chronic tumour of the spleen, is analogous to Kurloff's secondary
reaction of the bone-marrow. Such cases are frequently found in the
literature. For instance Mueller and Rieder bring forward three cases of
splenic tumour caused by congenital syphilis, cirrhosis of the liver,
neoplasm in the cranial cavity, and in which the numbers of the
eosinophils amounted to 12.3%, 7.0%, 6.5% respectively. In three cases
of acute splenic tumour in typhoid fever the figure 0.31% with a maximum
of 0.82%, was found. These authors have already raised the question
"whether the increase of the eosinophil cells is connected with the
splenic tumour or the bone-marrow? Perhaps the functional activity of
the latter is vicariously raised to meet the more or less complete
exclusion of the spleen from the formation of the blood; since Ehrlich
has distinctly asserted that the probable place of formation of the
eosinophil cells is the bone-marrow."
From what has been brought forward no doubt can now remain that the
question has been decided quite in Ehrlich's favour.
But what then are the physiological functions of the spleen, since that
organ is unnecessary for the persistence of life? Doubtless its chief
duty is the taking up of the greater part of the decaying fragments of
red and white blood corpuscles in the blood-stream, so that this
valuable material is not quite lost for the organism. Thus Ponfick has
found that after destruction of the red corpuscles the spleen takes up a
portion of their "shadows," and for this reason calls the splenic tumour
a spodogenous splenic tumour ([Greek: spodos], ruins). Ehrlich has made
a corresponding observation for the products of dissolution of the white
blood corpuscles, and has proved that the splenic tumour which occurs in
many infectious diseases and in phosphorus poisoning is to a large
extent caused by the parenchyma of the spleen taking up the remains of
the neutrophil protoplasm.
The question of the relation of the spleen to the =fresh formation of red
blood corpuscles= is a problem of comparative anatomy. Observations on
this point made on one kind of animal can certainly not claim validity
for other kinds. In lower vertebrates, as in fishes, frogs, tortoises,
and also in birds, the blood-forming activity of the spleen is
pronounced and of great importance. In mammalia on the other hand, in
some cases this function cannot be demonstrated, and in others only to a
very small degree. In the spleen of normal mice nucleated red blood
corpuscles are seen in relatively large numbers; in the rabbit they are
less numerous and often only to be found with difficulty. In the dog
they only make their appearance after anaemia from loss of blood,
normally they are absent. =In the human spleen nucleated red blood
corpuscles are not to be found normally or in cases of severe anaemia,
but exclusively in leukaemic diseases.= U. Gabbi in his recently published
work on the haemolytic function of the spleen, also emphasises the
difference between the various animal species. In guinea-pigs he found
that the spleen acts largely as a scavenger of the red blood corpuscles;
in rabbits very slightly. Consequently after removal of the spleen in
guinea-pigs the number of red blood corpuscles rose 377,000 in the cubic
millimetre, and the amount of haemoglobin 8.2%. After splenectomy in
rabbits the increase in these values is absent.
Shortly summarising our analysis of the facts before us, we must say
that =the importance of the spleen for the production of the white blood
corpuscles can in no respect be considerable=, and that if these cells
really are produced by it, they must be free from granulations. The
spleen therefore stands functionally in closer connection with the
lymphatic gland system than with the bone-marrow. =The spleen has not the
least connection with ordinary leucocytosis[14].=
([beta]) The Lymphatic Glands.
As it is impossible experimentally to prevent the lymphatic glands as a
whole from contributing to the formation of the blood, we are dependent
almost entirely on clinical and anatomical researches for an elucidation
of their function.
Since Virchow's definition of the lymphocyte it has been admitted that
the lymphocytes of the blood, both the small and larger kinds, are
identical with those of the lymphatic glands and the rest of the
lymphatic system. This is proved by the complete agreement in general
morphological character, in staining properties of the protoplasm and
nucleus, and from the absence of granulation.
Abundant clinical experience testifies that the lymphocytes of the blood
really do arise from the lymphatic system. Ehrlich had previously
observed that when extensive portions of the lymphatic glandular system
are put out of action by new growths and similar causes, the number of
the lymphocytes may be considerably diminished. These observations have
since that time been confirmed by various authors. For example, Reinbach
describes several cases of malignant tumour, particularly sarcoma, in
which the percentage of lymphocytes, which normally amounts to about
25%, was very considerably lowered; in one case of lymphosarcoma of the
neck they only made up 0.6% of the total number. These conditions are
quite easily and naturally explained by the exclusion of the lymphatic
glands. It is difficult for the advocates of the view that the
lymphocytes are the early stages of all white blood corpuscles to
reconcile it with these facts. According to their scheme the low number
of lymphocytes is to be explained in such cases by their unusually rapid
transformation to the polynuclear elements--the old forms; or to
appropriate the expression of Uskoff, by a too rapid ageing of the
lymphocytes.
Further evidence for the origin of the lymphocytes of the blood from the
lymphatic glands is to be obtained from those cases in which we find an
increase of the lymphocytes in the blood. These "lymphocytoses" occur,
in comparison with other leucocytoses, relatively seldom. Under certain
conditions in which a hyperplasia of the lymphatic glandular apparatus
makes its appearance, we often see at first an increase of the
lymphocytes in the blood. Ehrlich and Karewski in some unpublished work
have investigated together a large number of typical cases of lymphoma
malignum, and were able constantly to observe a lymphocytosis, which in
some cases was of high degree and bore almost a leukaemic character.
Relying on these facts Ehrlich and Wassermann (_Dermatolog.
