1900. Immunity--Natural Immunity--Artificial Immunity.
For centuries the question of immunity has occupied the human mind
because the prevention of disease has ever been one of the greatest
preoccupations of Man. Savages had already observed that man can become
refractory to the venom of serpents, either through a slight bite or
by the application of certain preparations of that venom on scarified
skin. It was also a popular and very ancient notion that the contact
of a slightly scratched hand with the pustules of cow-pox conferred
immunity against human small-pox. It was on this observation that
Jenner founded his method of antivariolic vaccination. The latter, in
its turn, suggested to Pasteur the idea of attempting antimicrobian
vaccinations. Having ascertained that old cultures of chicken cholera,
previously very virulent, had become harmless, he wondered whether
they had become a vaccine and proved by experiment that they had. That
led him to the principle of the attenuation of viruses and to that of
vaccination by attenuated microbes. Thus the problem of the mechanism
of immunity was stated.
The first theories propounded on the subject concerned the humors.
Pasteur supposed that immunity was due to the absorption, by the
vaccinating microbes, of certain nutritive substances in the humors,
which, not being renewed for some time, were missed by the microbes
afterwards introduced into the organism, which therefore could not
develop completely. Chauveau, on the other hand, thought that, in cases
of immunity, the humors contained substances which were unfavourable
to microbes. Those theories explained particular facts, but were not
applicable to the generality of cases.
Other theories,[21] whilst attributing an active part to the organism
itself, failed to account for the mechanism of immunity in general.
This was due to the fact that knowledge at that time lacked the two
essential elements, _i.e._ the modifications suffered by the organism
which was becoming immunised, and the fate of the microbes in the
refractory organism.
[21] Naegeli, Büchner, Gravitz.
The disappearance of the microbes in the cured or refractory animal
had indeed been observed;[22] the inflammatory reaction of the organism
in the course of immunisation had been noted;[23] microbes had long
ago been observed inside the white globules of pus;[24] but, either an
erroneous interpretation was given to the facts observed, or, rather,
the links of causality between those factors failed to be established
because they were observed solely in the complicated organism of
superior beings. Humoral theories, less easy to test, preserved an
appearance of generality and were easily admitted.
[22] Chauveau.
[23] Büchner.
[24] Hayem, Birsch, Hirschfeld, Kleps, Recklinghausen, Waldeyer,
and Virchow.
Such was the state of the question when Metchnikoff approached it
from a naturalist's point of view. He knew the life of unicellular
beings and that of the lower multicellular organisms in their
complete simplicity; he knew their mode of defence by ingestion and
intracellular digestion. Having become familiar with these phenomena,
visible in the single cell, he was better able to see his way in
the complicated _milieu_ of higher beings. He was therefore able
to discover the connection between the divers factors which other
scientists had observed singly. He was able to prove that it is the
combination of these factors, _i.e._ inflammation, the ingestion of
living and virulent microbes, and their disappearance by means of
intracellular digestion which makes immunity possible. He demonstrated
that "there is but one permanent element in natural or acquired
immunity, and that is phagocytosis."
The extension and importance of this factor, applicable to the whole
animal kingdom, proved the truth and general scope of the phagocyte
doctrine of immunity.
In 1900, Metchnikoff presented to the International Congress in Paris
a complete tabulation of his researches and fought his contradictors
for the last time, after which, convinced that his deductions were
solid, he began to write a work on _Immunity in Infectious Diseases_.
In it he epitomised, as in a great harmonious chord, the results of
his researches, reaching over a period of nearly twenty years; he
affirmed and gave final expression to his doctrine of immunity, based
on the comparative study of the mechanism of that phenomenon and of
its evolution along the whole scale of living beings; he related his
controversies, analysed the objections to his doctrine, expounded the
theories of other scientists concerning immunity, and gave a general
view of the present state of the question. This book is a living
picture of a long and important part of Metchnikoff's scientific
achievements.
* * * * *
The question of immunity is of such great importance, the mechanism
of this phenomenon and the physiology of intracellular digestion are
so complicated, that I have thought it useful to epitomise here the
exposition given of it by Metchnikoff in his book. Readers who do not
care to go further into the subject can pass over the next few pages
without hindering their comprehension of the following chapters.
