Going beyond the defense reaction in its general aspect, that is, independent of the place in the organization where the characteristic processes occur, we considered it in relation to hierarchic organization of entities. Conceptually, it can be accepted that each hierarchic entity, having a certain degree of biological independence, will have its own problems to resolve when it faces an antigen. Each will react for itself and, for this reason alone, there will be differences in the defense mechanism at different levels. It can also be accepted that because of differences in the means at their disposal, the various entities will show individual peculiarities in their responses.

Although some information is missing, our systematization of the defense reaction according to the manifestations at various organizational levels, stands. For each stage, manifestations having common basic characteristics can be identified at different levels such as cellular, tissular, organic, and systemic. At the cellular level, the first phase of the diphasic phenomenon corresponds to a manifest increase in membrane permeability and intracellular hydrolytic processes. The changes seen in the first phase of shock can be interpreted as resulting in part from such processes. We will note here only that, for cells, the first phase is characterized by vacuolization of the cytoplasm and even of the nuclei similar to the vacuolization seen in the leucocytes in the presence of a colloidal metal. In superacute shock, which corresponds to the first part of the diphasic phenomenon, we observed such vacuoles in central nervous system, liver and pulmonary alveolar cells. (See Shock, Chapter 9) The same process at the tissular level causes lytic changes and, if this lysis acts upon vessels, produces petechiae. For the systemic level, the first phase of the diphasic phenomenon is marked by the changes occurring in blood. The leucocytes, rich in hydrolytic enzymes, have a pronounced lytic tendency. The liberated enzymes act upon the blood constituents and can impart to this stage the acute dramatic aspect often seen in clinical hemo shock.

The prolonged lipidic phase of the antiheterogeneous reaction will have different manifestations according to the level affected. These differences will correspond closely to the antagonistic influence exercised by the two groups of lipids, sterols and fatty acids. We have discussed previously the intervention of these lipids at different levels. We will mention briefly here their role in the different phases of the defense mechanism.

We have seen that, in general, the changes at the nuclear level correspond to prolonged youth if they are produced by the predominant intervention of sterols and to a rapid aging with karyorrhexis and pyknosis when produced by fatty acids. Similar manifestations can be recognized in this phase of the defense mechanism at the cellular level for the cytoplasm and protoplasm formations, with aging signs and necrosis induced by fatty acids, and predominance of youthful characteristics induced by sterols. For the tissular level, intervention of fatty acids induces local alkalosis and edema, while the sterols induce a local acidosis and fibroblastic reaction. Lysis of vessels with hemorrhages occurs in processes in which fatty acids predominate. The predominance of sterols leads to a marked tendency of the vascular endothelium to proliferate and this, in turn, can lead to vascular obliteration and ischemic infarcts if the vessels are terminal. At the organic level, the prolonged lipidic response is more manifest than at lower levels as the result of impaired specific function of the organ. Dualism in clinical manifestations is evident; oliguria or polyuria, diarrhea or constipation, insomnia or somnolence are examples of organic impairments seen as clinical manifestations of this stage of the defense mechanism. At the systemic level, dual manifestations are even more pronounced. Hypothermia, hypotension, cold perspiration, enophthalmia and dark colored blood are related to predominance of fatty acids, opposite manifestations to predominance of sterols. Although these prolonged manifestations, part of the nonspecific antiheterogeneous lipidic response, can occur concomitantly at the various levels of the organization, usually they affect one or several levels. The manifestations corresponding to the one level or several levels will predominate.

The allergic stage shows the same clinical manifestations common to the antiheterogeneous response with its enzymatic or prolonged lipidic processes. The fundamental difference in the allergic stage is the obligatory incubation period of 6 or more days. Once the allergic complex is realized, the manifestations are the same as those produced by highly active antigens inducing a direct antiheterogeneous reaction.

The qualitative differences in the capacity of the hierarchic entities to combat various noxious agents can explain the differences in the manifestations of allergic processes taking place at the cellular or tissular levels as compared to those in the blood, which is at the systemic level. At any level, the mobilization of lytic enzymes able to break down the allergic antigen antibody complex can be so intense as to bring rapid death of the entity or can be slow and prolonged. However, at the systemic level, as in the circulating blood, the products resulting from exaggerated lysis are more rapidly and completely disposed of than in cytoplasm or interstitial fluids. In the latter, they will be present for a long time and their noxious influence will persist. If the lytic products appear in moderate amounts in blood, the organism may be able to dispose of them without any clinical manifestations.

For these reasons, the presence of antigens in the blood when coagulant antibodies start to appear will not induce serious manifestations and will even prevent them. As coagulant antibodies appear gradually in the blood, only small amounts of antigen antibody complex will be produced at any one time. Although highly noxious in large amounts, the complexes can be resolved through lytic processes if formed gradually, and consquently will not provoke clinical manifestations.

At the tissular and cellular levels, a similar progressive appearance of antigen coagulant antibody complex cannot be resolved in the same way. The lytic reactions which break down this complex cannot occur with the efficiency noted in the blood. The complexes and the products of lysis will progressively accumulate and the consequent manifestations will become more and more intensive. It is for this reason that long lasting allergic manifestations correspond to serious local conditions. Even if the antigen antibody complexes are produced at a moderate rate, when antibodies appear and the antigen is present, they will induce little or no systemic manifestations. On the contrary, serious allergic manifestations will arise if the complexes are formed at the cellular, tissular or even organic levels. Because the defense processes at these levels cannot resolve them at the same rate as they appear, as defense processes in the blood can do, severe local manifestations result. This may lead to necrosis and even rejection of altered cells or tissues. These represent the very important differences which exist between allergic processes which occur in the blood and those which occur at the different levels following the appearance of allergic antibodies while the antigen is still present.

The fact that there will be no reaction when small amounts of the allergic complex are progressively formed, as in cases in which antigens are present in the blood at the moment of appearance of the allergic antibodies, is confirmed indirectly by the possibility of preventing severe systemic manifestations through skeptophylactic or desensitization procedures. The introduction of very small amounts of antigen thus produces only small amounts of complex at any one time, avoiding clinical manifestations. With progressive doses however, the antigens will fix circulating antibodies in sufficient proportion to prevent the formation of important amounts of the same complexes after further administration of the antigen. The presence of the second phase of the diphasic phenomenon, with the exaggeration of constituents antagonistic to those present in the first phase, will also act to prevent the occurrence of an intensive first phase when the antigen appears anew.

The situation changes entirely when antibodies appear and the antigen no longer is present. They can then accumulate in the blood in large amounts. Thereafter, sudden appearance of the antigen in sufficient quantity will form a large amount of the allergic complex and the subsequent reaction can be so violent as to kill the subject. This occurs in anaphylactic shock. When the antigen is limited to other levels, important local changes can be induced.

The neutralizing immune antibodies, if manifestations already exist, will prevent new ones from appearing and this will permit healing processes to take place without further interference. The antibodies will prevent manifestations at the respective level if the antigen appears again.