Zeitschr._ Vol. I., 1894) made the diagnosis _in vivo_ of
malignant lymphoma in a rare skin disease, chiefly from the
absolute increase of the lymphocytes alone, although no
swelling of the glands was palpable. The post-mortem shewed
that the chief condition was a swelling of the retro-peritoneal
lymph glands to lumps as large as a fist.
The lymphocytosis following extirpation of the spleen also belongs to
this category, since a vicarious enlargement of the lymph glands is
always to be observed in these cases.
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. The eosinophils on the other hand shew a marked relative
reduction in this condition. The leucocytosis of digestion consequently
differs essentially from the other kinds, in which the neutrophil
elements are chiefly increased. The simultaneous increase of lymphocytes
and polynuclears is doubtless brought about by a super-position of a
raised income of lymphocytes, and an ordinary leucocytosis caused by the
assimilated products of metabolism.
The influence of the digestive tract is still more evident in certain
diseases, more particularly in intestinal diseases of infants. A
considerable increase of the lymphocytes in the blood-stream is here to
be observed. Thus Weiss found an important increase of the white blood
corpuscles in simple catarrh of the stomach and intestines, which
presented the main features of a lymphocytosis.
Whooping-cough, according to the recent observations of Meunier, also
belongs to the small number of diseases which are accompanied by a
pronounced lymphaemia. In the convulsive period of this disease both the
polynuclear cells and the lymphocytes are increased, the latter in
preponderating amount. The former cells are increased to twice, the
lymph cells to four times their normal amount. Doubtless in these cases
also the lymphocytosis is due to the stimulation and swelling of the
tracheobronchial glands.
An increase of the lymphocytes from chemical stimuli is exceedingly
rare, though, as is well known, a large number of substances (bacterial
products, proteins, nucleins, organic extracts, and so forth) can call
forth a polynuclear leucocytosis. In quite isolated cases, an increase
of the lymphocytes in the blood in consequence of the injection of
tuberculin into tuberculous individuals has been seen. (E. Grawitz.)
From the rarity of these cases it can scarcely be doubted that here a
tuberculous disease of the glands also plays a part, so that the
increased immigration of lymphocytes is brought about not by a chemical
property of the tuberculin but by the extensive specific reaction of the
diseased glands.
Only one single substance has so far been mentioned in the literature as
capable in itself of producing a lymphocytosis. Waldstein asserts that
he has produced by injection of pilocarpine, a lymphaemia which undergoes
a progressive increase with a rise in number of the injections.
The origin also of lymphocytosis is therefore sharply marked off from
that of the ordinary leucocytosis, which consists in an increase of the
neutrophil elements. Whilst the latter is admittedly the expression of
chemiotactic action, and arises by action at a distance of soluble
substances on the bone-marrow, lymphocytosis is due to a local
stimulation of certain glandular areas. Thus in the leucocytosis of
digestion, of intestinal diseases of children, we refer it to the
excitation of the lymphatic apparatus of the intestine, in tuberculin
lymphaemia we recognise mainly a reaction of the diseased lymph glands.
Hence we conclude that a lymphocytosis appears when a raised lymph
circulation occurs in a more or less extended area of lymphatic glands,
and when, in consequence of the increased flow, more elements are
mechanically washed out of the lymph glands. The pilocarpine
lymphocytosis does not contradict this view, for pilocarpine causes
extraordinary though transient variations in the distribution of water,
whereby the inflow into the blood of fluid containing lymph cells is
increased. We therefore regard =lymphocytosis= as the result of a
=mechanical= process; whilst =leucocytosis= is the expression of =an active
chemiotactic reaction= of the polynuclear elements.
This view finds its best support in the fact that the polynuclear
leucocytes possess lively amoeboid movement, which is completely
wanting in the lymphocytes.
Corresponding to the absence of contractility in the lymphocytes it is
also observed that in =inflammatory= processes in contradistinction to the
polynuclear neutro-and oxyphils, the lymphocytes are not able to pass
through the vessel wall. A very interesting experiment on this point was
described by Neumann years ago. Neumann produced suppuration in a
patient with lymphatic leukaemia, in whom the blood contained only a
very small number of polynuclear cells. Investigation of the pus shewed
that it consisted exclusively of polynuclear cells, and that not a
single lymphocyte had come into the exudation, although this kind of
cell was present so abundantly in the blood.
Histological examination of all fresh inflammatory processes, in which
mainly polynuclear elements are found, leads to accordant results. It is
well known that small-celled infiltration occurs in the later stage of
inflammation, apparently consisting of lymph cells; nevertheless this
does not in the least prove that these lymphocytes have emigrated here
from the blood vessels. This is not the place to enter into the very
extensive controversy on this point. We are content to refer to the most
recent very thorough paper of Ribbert. Ribbert regards these foci of
small-celled infiltration as the analogues of the lymphatic nodules, and
explains their origin by an increase in size of the foci of lymphatic
tissue, normally present, though in a condition but little developed.
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 anaemia, have
been described in the chapter on the red blood corpuscles. Ehrlich's
view that the blood formation in pernicious anaemia 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 haematopoietic 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 leukaemia even in the
circulating blood, in the neutrophil as well as in the eosinophil group.
Ehrlich has repeatedly found in leukaemic blood polynuclear eosinophil
cells, whose granules must almost exclusively be regarded as young
forms[15].
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' exochen][16]. When
myelocytes, no matter of what size, appear in considerable numbers in
the blood of an adult, a leukaemia 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 leukaemia, 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 leukaemic blood. These forms,
which were first recognised by H. F. Mueller, are however of less
importance, for in myelogenic leukaemia 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.