The Mechanism of Tuberculin Hypersensitiveness
Authors: Hanks John H. 
Published: January 2023

Discussion and Summary
The results of the foregoing experiments lead us to agree with Dienes and Schoenheit that the injection of ordinary protein antigens into appropriately prepared tuberculous lesions produces a sensitization which fulfills the commonly accepted requirements for the tuberculin type of hypersensitiveness. An elucidation of the factors which are responsible for this “tuberculin type” of sensitization to ordinary protein antigen will very likely explain the mechanism by which the protein of the tubercle bacillus induces tuberculin hypersensitiveness when it (tuberculin) is liberated from the bacilli in sites of tuberculous infection.
We do not mean to imply that the immunologic condition in these tuberculous animals, in regard to horse serum and egg white, is in every way identical with the sensitization of the tuberculous animal toward tuberculin. Certain discrepancies of this sort have been pointed out in the publications of Dienes and Schoenheit and others have been observed in our work, but their consideration or explanation at this time would obscure the issue in this series of experiments. For the sake of our present purpose, chief interest has centered around the occurrence or non-occurrence of the “tuberculin type” of hypersensitiveness against ordinary protein antigens and a preliminary study of the conditions under which such hypersensitiveness may be produced.
The conclusion that the tuberculin type of hypersensitiveness may be induced by ordinary protein antigens is of sufficient importance to justify further experimental attempts to demonstrate the differences between anaphylactic and allergic (tuberculin type) hypersensitiveness to ordinary protein antigens. This is especially true when both forms of hypersensitiveness frequently appear to be simultaneously developed in the same individual and toward the same antigen. Thus far, we have been unable to find a better differential test for anaphylaxis and “allergy” than is to be had in Zinsser's “immediate” and “delayed” types of skin response. In addition to the confirmation of Zinsser's work by Dienes and Schoenheit (and others) and by our own observations of the differences between the “immediate” reaction and the tuberculin reaction, the general validity of such a differential method has recently been substantiated by clinical tests on tuberculous persons. In reporting a series of tuberculin tests with the whole protein (MA100) of the tubercle bacillus, Aronson and Nicholas (18) have drawn attention to the difference between the delayed (red and indurated) persistent reactions of infected individuals and the immediate (soft and boggy) transient response of non-tuberculous persons who had been sensitized by repeated injections of the tuberculo-protein.
Instances in which the delayed necrotic skin reactions to horse serum or egg white occurred in the absence of the immediate skin response have been noted in tables 1 and 3. It has been shown in table 2 that this sort of reaction could not be transferred to normal animals by means of the blood serum.
The conditions necessary for the production of this capacity for delayed necrotic skin reactions were always intimately associated with the local influence of the tuberculous lesions. Injection of antigen into tissues which were remote from the site of the tuberculous infection caused the development of the usual anaphylactic hypersensitiveness of actively sensitized normal control animals.
Attempts to eliminate the rôle of certain pathological features of tuberculous infection furnished evidence that neither the tubercle nor the inflammatory reaction of early tuberculous lesions were responsible for the “allergic” sensitization.
Insofar as the rôle of the tubercle was concerned, it could not be demonstrated that the enzymes in well-developed tuberculous lesions caused any modification in the antigenicity of horse serum; injection of protein antigens into the “anatomical” tubercle caused the same degree and type of hypersensitiveness that was observed in sensitized normal controls; and the injection of protein antigens into tuberculous lesions within twenty-four hours after tuberculous infection proved to be the most reliable means of inducing the “tuberculin type” of hypersensitiveness.
Inasmuch as it was impossible to show that either acute or chronic inflammatory lesions provided the local conditions for inducing the tuberculin type of hypersensitiveness, a method was developed whereby the tuberculin type of hypersensitiveness was consistently established without injecting the sensitizing antigen into inflamed tissue. The injection of horse serum or egg white into an apparently normal testicle which is adjacent to an infected testicle permits one to take advantage of the local influence of the tuberculous infection. It is entirely possible that the antigen comes in contact with inflamed tissues after leaving the testicle. Therefore, the chief importance attached to this procedure at the present time is the demonstration that the factors which promote the tuberculin type of sensitization may be sought elsewhere than in the primary tuberculous lesion or in the inflammatory lesion in the testicle itself.
Insofar as one is justified in drawing conclusions from this indirect method of approach, it seems probable that tuberculin hypersensitiveness may eventually be explained on some basis other than the formation of inflammatory lesions and tubercles about the sites of tuberculous infection.