Paul Ehrlich

“ The process of division goes on in the blood in such a manner that the nuclear rod first divides into two to four single nuclei, and then the whole cell splits up into as many fragments. These cells occur also in fresh pleuritic exudations. After a time the nucleus of these cells becomes free, and the little masses of protoplasm thus cut off are taken up mostly by the spleen substance. The free nucleus likewise shares in the destruction. It is of the greatest importance that these cells, which up to the present have not elsewhere been described, should receive more attention. ”

“ Müller and Rieder should themselves have raised the obvious objection that the same holds good for the nucleus of the neutrophils. They would then have seen the fault in their theory; for according to it the most important blood preparing organ constitutes as it were, not the cradle of the blood cells, [Pg 156] but their grave. The simplest and readiest explanation, based too upon histological observation, is surely this: that the mononuclear eosinophil cells grow into polynuclear in the bone-marrow, but that the latter only reach the blood by means of their power of emigration. ”

“ All methods of staining available for the blood require the fixing of the proteids of the blood. A general formula cannot be given, since the intensity of the fixation must be regulated in accordance with the kind of stain that is chosen. Relatively slight degrees of hardening suffice for staining in simple watery solutions, for example, in the triacid fluid, and can be attained by a short, and not too intense action of several reagents. For other methods, in which solutions that are strongly acid or alkaline are employed, it is however necessary to fix the structure much more strongly. ”

“ Since the beginning of histology the word 'granular' has been used to describe the character of cellular forms. This term is not a very happy one, since many circumstances produce a granular appearance of the protoplasm. Modern work has shewn that many cells, formerly described as granular, owe this appearance to a reticular protoplasmic framework. And we have no more right to call cells granular in which proteid precipitates occur, either spontaneously as in coagulation, or from reagents (alcohol) . ”

“ The pathology of the blood, especially of the corpuscular elements, though one of the most interesting, is certainly one of the most confusing, of all departments of pathology, and to those who have not given almost undivided attention to this subject it is extremely difficult to obtain a comprehensive and accurate view of the blood in disease. ”

“ On the grounds merely of microscopical investigations we conclude that the bone-marrow is by far the most important of the blood-forming organs, for its function is the exclusive production of red blood discs as well as of the chief group of the white corpuscles, the polynuclear neutrophil.
The physiological, experimental investigation of the functions of the bone-marrow offers insurmountable difficulties. An exclusion of the whole bone-marrow or of larger portions only is an impossible operation. ”

“ The chief characteristic is, as Ehrlich has always particularly insisted, the constitution of the nucleus. The nuclei of cells which are with certainty to be reckoned among the normoblasts are marked by the absence of structure, their sharply defined contour, their intense affinity for nuclear stains. That is by properties which histology sums up under the name Pyknosis (Pfitzner) and recognises as signs of old age. The nuclei of the megaloblasts are round, shew a good deal of structure, and stain far less deeply. ”

“ Whilst for instance the majority of the granules are more or less rounded forms, in some classes of animals, e.g. in birds, the analogues of the granules of mammalian blood are characterised by a decided crystalline form, and a strong oxyphilia. The substance of the mast cell granulations is also crystalline in some species of animals.
The size of the individual granules is constant in any animal species for every kind of granule—excepting only the mast cells. The eosinophil granulation reaches its greatest size in the horse, where really gigantic examples are found. ”

“ Bearing in mind that polynuclear neutrophil cells are developed and stored up only in the bone-marrow, that in ordinary leucocytosis only the polynuclear forms are increased in the blood-stream, it is evident that leucocytosis is purely a function of the bone-marrow, as Ehrlich has always insisted with all distinctness. ”

“ 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. ”

“ The standard of comparison for a leukæmic patient suffering from severe sepsis is not the blood of a healthy person with normal numerical proportions, but that of a patient similarly attacked by a severe sepsis. Now we know that in sepsis the number of eosinophil cells is enormously diminished, so that Zappert, in five cases of this nature, was unable to recognise any eosinophils in the blood. In contrast to this stands a case of myelogenic leukæmia described by Rieder and Müller, complicated by a severe and lethally ending suppurative process. ”

“ 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. ”

“ On investigating the conditions under which in healthy individuals an increased number of lymphocytes enter the blood-stream, we have in the first place to notice the digestive canal, whose wall contains a thick layer of lymphatic tissue. According to the results of Rieder the proportion of the lymphocytes to polynuclears is practically normal in the leucocytosis of digestion, indeed the lymphocytes are rather in excess. ”

“ Ehrlich's demonstration of megaloblasts has sufficed for this logical advance. All researches, which try to obscure or totally deny the distinction between megaloblasts and normoblasts are wrecked by the simple clinical fact that in pernicious anæmia the blood is megaloblastic.
The appearance of megaloblasts and megalocytes is therefore evidence that the regeneration of the blood in the bone-marrow is not proceeding in the normal manner, but in a way which approximates to the embryonic type. ”

“ Leucocytosis is now recognised to be chiefly an increase of the normal polynuclear neutrophil leucocytes; whereas myelogenic leukæmia brings elements into the blood that are abnormal. The cells here introduced are so characteristic as to render the diagnosis of leukæmia possible, even in the very rare cases where the total number of the white blood corpuscles is not to any extent increased. The best example of which we are aware is a case observed by v. Noorden, in which the proportion of white to red was only 1:200. ”

“ Great importance has always been attached to the investigation of the specific gravity of the blood; since the density of the blood affords a measure of the number of corpuscles, and of their hæmoglobin equivalent. ”

