Chapter XXVI: Theories of Immunity

Pasteur and the bacteriologists of his time discovered that bacteria cease to grow in artificial culture media after a time, because of the exhaustion of the food material in some cases and because of the injurious action of their own products in other instances. These facts were brought forward to explain immunity shortly after bacteria were shown to be the cause of certain diseases. Theories based on these observations were called (1) “_Exhaustion Theory_” of _Pasteur_, and (2) “_Noxious Retention Theory_” of _Chauveau_ respectively. The fact, soon discovered, that virulent pathogenic bacteria are not uncommonly present in perfectly healthy animals, and the later discovery that immunity may be conferred by the injection of dead bacteria have led to the abandonment of both these older ideas. The (3) “_Unfavorable Environment_” theory of _Baumgartner_, _i.e._, bacteria do not grow in the body and produce disease because their surroundings are not suitable, in a sense covers the whole ground, though it is not true as to the first part, as was pointed out above, and is of no value as a working basis, since it offers no explanation as to _what the factors are_ that constitute the “_unfavorable environment_.” Metchnikoff brought forward a rational explanation of immunity with his (4) “_Cellular or Phagocytosis Theory_.” As first propounded it based immunity on the observed fact that certain white blood corpuscles, _phagocytes_, engulf and destroy bacteria. Metchnikoff has since elaborated the original theory to explain facts of later discovery. Ehrlich soon after published his (5) “_Chemical or Side-chain Theory_” which seeks to explain immunity on the basis of _chemical substances_ in the body which may in part destroy pathogenic organisms or in part neutralize their products; or in some instances there may be an absence of certain chemical substances in the body cells so that bacteria or their products _cannot unite_ with the cells and hence can do no damage.

PAUL EHRLICH]

At the present time it is generally accepted, in this country at least, that Ehrlich’s theory explains immunity in many diseases as well as many of the phenomena related to immunity, and in other diseases the phagocytes, frequently assisted by chemical substances, are the chief factors. Specific instances are discussed in _Pathogenic Bacteriologies_ which should be consulted. It is essential that the student should be familiar with the basic ideas of the chemical theory, not only from the standpoint of immunity, but also in order to understand the principles of a number of valuable methods of diagnosis.

The chemical theory rests on three fundamental physiological principles: (1) the response of cells to stimuli, in this connection _specific chemical stimuli_, (2) the presence within cells of _specific chemical groups_ which combine with chemical stimuli and thus enable them to act on the cell, which groups Ehrlich has named _receptors_, and (3) the “_over-production_” activity of cells as announced by Weigert.

1. That cells respond to stimuli is fundamental in physiology. These stimuli may be of many kinds as mechanical, electrical, light, thermal, chemical, etc. The body possesses groups of cells specially developed to _receive_ some of these stimuli--touch cells for mechanical stimuli, retinal cells for light, temperature nerve endings for thermal, olfactory and gustatory cells for certain chemical stimuli. _Response_ to chemical stimuli is well illustrated along the digestive tract. That the chemical stimuli in digestion may be more or less specific is shown by the observed differences in the enzymes of the pancreatic juice dependent on the relative amounts of carbohydrates, fats, or proteins in the food, the specific enzyme in each case being increased in the juice with the increase of its corresponding foodstuff. The cells of the body, or certain of them at least, seem to respond in a specific way when substances are brought into direct contact with them, that is, without having been subjected to digestion in the alimentary tract, but injected directly into the blood or lymph stream. Cells may be affected by stimuli in one of three ways: if the stimulus is too weak, there is no effect (in reality there is no “stimulus” acting); if the stimulus is too strong, the cell is injured, or may be destroyed; if the stimulus is of proper amount then it excites the cell to increased activity, and in the case of _specific chemical stimuli_ the increased activity, as mentioned for the pancreas, shows itself in an _increased production of whatever is called forth by the chemical stimulus_. In the case of many organic chemicals, the substances produced by the cells under their direct stimulation are markedly specific for the particular substance introduced.