Diseases affect all living beings, and the greater number of plants and
animals would cease to exist without innate or acquired immunity.
Unicellular beings are generally immune against infectious diseases,
which are rarely observed in them. Their body being almost entirely
made up of digestive protoplasm, the microbes which they absorb are
directly introduced into a noxious medium and are destroyed therein
like any other food. If the microbes are indigestible, they are
immediately rejected; hence, in the majority of cases, they cannot
become harmful.
This resistance of unicellular beings to many microbes and microbian
toxins is due not only to the intense digestive power of the cell but
also to the extreme sensitiveness which rules over the choice of food.
Owing to this protoplasmic sensitiveness (_chimiotaxis_) protozoa are
attracted towards certain microbes or substances (positive chimiotaxis)
and repelled by others (negative chimiotaxis). Thus, many ciliate
infusoria choose bacteria only for their food; they are sharply
repelled by dead infusoria, etc.
Therefore, in the _natural_ immunity of unicellular beings, two
fundamental elements may already be observed: sensitiveness and
intracellular digestion. No researches have yet been made on the
possibility of conferring on protozoa an artificial immunity against
certain pathogenic microbes and their poisons. But unicellular beings,
insensible to microbian poisons, are the reverse to many chemical
substances which, in their normal life, they have no opportunity of
ingesting.
It has been proved by experiment that, against many of those chemical
substances, an artificial immunity may be given to the protozoa by
accustoming them gradually. Very diluted solutions are added at first
to the medium in which they live and, by gradually concentrating
those solutions, an artificial immunity is conferred; the negative
chimiotaxis becomes positive, allowing the protozoa to absorb and
digest the poison, now become a food.
_Habit_ is therefore the fundamental condition of artificial
immunity; it must be that also of immunity naturally acquired. Having
accidentally digested enfeebled microbes or having suffered an attack
of disease, the unicellular being becomes accustomed to a stronger
virus and becomes immune against it. The fact that so many unicellular
beings have become thus accustomed is therefore connected with their
sensitiveness and their digestion. Accordingly, sensitiveness, habit,
and digestion are the fundamental factors of the mechanism of immunity
in protozoa; this immunity thus indisputably belongs to the category of
purely _cellular_ phenomena.
Having arrived at this conclusion, Metchnikoff thought that the same
mechanism of immunity must be found in other primitive and analogous
cells, such as the phagocytes of multicellular beings. This was
proved by a whole series of observations and by the fact that the
immunity of higher animals is connected with an intense phagocytosis.
In fact, as he ascended the scale of beings and studied their natural
and artificial immunity, he ascertained that, in all of them, the
essence of immunity, masked by the complexity of the organism, reduced
itself to the _phagocytes becoming accustomed_ to noxious agents. The
mechanism of immunity in protozoa could therefore really be compared
with that of immunity in multicellular beings.
Becoming accustomed and becoming immune are phenomena of a general
order, for they can be manifested not only by animals, but also by
plants. They, too, have to defend themselves against numerous diseases.
Lower vegetables, such as myxomycetes (beings which stand on the limit
between the animal and vegetable kingdoms), have an amoeboid phase,
in which they are but a simple heap of formless protoplasm. During that
stage of their life, myxomycete behave towards noxious agents exactly
in the same way as unicellular beings and, like them, acquire immunity
by becoming gradually accustomed.
In higher vegetables, the mechanism is different because of their
structure. The cells of nearly all plants are immobilised by rigid
membranes; therefore they cannot surround their prey, but protect
themselves by the production of tough membranes (cicatrisation) and
by the secretion of various juices. Certain of these juices (gums
and resins) become solid when exposed to the air and constitute a
sort of natural (dressing); others (essences) are antiseptic. The
secretion of these cellular juices in plants is therefore a powerful
means of defence. This defence is due to the extreme sensitiveness
of the protoplasma of vegetable cells: they react against irritation
by a defensive secretion. Vegetables, as well as unicellular beings,
can accustom themselves or become artificially accustomed to noxious
influences and acquire immunity.
