Part 16

It consequently follows from clinical and morphological researches, as well as from the observations on inflammatory processes, =that the lymphocytes are in no way connected with the polynuclear leucocytes=. We shall reach the same result in another way in the following section.

([gamma]) The Bone-marrow.

The spleen and lymphatic glands were at first regarded as the sole places of formation of the blood corpuscles. The almost simultaneous researches of Neumann and Bizzozero first attracted general attention to the importance of the bone-marrow. These authors showed that the early stages of the red blood corpuscles are produced there; a discovery which was quickly and generally recognised, and which soon became pathologically useful through the observations of Cohnheim and others. In this connection the observation was of great value, that after severe loss of blood the fatty marrow of the larger hollow bones again changes to red marrow, as it is evidence of the increased demands on the regenerative function of the bone-marrow.

We are unaware of a second place of formation of the red blood corpuscles in man. In other mammalia however, as we have above mentioned (see page 99), the spleen may also take a small share in the production of erythrocytes. The type which the normal blood formation follows in adults, and the deviations therefrom shewn in pernicious anæmia, have been described in the chapter on the red blood corpuscles. Ehrlich's view that the blood formation in pernicious anæmia belongs to a different type, which is analogous to the embyronic, was also described there.

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=.

The granulated cells of the bone-marrow fall into two groups.

The first group of the cells with "=special granules=" is very important since it constitutes a characteristic for certain species of animals. According to the class of animal they shew different tinctorial and morphological properties. Man and monkey for example have neutrophil granulation; guinea-pig and rabbit the pseudo-eosinophil granulation described by Kurloff; in birds we find two specific granulations present side by side, which both are oxyphil, and of which one is imbedded in the protoplasm in crystalline form, the other in the form of granules.

The kinds of special granulations so far investigated have the common property, that they stain in acid and neutral dyes respectively; they shew a much smaller affinity for the basic dyes. The fact that they greatly exceed the other elements of the bone-marrow in all classes of animals, is evidence of the importance of these granules.

The second group of bone-marrow cells contains granules which we find in the whole vertebrate series from the frog to man, and which therefore are not characteristic for any one species of animal. They are, (1) the eosinophil cells, (2) the basophil mast cells.

The bone-marrow forms which are free from =granules= consist mostly of mononuclear cells of different type. They are not nearly so numerous, or so important as the granulated kind, more especially as the first and predominant group.

Amongst the granule-free forms the =giant cells= deserve special mention, for they are an almost constant constituent of the bone-marrow of the mammalian class. According to the recent researches of Pugliese the giant cells are considerably increased after extirpation of the spleen in the hedgehog; an organ of quite extraordinary size in this animal and doubtless therefore possessing important hæmatopoietic functions.

Pugliese asserts that in the hedgehog after splenectomy the nucleated giant cells pass into leucocytes by amitotic nuclear division. Unfortunately in his preliminary communication there are no notes of the granules of the bone-marrow cells.

On examining a stained dry preparation of the bone-marrow of the guinea-pig, rabbit, man, etc. it is seen that the characteristic finely granular cells are present in all stages of development, from the mononuclear through the transitional to the polynuclear (polymorphously nucleated) forms, which we meet with in the circulating blood. A glance at a preparation of this kind shews that the bone-marrow is clearly the factory where typical polynuclear cells are continuously formed from the granule-containing mononuclears.

Here also the same process of ripening can be seen in the polynuclear eosinophil leucocytes.

Ehrlich has been able by special differential staining to bring forward proof that the constitution of the granulation changes during the metamorphosis of the mononuclear to the polynuclear cells. In the young granules there is prominent a basophil portion that becomes less and less marked as the cell grows older. The pseudo-eosinophil granules of the mononuclear cells, of the guinea-pig for example, stain bluish-red in eosine-methylene blue after long fixing in superheated steam: in the transitional stages this admixture is gradually lost, and finally completely vanishes in the granules of the polynuclear leucocytes which stain pure red. Analogous observations may be made in the eosinophil cells of man and animals, and in the neutrophils of man. Hence it is even possible to decide whether an isolated granule belonged to an old or to a young cell.

