CHAPTER XXIX.
RECEPTORS OF THE THIRD ORDER.
CYTOLYSINS.
Before Koch definitely proved bacteria capable of causing disease several physiologists had noted that the red corpuscles of certain animals were destroyed by the blood of other animals (Creite, 1869, Landois, 1875), and Traube and Gescheidel had shown that freshly drawn blood destroys bacteria (1874). It was not until about ten years afterward that this action of the blood began to be investigated in connection with the subject of immunity. Von Fodor (1885) showed that saprophytic bacteria injected into the blood are rapidly destroyed. Flügge and his pupils, especially Nuttall in combating Metchnikoff’s theory of phagocytosis, announced in 1883, studied the action of the blood on bacteria and showed its destructive effect (1885–57). Nuttall also showed that the blood lost this power if heated to 56°. Buchner (1889) gave the name “alexin” (from the Greek “to ward off”) to the destroying substance and showed that the substance was present in the blood serum as well as in the whole blood, and that when the serum lost its power to dissolve, this could be restored by adding fresh blood. Pfeiffer (1894) showed that the destructive power of the blood of animals immunized against bacteria (cholera and typhoid) was markedly specific for the bacteria used. He introduced a mixture of the blood and the bacteria into the abdominal cavity of the immunized animal or of a normal one of the same species and noted the rapid solution of the bacteria by withdrawing portions of the peritoneal fluid and examining them (“Pfeiffer’s phenomenon”). Belfanti and Carbone and especially Bordet (1898) showed the specific dissolving action of the serum of one animal on the blood corpuscles of another animal with which it had been injected. Since this time the phenomenon has been observed with a great variety of cells other than red blood corpuscles and bacteria—leukocytes, spermatozoa, cells from liver, kidney, brain, epithelia, etc., protozoa, and many vegetable cells.
It is therefore a well-established fact that the proper injection of an animal with almost any cell foreign to it will lead to the blood of the animal injected acquiring the power to injure or destroy cells of the same kind as those introduced. The destroying power of the blood has been variously called its “cytotoxic” or “cytolytic” power, though the terms are not strictly synonymous since “cytotoxic” means “cell poisoning” or “injuring,” while “cytolytic” means “cell dissolving.” The latter term is the one generally used and there is said to be present in the blood a specific “cytolysin.” The term is a general one and a given cytolysin is named from the cell which is dissolved, as a bacteriolysin, a hemolysin (red-corpuscle-lysin), epitheliolysin, nephrolysin (for kidney cells), etc. If the cell is killed but not dissolved the suffix “cidin” or “toxin” is frequently used as “bacteriocidin,” “spermotoxin,” “neurotoxin,” etc.
The use of the term “cytolysin” is also not strictly correct, though convenient, for the process is more complex than if one substance only were employed. As was stated above, the immune serum loses its power to dissolve the cell if it is heated to 55° to 56° for half an hour, it is inactivated. But if there be added to the heated or inactivated serum a small amount of normal serum (which contains only a very little cytolytic substance, so that it has no dissolving power when so diluted) the mixture again becomes cytolytic. It is evident then that in cytolysis there are two distinct substances involved, one which is present in all serum, normal or immune, and the other present only in the immune cytolytic serum. This may be more apparent if the facts are arranged in the following form:
- I. Immune serum dissolves cells in high dilution.
- II. Heated immune serum does not dissolve cells.
- III. Normal serum in high dilution does not dissolve cells.
- II. + III., i.e., Heated immune serum plus diluted normal serum dissolves cells.
Therefore, there is something in heated immune serum necessary for cell dissolving and something different in diluted normal serum which is necessary. This latter something is present in unheated immune serum also, and is destroyed by heat. Experiment has shown that it is the substance present in all serum both normal and immune that is the true dissolving body, while the immune substance serves to unite this body to the cell to be destroyed, i.e., to the antigen. Since the immune body has therefore two uniting groups, one for the dissolving substance and one for the cell to be dissolved, Ehrlich calls it the “amboceptor.” He also uses the word “complement” to denote the dissolving substance, giving the idea that it completes the action of dissolving after it has been united to the cell by the amboceptor, thus replacing Buchner’s older term “alexin” for the same dissolving body.
AMBOCEPTORS.
The theory of formation of amboceptors is similar to that for the formation of the other types of antibodies. The cell introduced contains some substance, which acts as a chemical stimulus to some of the body cells provided with proper receptors so that more of these special receptors are produced, and eventually in excess so that they become free in the blood and constitute the free amboceptors. It will be noticed that these free receptors differ from either of the two kinds already described in that they have two uniting groups, one for the antigen (cell introduced) named cytophil-haptophore, the other for the complement, complementophil haptophore. Hence amboceptors are spoken of as receptors of the third order. They have no other function than that of this double combining power. The action which results is due to the third body—the complement. It will be readily seen that complement must possess at least two groups, a combining or haptophore group which unites with the amboceptor, and an active group which is usually called the zymophore or toxophore group. Complements thus resemble either toxins, where the specific cell (antigen) is injured or killed, or enzymes, in case the cell is likewise dissolved. This action again shows the close relation between toxins and enzymes. Complement may lose its active group in the same way that toxin does and becomes then complementoid. Complement is readily destroyed in blood or serum by heating it to 55° to 56° for half an hour, and is also destroyed spontaneously when serum stands for a day or two, less rapidly at low temperature than at room temperature.
Amboceptors appear to be specific in the same sense that agglutinins are. That is, if a given cell is used to immunize an animal, the animal’s blood will contain amboceptors for the cell used and also for others closely related to it. Immunization with spermatozoa or with epithelial or liver cells gives rise to amboceptors for these cells and also for red blood corpuscles and other body cells. A typhoid bactericidal serum has also some dissolving effect on colon bacilli, etc. Hence a given serum may contain a chief amboceptor and a variety of “coamboceptors,” or one amboceptor made up of a number of “partial amboceptors” each specific for its own antigen (“amboceptorogen”). Amboceptors may combine with other substances than antigen and complement, as is shown by their union with lecithin and other “lipoids,” though these substances seem capable of acting as complement in causing solution of blood corpuscles.