“ One of the most important points indicated in the following pages is that the cellular elements of the blood must be studied as a whole and not as isolated factors, as "it has always been shown that the character of a leukæmic condition is only settled by a concurrence of a large number of single symptoms of which each one is indispensable for the diagnosis, and which taken together are absolutely conclusive." ”

“ It will be the task of further investigations to examine accurately inflammatory products, e.g. pleuritic exudations, in leukæmic patients, with the object of elucidating the question, whether under special conditions of disease all the leucocytes characteristic for leukæmia may not be able to wander from the blood. Thus in a case of pleurisy in a leukæmic patient, Ehrlich received the impression from the preparations that a "myeloid" emigration had in fact occurred, carrying all the elements in the blood into the exudation. ”

“ The breaking up of ordinary pus cells or lymphocytes does not appear to give rise to any such substances; but there is much evidence that the decomposition products of epithelial and epithelioid cells act chemiotactically. Thus we can explain the frequent occurrence of eosinophilia in all kinds of skin-diseases. Again, in all atrophic conditions of the gastric, intestinal and bronchial mucous membrane there occurs a local accumulation of eosinophil cells; further, this kind of cell is increased in the neighbourhood of carcinoma. ”

“ Instead of the latter, we find in these cells a roundish, nucleus-like form in the protoplasm, which also takes the nuclear stains, and possibly is to be considered an accessory nucleus. We have received the impression that we have here to deal with a vacuole filled with substance secreted by the cell. In a large series of preparations, it is possible to obtain some elucidation of the development and fate of these appearances. They first appear as point-like granules in the protoplasm, bearing no relation to the cell nucleus; they gradually increase, and acquire a considerable circumference. ”

“ The clearest proof that the neutrophil, eosinophil, and mast cells are entirely separated from one another by the fundamental diversity of their protoplasm, of which the granulation is but a specially striking expression, is afforded by the study of the various forms of leucocytosis. As will be shewn in detail in the following chapter, neutrophil and eosinophil leucocytes behave quite differently in their susceptibility to chemiotactic stimulation. Substances strongly positively or negatively chemiotactic for one cell group are as a rule indifferent for the other ”

“ With the abundant information, the well argued deductions and the carefully drawn up statement here placed before us it may be claimed that we are now in a position to make diagnoses that not long ago were quite beyond our reach, whilst a thorough training of our younger medical men in the methods of blood examination must result in the accumulation of new facts of prime importance both to the pathologist and to the physician. ”

“ With regard to the significance of the blood platelets, most authors, of whom we should before all [Pg 192] mention Hayem, Bizzozero, Laker, assume justifiably that they are preformed in the living blood. The view opposed to this, advocated more particularly by Löwit, that these forms first arise in the blood after it has left the vessels, we may describe on the grounds of our own extensive observations as inaccurate.
The blood platelets, on the grounds of their small size and complete lack of nuclear substance, are generally regarded as not analogous to real cells. ”

“ The Lymphocytes. These are small cells, as a rule approximating in size to the red blood corpuscles. Their body is occupied by a large round homogeneously stained nucleus centrally situated, whilst the protoplasm surrounds the nucleus as a concentric border. Between nucleus and protoplasm there is often found a narrow areola, which doubtless results from artificial retraction. Nucleus and protoplasm are basophil, nevertheless in many methods of staining the protoplasm possesses a much stronger affinity for the basic stain than does the nucleus. ”

“ In this section we have therefore to deal chiefly with the white blood corpuscles and their connection with the bone-marrow. In man as in a large number of animals (for example the monkey, guinea-pig, rabbit, pigeon and so forth) the bone-marrow exhibits the peculiarity that the cells it produces bear a specific granulation, in sharp contrast to the lymphatic glandular system, which contains elements free from granules, in the whole animal series. ”

“ One expression of these distant actions is, as Leichtenstern insists, the eosinophilia of the blood. We do not think we should assume on the evidence before us, that the substance which attracts the eosinophil cells is identical with the cause of the anæmia. Many observations, the absence, for example, of eosinophilia in Bothriocephalus anæmia (Schauman) , render probable the existence of two different functions. In any case the substance causing the eosinophilia is more widely distributed than that to which the anæmic condition is due.
Leukæmia. ("Mixed leucocytosis.") ”

“ The red blood corpuscles have consistently shewn themselves as almost exclusively concerned with variations in the specific gravity of the total blood; partly by variations in number, or changes in their distribution; partly by their chemical instability; loss of water and absorption of water, and variations in the amount of iron.
The plasma of the blood on the contrary—and there is no essential difference between plasma and serum (Hammerschlag) —is much more constant. ”

“ Quite recently Pappenheim, partly in conjunction with O. Israel, has carried out very thorough researches on these particular points. As the subject for observation he chose the blood of embryonic mice. He was able in the first place, like Rindfleisch, to produce the exit of the nuclei from the cells by the addition of "physiological" salt solution to fresh blood, and is of the opinion that the exit of the nucleus from the erythroblasts only takes place artificially. ”

“ He says that a distinction between so-called lymphocytes and the leucocytes with polymorphous nuclei, on the grounds of the form of the cell and nature of the nucleus, is not possible at the present time. Neither is a classification based on the granules admissible, since the same granules [Pg 83] occur in different cells, and different granules in the same cell. The work of Gulland and Arnold takes into consideration the differential staining of the granules in various ways. In spite of their facts we disagree with their conclusions ”

“ In these cases the space of time, amounting often only to minutes, is far too short for a new formation of leucocytes to be conceivable; there must be places in which these cells are already completely formed, and able thence to emigrate on any suitable stimulus. This place is single, and is the bone-marrow alone. Here all mononuclear forms gradually ripen to the polynuclear contractile cells, which obey each chemiotactic stimulus by emigration, and which thus bring about sudden leucocytosis. ”