Histology of the Blood, Normal and Pathological

by Paul Ehrlich; Adolf Lazarus

1. That in various diseases of the nose, especially in mucous polypi and hyperplasia of the mucous membrane (Leyden, Benno Lewy and others), a great accumulation of eosinophil cells is found in these tissues, whilst they are apparently not increased in the blood. This objection is easily laid aside from the chemiotactic point of view. For if in the places in question substances are present which act chemiotactically on the eosinophil leucocytes, in the course of time marked accumulation must occur, without an increase of their number in the blood. One might as well conclude from Neumann's experiment in lymphatic leukæmia, for example, where the artificial suppuration consisted only of polynuclear neutrophil cells, that the polynuclear cells were formed in the tissue, since in the blood they were present in very small percentage. For in this case too the same incongruity between the blood and the particular tissue exists.

2. Adolph Schmidt has urged the converse argument. He shewed that in the sputum of patients with myelogenic leukæmia no more eosinophil cells were present than are commonly to be found in the bronchial secretion, although the blood was unusually rich in eosinophil cells. In our opinion however this observation does not support the hypothesis of local origin, but on the contrary is clear evidence that not the larger or smaller number of eosinophil cells in the blood decides their emigration, but the presence of specifically active chemical stimuli. For we know from our observations on leucocytosis in infectious diseases that the bacterial stimulating substances act on the eosinophil cells rather in a negative than in a positive sense. And if ordinary sputum is not rich in eosinophils in spite of a marked eosinophilia of the blood, this only corresponds to our experience in general. Indeed, this phenomenon is quite similar to Neusser's pemphigus experiment, where the specific foci of disease shewed an eosinophilia, whilst abscesses produced artificially, on the contrary, only neutrophil cells. Finally we may employ, to support our view, another analogous experiment of Schmidt himself. He found numerous eosinophil cells in the sputum of an asthmatic patient, but only neutrophil cells in an artificially produced suppuration of the skin.

Thus we see that the chief reasons brought forward by the supporters of the theory of local origin are not proof against the most obvious objections that can be raised from the chemiotactic standpoint. Moreover, neither histological nor experimental proof has been given for this theory in spite of numerous investigations in this direction. All the same, it should not be out of place to explain the possibilities that are given for a local origin of the eosinophil cells. First, the eosinophil cells might be the result of a progressive metamorphosis of the normal tissue cells. That such a process is possible, is proved by the local origin of the mast cells. These may arise, as Ehrlich and his school have always assumed, by transformation of pre-existing connective tissue cells[29]; but that the same holds good for the eosinophil cells as well, has nowise as yet been proved. Secondly, it is conceivable, that isolated eosinophil cells, pre-existing in the tissues, should rapidly multiply, and so produce the local accumulation only. Numerous mitoses could be considered an adequate proof of this process. But so far no figures of nuclear division have been observed; indeed A. Schmidt, who has directed special experiments thereto from the standpoint of his theory, has found them entirely absent.

As a third possibility for the local origin of the eosinophil cells, their direct descent from neutrophil cells is conceivable, and is by many regarded as a kind of ripening. This assumption nevertheless must be described as unsound, since the necessary condition of its foundation, namely the observation of corresponding transitional stages, has not so far been fulfilled.

By the inductive method then we conclude that a local origin of the eosinophil cells can hardly come under discussion. And this conclusion is strengthened by comparison with the behaviour of the mast cells, which are related to the eosinophils in many points, and only differ from them essentially in the nature of their granulation. The mast cells too, like the eosinophils, form a normal constituent of the bone-marrow, and occur regularly besides in normal blood, though in very small number—according to Canon they amount to 0.28% of the leucocytes. We know that the mast cells are produced in large quantities locally, wherever an over-nutrition of the connective tissue occurs, for instance in chronic diseases of the skin, elephantiasis, brown induration of the lungs. In the case of the mast cells, then, we see the conditions actually realised, which the supporters of the theory of the local origin of the eosinophil cells only assume. We should therefore expect that an increase of mast cells in the blood or in certain inflammatory exudations would be by no means seldom. With this point in mind Ehrlich has subjected the sputum in emphysema and brown induration of the lungs to exact examination for 20 years. Nevertheless he has obtained entirely negative results. The special blood investigations of Canon have likewise proved to be practically negative. In 22 healthy persons Canon entirely failed to find the mast cells on nine occasions, in the others he found on the average 0.47%; the highest percentage number obtained was 0.89%. Only in a few cases of skin disease was a slight increase indicated. The average amounted to 0.58%, a number, therefore, which is often to be found in healthy individuals. A leucocytosis of mast cells, comparable with the eosinophil or neutrophil forms of leucocytosis, has not been demonstrated in the cases of Canon or other observers. On the other hand, the mast cells undergo a considerable increase in myelogenic leukæmia, in many cases equalling or even exceeding that of the eosinophils. We shall not err in deriving the mast cells of the blood solely from the bone-marrow, on the grounds of this fact; or in conjecturing that their origin is not from the connective tissue, even when they are there excessively increased[30].

We think we have shewn in the preceding paragraphs that the evidence, so far brought forward for a local origin of the eosinophil cells, does not withstand the objections that have been raised. The task now lies before us, to produce positive proof that the accumulations of eosinophil cells in the organs and secretions must be explained by emigration from the blood.

This proof offers great difficulties in as much as we normally find eosinophil cells in many places. Here then we cannot trace a process step by step, but we have to deal with final conditions. Could we observe the genesis of eosinophil cells in organs usually free from them, it would be easier to clear up this question. Up to the present but a single observation on this point is available. Michælis established the interesting fact, that on interrupting lactation in suckling guinea-pigs, in the course of a few days numerous eosinophil cells collect in the mammary glands, but not in the lumen of the canaliculi. The eosinophil cells are further polynuclear, exactly corresponding to those of the blood, and therefore to be regarded as immigrants. We may explain this condition according to modern views as follows. Under certain conditions the mammary gland is capable of an internal secretion, by means of which substances are produced that are specifically chemiotactic for the eosinophil cells. When the external secretion of milk is disturbed, the internal secretion is abnormally increased. The fact too that in Michælis' researches no eosinophil cells passed into the true secretion of the gland may be thus explained[31].

Exactly similar observations have been made on pathological material, first recorded in the brilliant and fundamental work of Goldmann. In a case of malignant lymphoma Goldmann found a considerable accumulation of eosinophil cells within the tumour, and demonstrated anatomically, that it was brought about by an emigration of the cells from the vascular system. Hence Goldmann concluded that the eosinophil cells pass over into the tissue in question, at the call of certain chemiotactic products. Goldmann, and later Kauter, shewed that these eosinophil cells were not merely due to an ordinary inflammation; for in a large number of other diseases of the lymph glands—particularly the tuberculous, they were entirely absent. Similarly Leredde and Perrin have shewn in their investigations of Dühring's disease, that the eosinophil cells, which are also present in the cutaneous tissue in large numbers, apart from the contents of the bullæ, are due to an emigration from the blood-stream.

Thus it is evident from a number of various facts, that the eosinophil cells found in the tissues are not formed there, but have immigrated from the blood-stream. It naturally often happens that this appearance is not preserved equally distinctly in all cases. For, as has been seen in the ordinary polynuclear leucocytes, the immigrated polynuclear eosinophils may similarly change to mononuclear cells; they may perhaps settle down, and approximate to the character of fixed connective tissue cells. Such appearances may readily give rise to the view that in this case the reverse nuclear metamorphosis has occurred; that is a progressive development from mononuclear eosinophil to polynuclear cells.