstrated that certain pathogenic micro-organisms, e.g. the Pneumococcus, staphylococci, streptococci and the Bacillus coli, are always, or almost constantly, found among the microbial flora of healthy persons.

This observation has necessarily led to the conclusion that in addition to the micro-organism there exists a secondary cause of infective diseases—a predisposition, or absence of immunity. An individual in whom one of the above-mentioned pathogenic species is present, manifests a permanent or transitory refractory state as regards this specific organism. As soon however as the cause of this immunity ceases to act, the micro-organism gets the upper hand and sets up the specific disease. It is thus in diabetic persons that boils make their appearance as the result of the development of Staphylococcus pyogenes, a micro-organism that is almost always found in abundance on the skin and mucous membranes of the human subject. The diabetes is, in these cases, the cause of the suspension of the immunity which exists in the healthy individual.

People who carry the Pneumococcus on their mucous membranes may remain for long without being attacked by fibrinous pneumonia or any of the other maladies due to this micro-organism. But often, in consequence of some special circumstance, a cold for example, the refractory state gives way to a more or less marked susceptibility.

It is unnecessary to multiply the number of such examples; they demonstrate in the clearest fashion that, in addition to the causes of disease which come from the outer world and which are represented by the micro-organisms, there are yet other causes which lie within the organism itself. When these internal factors are powerless to prevent the development of the morbific germs, a disease is set up; when, on the other hand, they resist the invasion of the micro-organisms properly, the organism is in a refractory condition and exhibits immunity.

Diseases in general and infective diseases in particular were developed on the earth at a very remote epoch. Far from being peculiar to man, animals and the higher plants, they attack inferior forms and are widely distributed among unicellular organisms, Infusoria and Algae. Diseases undoubtedly play an important rôle in the history of life on our planet, and it is very probable that they have contributed in a marked degree to the extinction of certain species. When we observe the ravages produced by parasitic Fungi among the young fish which we are trying to rear, or the destruction of crayfish in certain countries in consequence of the rapid increase of epizootic germs, we are involuntarily led to the conclusion that pathogenic micro-organisms must have brought about the disappearance of certain animal and vegetable species.

Darwin^[3], in the chapter on the extinction of species in his book On the Origin of Species, states upon the authority of several observers that insects so annoy elephants that these large mammals become incapable of reproducing themselves in sufficient numbers. Now it is proved that many Insects inoculate pathogenic micro-organisms and thus transmit destructive diseases. A most formidable epizootic disease, provoked by a flagellated Infusorium, the Trypanosoma brucei, is inoculated into large mammals in South Africa by a fly, the Tsetse fly; in certain districts this disease is so widespread and so destructive that the rearing of domestic animals becomes impossible.

Parasites strike then with great intensity, bringing about the destruction of numerous human beings, animals and plants. Nevertheless, in spite of the disappearance of a large number of species, the world continues well populated. This fact proves that, by the special means at the disposal of the organism, without any aid of the medical art or special human intervention, many living species have held their own throughout the ages. Everybody has seen how dogs lick their wounds, moistening them with a saliva full of micro-organisms. These wounds heal well and quickly without dressings or antiseptics.

In all these examples the resistance of the organism depends on immunity, a condition very general in nature. This immunity against infective diseases is very complex and its thorough study could only be undertaken after we had acquired an extended knowledge of these diseases, and after adequate methods of research had been devised.

By immunity against infective diseases we understand the resistance of the organism against the micro-organisms which cause these diseases. We have here to do with an organic property of living beings and not with the immunity which belongs to certain countries or localities. For this reason information on the causes of the immunity in Europe and in mountainous regions from yellow fever will not be found in this book, nor why the majority of Europeans do not take recurrent fever. The inhabitants of our continent do not possess organic immunity against either the virus of yellow fever or Obermeyer’s spirillum of recurrent fever. Indeed they are very susceptible to these diseases. It is solely the conditions of life, in the majority of European countries, that prevent the invasion by the specific germs and the creation of epidemic foci. The same point of view ought also to be applied to animals. Our small laboratory rodents, mice and guinea-pigs, are much more susceptible to anthrax, whether inoculated beneath the skin or in any other part of the body, than are the large domestic mammals such as the ox and the horse. And yet these latter are very liable to epizootic anthrax, whilst the rodents mentioned are seldom, if ever, attacked by spontaneous anthrax. This apparent immunity in no way depends on the existence of a true immunity of the organism, but solely on the conditions under which mice and guinea-pigs live.

We shall therefore in this volume treat only of the phenomena of organic immunity in living beings, and the problem, even restricted within these limits, still appears sufficiently complex. With the object of rendering its study as easy as possible, it will be useful to commence by giving an account of the phenomena of immunity in the lowest organisms.

Immunity against infective diseases should be understood as the group of phenomena in virtue of which an organism is able to resist the attack of the micro-organisms that produce these diseases. It is impossible, at present, to give a more precise definition, and useless to insist upon it. Some have thought it necessary to distinguish between immunity properly so called, that is to say a permanent refractory state, and “resistance,” or a very transient property of opposing the invasion of certain infective micro-organisms. It is not possible to maintain this distinction, for in reality the limits between these two groups of phenomena are far from being constant.

Immunity may be inborn or acquired. The former is always natural, that is to say, independent of the direct intervention of human art. Acquired immunity is also often natural, from the fact that it is established as the result of the spontaneous cure of an infective disease. But in a great number of cases acquired immunity may be the result of direct human intervention as in the practice of vaccination.

For a long time all the phenomena of immunity against infective diseases were collected into a single group. Later, it was recognised, as the result of the demonstrations summarised at the beginning of this chapter, that it is necessary to distinguish sharply between immunity against the pathogenic micro-organisms themselves and that against microbial poisons. Hence the idea of antimicrobial and antitoxic immunities. In the course of this work this essential distinction must always be borne carefully in mind.