As to animals, Metchnikoff had already proved long ago that they
defend themselves against morbid agents by phagocytosis, _i.e._ by
intracellular digestion. It is always to be found in cases of immunity
and is indispensable to it, on the same grounds as in unicellular
beings. The organism of multicellular animals possesses various
cells which play the part of phagocytes. There are some in the blood
and humors, as also in the divers organs and in the tissues. These
phagocytes are either mobile--leucocytes, or fixed--tissue-cells.
However, all those cells may be classed into two principal groups: the
microphages and the macrophages. Both categories of cells are capable
of digesting microbes, but it is chiefly done by the microphages,
whilst macrophages more especially digest figured elements (cells) of
animal origin and poisons. It may be said that the microphages are
vegetarians whilst the macrophages are chiefly carnivorous.
What, then, is the mechanism of phagocytic digestion?
Intracellular digestion by phagocytes is accomplished by means of
digestive ferments, similar to those of our own digestive organs. "In
both cases," says Metchnikoff, "a diastasic action is due to soluble
ferments produced by living elements. In intracellular digestion, the
diastases digest within the cells, whereas in extracellular digestion
the phenomenon takes place outside the cells, in the cavity of the
gastro-intestinal tube."
Only gradually has intracellular digestion given place to the digestion
by secreted juices. The link between these two modes is to be found
in certain transparent Invertebrates, such as the floating mollusc
_Phyllirhoë_. The nourishment is first digested in the cavity of the
digestive tube by secreted juices, and its treatment is completed
within the amoeboid cells of the cæcum.
In higher animals, the digestion of food is due to several digestive
ferments (rennet, pepsin, trypsin, enterokinase, etc.) produced by
divers organs (stomach, pancreas, intestines). The phagocytes also
manufacture several digestive ferments; their principal digestive juice
is a soluble ferment of the trypsin category, to which Metchnikoff gave
the name of _cytase_.[25]
[25] It is also called _alexine_ or _complement_ by other writers.
To the morphological difference of the phagocytes corresponds also
a difference in the properties of their cytases, which are suited
to the digestion of this or that food. The cytases are kept within
the interior of the cells and only escape into the humors when the
phagocytes are damaged (Pfeiffer's phenomenon). This kind of ferment
does not withstand a temperature above 55° to 58° C. In natural
immunity, it plays the principal part by digesting morbid agents inside
the phagocytes like any other food. But, in artificial immunity,
other soluble ferments come into play, developed in consequence of
vaccination.
The principal of those is the _fixator_.[26] It is less sensitive
than cytasis to high temperatures and can bear a temperature of 65°
to 68° C. It is incapable, by itself, of killing and digesting, but
by _fixing_ on them, it _bites_ them, so to speak, and makes them
sensitive to the action of the phagocytic cytases, which can thus
digest them more easily.
[26] Designated by other writers by various synonyms: preventive,
or sensibilising substance, immunising body, amboceptor.
The _fixator_ may be compared to _enterokinase_, a special ferment in
the small intestine of higher animals which also does not by itself
digest food but which activates in a high degree the digestive power of
pancreatic ferments. However, it has the property of fixing itself on
fibrin; it is obvious that enterokinase and the fixator have the same
essential properties. This similarity again proves that the destruction
of morbid agents by the phagocytes really corresponds with actual
digestion.
It is in consequence of the digestion of vaccinal products that the
phagocytes manufacture the _fixator_. Created at the expense of a
given vaccinal substance, the _fixator_ has a specific character which
corresponds with that substance, whereas the cytase already existing
within the phagocytes never has a specific character.
_Artificial_ immunisation generally produces the formation of so
great a quantity of fixators that the phagocytes are unable to retain
them and excrete them in part in the ambient humors, _i.e._ the blood
plasma, or serum. When, afterwards, virulent morbid agents (microbes
or figured elements) are introduced into an organism which has been
immunised against them, they are at once faced, in the humors, with
_fixators_, which immediately exert a biting action on them and render
them sensitive to the action of the intracellular cytasis of the
phagocytes. The same mechanism explains the specificity of the serums
of vaccinated animals.
