io82 A CRITIQUE OF THE EHRLICH THEORY 



no suggestion whatsoever of a passive hypersensitiveness.' Moreover, if a protein- 

 hypersensitive dog is exsanguinated as completely as possible and transfused from an 

 immune donor, the hypersensitive tissues are completely desensitized after an incu- 

 bation period of about forty-eight hours.^ Control transfusions from a normal donor 

 give no suggestion of this passive desensitization. 



The foregoing typical findings are impossible to harmonize with the Ehrlich theory 

 by any number of minor hypotheses as to the number, type, avidity, and valence of 

 specific receptors. I believe we are forced to the conclusion that the formation of anti- 

 bodies is quite a different process from the assumed multiplication of preformed ses- 

 sile receptors, with their subsequent desquamation into the body fluids. 



THE ENZYME THEORY OF ANTIBODY FORMATION 



This conclusion might be acceptable to serologists provided an equally plausible 

 immunological theory were available. I believe such a theory can be readily formu- 

 lated from our current conceptions of cell nutrition. 



Cell nutrition is currently conceived to be mediated largely through enzymes. The 

 main enzymes are of two types: hydrolyzing enzymes and synthesizing enzymes. It 

 is immaterial for our present purpose whether or not hydrolyzing and synthesizing 

 enzymes are considered as separate molecular entities, or as reversible actions of the 

 same entities. These enzymes with activators and inhibitors are demonstrable in both 

 cellular content and body fluids. 



According to the enzyme theory of antibody formation, antigens introduced into 

 the animal body are subjected to two main denaturing processes: First, to a series of 

 extracellular and intracelluar hydrolytic cleavages, supplemented by colloidal dis- 

 sociations, ionic dispersions, and the like, by means of which the antigen is broken 

 down into simpler components. The stages and sequences in this process are presum- 

 ably similar to those of gastro-intestinal digestion, the details, of course, varying with 

 dosage, portal of entry, and topographical distribution. The diffusability of the anti- 

 gen or its cleavage products through cellular membranes and its phagocytability 

 would be one of the major determining factors in this topographical distribution. 

 Many of the earlier cleavage products would presumably have the same specificity as 

 the initial antigen, since it is known that complex proteins subjected to artificial 

 tryptic digestion retain their specificity until reduced to relatively simple digestive 

 products. Later cleavage products would presumably be less highly specific or even 

 non-specific. It is even conceivable that some of the cleavage products might have a 

 specificity other than that of the initial antigen, thus setting up a secondary wave of 

 specific immunological adaptations in the body. 



The second main denaturing process would be a series of chemical syntheses, co- 

 agulations, conjugations, adsorptions, and the like, between the initial antigen or its 

 cleavage products and normal or denatured extracellular and intracellular proteins. 

 Here, also, the details would vary with dosage, portal of entry, and topographical dis- 

 tribution. Many of the earlier synthetic products would presumably have the same 

 specificity as the initial antigen. Later conjugates would presumably be less highly 

 specific, or might even acquire a new specificity. Some of the resulting conjugates or 



^ J.A.M.A.,S6, 12JJ. 1926. ^ J. Ii)rmnnol., 13, SO- 1927. 