2. Since chemical action always implies at least two bodies to react, Ehrlich assumes that in every cell which is affected by a chemical stimulus there must therefore be a chemical group to unite with this stimulus. He further states that there must be as many different kinds of these groups as there are different kinds of chemicals which stimulate the cell. Since these groups are present in the body cells to _take up_ different kinds of chemical substances, Ehrlich calls them _receptors_. Since these groups must be small as compared with the cell as a whole, and must be more or less on the surface and unite readily with chemical substances he further speaks of them as “side-chains” after the analogy of compounds of the aromatic series especially. The term _receptors_ is now generally used. As was stated above, the effect of _specific chemical stimuli_ is to cause the production of _more of the particular substance_ for which it is specific and in the class of bodies under discussion, the _particular product is these cell receptors_ with which the chemical may unite.

3. Weigert first called attention to the practically constant phenomenon that cells ordinarily respond by doing more of a particular response than is actually called for by the stimulus, that there is always an “overproduction” of activity. In the case of chemical stimuli this means an _increased production of the specific substance_ over and above the amount actually needed.

The student will better understand this theory if he recalls his fundamental physiology. Living substance is characterized, among other things, by irritability which is instability. It is in a constant, state of unstable equilibrium. Whenever the equilibrium becomes permanently stable the substance is dead. It is also continually attempting to restore disturbances in its equilibrium. Whenever a chemical substance unites with a chemical substance in the cell, a receptor, the latter is, so far as the cell is concerned, _thrown out of function_ for that cell. The chemical equilibrium of the latter is upset. It attempts to restore this and does so by making a _new_ receptor to take the place of the one thrown out of function. If this process is continued, _i.e._, if the new receptor is similarly “used up” and others similarly formed are also, then the cell will prepare a supply of these and even an excess, according to Weigert’s theory. Whenever a cell accumulates an excess of products the normal result is that it excretes them from its own substance into the surrounding lymph, whence they reach the blood stream to be either carried to the true excretory organs, utilized by other cells or remain for a longer or shorter time in the blood. Hence the excess of receptors is _excreted from the cell that forms them_ and they become _free_ in the blood. These free receptors are termed _antibodies_. _They are receptors_ but instead of being retained in the cell are _free in solution in the blood_. One function of the free receptor, the antibody, is _always to unite with the chemical substance which caused it to be formed_. _It may have additional functions._ The chemical substance which caused the excess formation of receptors, antibodies, is termed an _antigen_ for that particular kind of antibody.

To recapitulate, Ehrlich’s theory postulates _specific chemical stimuli_, which react with _specific chemical substances in the body cells, named receptors_, and that these _receptors_, according to Weigert, are _produced in excess_ and hence are excreted from the cell and become _free receptors_ in the blood and lymph. These _free receptors_ are the various kinds of _antibodies_, the kind depending on the nature of the stimulus, antigen, the substance introduced. Any substance which when introduced into the body causes the formation of an antibody of any kind whatsoever is called an _antigen_,[23] _i.e._, anti (body) former.

The foregoing discussion explains Ehrlich’s theory of immunity. According to this theory the _manner of formation of all antibodies_ is the same. The _kind of antibody_ and the _manner of its action_ will differ with the _different kinds of antigens_ used.

The succeeding chapters discuss some of the kinds of antibodies, the theory of their action and some practical applications. It must be borne in mind throughout the study of these, as has been stated, that _every antibody has the property of uniting with its antigen whether it has any property in addition or not_.

Just what antibodies are chemically has not been determined because no one has as yet succeeded in isolating them chemically pure. To the author they appear to be enzymes.

Antigens were considered by Ehrlich to be proteins or to be related to proteins. Most workers since Ehrlich have held similar views. Dr. Carl Warden of the University of Michigan has been doing much work in recent years in which he is attempting to show that the antigens are not proteins but are fats or fatty acids. Mr. E. E. H. Boyer, in his work (not yet published) in the author’s laboratory for the degree of Ph.D., received in June, 1920, succeeded in producing various antibodies from _Bacterium coli_ antigens. In these antigens he could detect only fatty acids or salts of fatty acids. If the work of these men is confirmed, it will open up a most interesting and extremely important field in immunity and in preventive medicine. It is not apparent that the nature of the antigen would affect Ehrlich’s theory of the formation of antibodies.

The author has no doubt that eventually the formation of antibodies and the reactions between them and their antigens will be explained on the basis of physical-chemical laws, but this probably awaits the discovery of their nature.