It is still impossible to judge with certainty the rate at which the ripening of the mononuclear to the polynuclear cells proceeds, or further to decide if the ripening of the granules always runs parallel in point of time with that of the whole cell. On the grounds of our observations we would suppose that in general the two processes run their course side by side, but that in special cases the morphological ripening of the cell may proceed more rapidly than that of the granules. It is particularly easy to observe this point in eosinophil cells. Ehrlich had already mentioned in his first paper (1878) that side by side with the typical eosinophil granules isolated granules are often found which shew a deviation in tinctorial properties: for instance, they stain more of a black colour in eosine-aurantia-nigrosin; in eosine-methylene-blue, bluish-red to pure blue. Ehrlich had already described these as young elements in his first paper. The same differences are found more sharply marked in leukæmia even in the circulating blood, in the neutrophil as well as in the eosinophil group. Ehrlich has repeatedly found in leukæmic blood polynuclear eosinophil cells, whose granules must almost exclusively be regarded as young forms.

Ehrlich regarded these as typical examples of a relative acceleration of the morphological ripening of the cells, as compared with the development of the granules.

=In normal blood we find only the ripe forms of the specific granulated cells of the bone-marrow. The mononuclear and transitional forms of the neutrophil group, do not under normal circumstances pass over into the blood-stream.=

Ehrlich regarded the mononuclear neutrophil granulated cells as characteristic for the bone-marrow, since they are found exclusively in the bone-marrow, never in the spleen or lymph glands, and for this reason named them "=myelocytes=," [Greek: kat' exochên]. When myelocytes, no matter of what size, appear in considerable numbers in the blood of an adult, a leukæmia of myelogenic nature is nearly always present. (For the very rare exceptions to this rule, which it may be added can never be confused with leukæmia, see pages 77, 78.)

Exactly similar conditions hold good for the eosinophil cells, in as much as the singly nucleated forms, which one may call eosinophil myelocytes, occur, almost exclusively, in leukæmic blood. These forms, which were first recognised by H. F. Müller, are however of less importance, for in myelogenic leukæmia the chief part of the foreign admixture of the blood is made up of Ehrlich's myelocytes.

Very important conclusions on the interesting question of leucocytosis can be drawn from these observations. 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. It is only on this assumption that the frequently sudden appearance of leucocytosis, as has so often been observed in morbid and experimental conditions, can be satisfactorily explained. 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.

The bone-marrow thus fulfils, amongst others, the extremely important function of a protective organ, by which definite injurious influences which affect the organism may be quickly and energetically combated. Just as in a fire-station ample means of assistance is continuously in readiness immediately to answer an alarm from any quarter.

We wish to insist once more, that the =large mononuclear leucocytes= and the transitional forms of the normal blood are not concerned in the increase in ordinary leucocytosis; in leucocytosis of high degree their relative number may indeed be lowered, in consequence of the exclusive increase of the polynuclear cells. It appears then that these elements do not react to chemiotactic stimuli, and that possibly they reach the blood by entirely different ways than the polynuclears do.

We believe that these non-granulated mononuclear cells of man are to be regarded as analogous to those of the guinea-pig described by Kurloff (see page 86). The mononuclear cells of man however are finally transformed into the neutrophil granulated cells, whilst the cells of Kurloff remain free from granules in the course of their metamorphosis. In acute leucocytosis in the guinea-pig only the pseudo-eosinophil polynuclear cells are increased, which wander as such out of the bone-marrow, but not the polynucleated non-granulated forms, which but slowly grow to maturity in the blood. Thus the peculiarities of guinea-pig's blood, in which two kinds of polynuclear cells are recognisable, throw light upon the corresponding conditions in human blood. The distinction in the latter is more difficult, since it is not evident in this case that the fully formed polynuclear neutrophil leucocytes have a twofold origin: for the majority wander fully formed from the bone-marrow into the blood, and only a considerably smaller number grow to maturity within the blood-stream from the mononuclear and transitional forms.

No definite statement can as yet be made as to the places of formation of the non-granulated large mononuclear leucocytes.

Kurloff has demonstrated, that in the guinea-pig these cells are present both in the bone-marrow and in the spleen, but that after extirpation of the spleen the absolute number does not change. The bone-marrow then in the guinea-pig can also preserve the balance of the large mononuclear, non-granular cells in the blood.

The numbers we found in our blood investigations in man after splenectomy were also normal. We may then doubtless assume that the large mononuclear granuleless cells of human blood also arise for the most part from the bone-marrow. In this tissue they are to be picked out in the medley of the different kinds of cells only with the utmost difficulty, owing to their small number and their but little characteristic properties. Consequently an exact investigation of their origin could probably only be successful if it were possible experimentally to produce a disease in which these forms in particular underwent important increase. This advance is not quite hopeless, since in man at least an absolute increase of the large mononuclear cells is observed in the post-febrile stage of measles.

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.