The quantity of specific fixators in the humors depends on the surplus
production of that ferment by the phagocytes and is not always the
same. That is why different serums are preventive in different degrees.
They are inactive if the phagocytes have not produced enough fixators
to pass any out into the humors. For a serum is only preventive when
it brings into the new organism into which it is injected a sufficient
quantity of fixators ready to sensibilise the morbid agents afterwards
introduced into the organism.
The over-production of antibodies--fixators or antitoxins--corresponds
up to a certain point with the frequency and quantity of vaccinal
injections; that is why serums are usually preventive in artificial
immunity and very rarely so in natural immunity. Through successive
inoculations, the cells become accustomed to digesting the microbes, or
figured elements, and manufacture, in consequence of that digestion,
growing quantities of fixators.
In natural conditions, on the other hand, morbid agents do not usually
penetrate into the organism in massive or repeated doses; therefore
digestion under natural conditions results in a less abundant
production of fixators which can be contained in the interior of the
phagocytes without leaking into the humors in sufficient quantities to
render the latter preventive.
It might be thought that immunity against pathogenic microbes is
accompanied by immunity against their toxins. In reality that is not
always the case, and very often the organism, now made refractory to
certain microbes, remains sensitive to their toxic products. Thus
antimicrobian immunity and antitoxic immunity constitute in most cases
two distinct properties. In order to confer antitoxic immunity recourse
must be had to vaccination by soluble poisons and toxins.
Immunity, acquired naturally, is so especially against microbes and
not against toxins, for, in nature, it is almost always by microbes
that the organism is threatened. As to _antitoxic_ immunity, it is
very probably due to the intracellular digestion of toxins by the
different macrophages. This hypothesis is supported by the experiments
quoted in the preceding chapter. During antitoxic vaccination, the
macrophages manufacture, probably at the expense of vaccinal toxins,
a certain quantity of _antitoxins_, substances which offer a great
similarity with the fixators. Like them, they are specific; they are
also produced in great quantities and excreted into the humors, which
they render antitoxic when sufficiently abundant; finally, they are
not very sensitive to high temperatures. That is why, in spite of the
impossibility of proving their origin directly, it is quite probable
that it is analogous to that of the fixators and that antitoxins are
manufactured by cellular elements, the macrophages in particular. For
it is they which absorb and digest toxins as well as soluble poisons.
This deduction is also supported by the antitoxic immunity which may be
conferred on _unicellular_ beings in which the cell alone enters into
play.
Phagocytes no doubt manufacture many other soluble ferments
corresponding with the elements which they absorb, for, in a vaccinated
organism, divers new specific properties of the serum are to be found,
such as that of agglutination, precipitation, etc. Humoral properties
may be more or less durable, in proportion as the products manufactured
by the phagocytes are more or less rapidly evacuated by the organism.
All these humoral properties, traced back to their first source, depend
upon the digestive activity of the phagocytes, since they are the
products of that digestion. In cases where it has not yet been possible
to make a direct demonstration of this, it becomes evident through
analogy and experiments pointing in that direction.
To sum up, according to Metchnikoff, "_Immunity in infectious diseases
is linked with cellular physiology, namely, with the phenomenon of
the resorption of morbid agents through intracellular digestion._
In a final analysis, the latter (as also the digestion of food
in the gastro-intestinal tube) reduces itself to phenomena of a
physico-chemical order; however, it is a real _digestion_ accomplished
by the living cell.... The study of Immunity, from a general point of
view, belongs to the subject of Digestion."
Immunity against diseases is but one of the manifestations of an
immunity on a much larger scale, always based, in final analysis, on
the sensitiveness of the living cellular protoplasm. The sensitiveness
of the nervous cells extends this phenomenon to the psychical domain.
They also are capable of becoming accustomed to external irritations of
all kinds, hence constituting a psychical immunity for the organism.
We all know that one can become accustomed to many painful or violent
sensations; and, as Metchnikoff says: "... It is very probable that
the whole gamut of Habit, starting from the unicellular beings, who
accustom themselves to live in an unsuitable medium, to cultured men
who acquire the habit of not believing in human justice, rests on one
and the same fundamental property of living matter."