Studies in the Osteopathic
Cells of the Blood: Volume
Louisa Burns, M.S., D.O., D.Sc.O.
The relations between the different classes of white
blood cells are not yet satisfactorily determined. The simple cellular
relations of the classes of leucocytes found in normal, adult, human blood
are quite different from the complicated relations of the blood cells in
abnormal conditions of adult blood and in normal conditions of early embryonic
In normal, adult, human blood the white cells are
divided into two distinct groups, the granular cells and the hyaline cells.
The granular cells are derived from red bone marrow, during adult life.
They are distinguished by the presence of granules within the protoplasm.
The hyaline cells do not, normally, show any granules within their protoplasm
by ordinary methods of staining. A very few granules may sometimes be brought
into view by certain staining methods, but these are scanty and are not
distinctive by ordinary staining of normal blood. The hyaline cells are
mostly derived from lymphoid tissues and are called lymphocytes for that
Granular cells include neutrophilic, eosinophilic
and basophilic, named according to the staining reactions of the granules.
Hyaline cells include large and small, named according to size. Even in
normal blood a few hyaline cells of intermediate size may be found, and
these are increased under abnormal circumstances.
The various kinds of white cells are best described separately.
Neutrophiles are white blood cells whose protoplasm
is filled with fine granules which are neutrophilic or feebly eosinophilic,
and whose nuclei are of extremely variable form. They are about ten microns
in diameter in the living state. They have a very delicate intergranular
hyaline protoplasm, and this is feebly basophilic. Neutrophiles make up
sixty to sixty-six per cent of the leucocytes in normal, adult, human blood.
Their number is subject to marked variation under varying physiological
states, and still more marked variation under abnormal conditions. They
are normally present only in the blood stream and bone marrow, not in the
tissue spaces. (Plates III, IV)
Neutrophiles are formed only in the red bone marrow,
during normal, adult, human life. Under certain abnormal conditions they
may be formed in the spleen and, probably, in other lymphoid tissue.
The granules of neutrophiles vary somewhat in their
staining reactions. Even in a single cell some granules are less eosinophilic
than others. In a smear certain cells may be more or less eosinophilic
than other cells, and in smears made from the blood of the same normal
person at different times there may be greater or less affinity for various
stains. As a rule, the physiological conditions of fatigue, hunger and
lowered blood pressure cause increased affinity for eosin and similar stains
(usually called acid-stains) while exercises, hot baths, deep breathing
and other conditions which cause moderate physiological leucocytosis cause
also diminished affinity for eosin and increased affinity for methylene
blue and other stains usually called basic. The intergranular protoplasm
may become definitely basophilic under such circumstances. Since younger
forms of neutrophiles show greater basophilia, it is quite probable that
the increased basophilia under such conditions is due to the associated
The thin, hyaline, intergranular protoplasm remains
present but is not usually visible in the normal adult stained cell.
This thinner material seems to be the active part
of the cell in ameboid movement, and the pseudopodia as first formed are
composed of it. The granules follow in a massive sort of motion, and as
they move they maintain a sort of united relationship. (One observer said
that they looked as if they were chained together as they marched along.)
In this respect the activity of the neutrophile differs from the activity
of the eosinophile.
In the younger forms a centrosome is occasionally
present. The younger forms also often contain mitochondria; these disappear
gradually with increasing senility of the cell.
The abnormal neutrophilic cells found in leukemia
contain peculiar rod-like masses of irregular contour; these may be mitochondria.
They may take neutral, acid or basic stains. The relations between these
bodies and the true neutrophilic granules have not yet been determined.
The granules are very small in normal neutrophiles,
but in excessive fatigue and under pathological conditions larger granules
may be found within the neutrophiles; these may be intensely basophilic,
eosinophilic or amphophilic, or they may retain their normal neutrophilic
or feebly acidophilic affinities. These atypical granules are never found
in normal blood.
The nuclei of neutrophiles present great variations
even in normal, adult, human blood. Mononuclear neutrophils have, as the
name indicates, a single round or roundish nucleus. This nucleus is centrally
placed and it may be slightly indented or reniform. The granules are finer
than those of the polymorphonuclear neutrophile and are definitely neutrophilic,
very rarely even feebly eosinophilic or acidophilic. The intergranular
protoplasm is rather more definitely basophilic and is often more abundant
than in the polymorphonuclear forms. Intermediate forms exist between the
mononuclear neutrophiles and the polymorphonuclear neutrophiles, and there
is some reason for believing that the mononuclear cells are immature forms
of the polymorphonuclear forms. Nuclear structures take the basic stains
with avidity. One or two nucleoli may be present.
The nucleus of the polymorphonuclear neutrophile
presents great variations both in normal and in abnormal blood. Neutrophiles
with deeply notched or saddle-shaped nuclei are grouped with the polymorphic
forms. Nucleoli are rarely found in the younger forms, and are never found
in older types. Apparently with increasing age of the cell, the nucleus
becomes more and more slender, finally approaching the form of a ribbon
or a cord, folded back and forth in a very irregular manner. This ribbon-like
structure may be variously indented and the wider portions may be connected
only by fine threads of nuclear substance. Rarely these lobules may be
completely separated; at least, no nuclear substance connecting them can
be demonstrated by ordinary staining methods. In normal blood the number
of distinct lobules rarely exceeds four; in abnormal blood there may be
six or even ten or more distinct lobules in a single cell.
These nuclei do not show such distinct structure
as is found in the mononuclear forms. Cells with the greatest number of
nuclear lobules show the greatest senility in the character of the nuclear
structures. The chromatin is in large irregular masses and is avidly or
feebly basophilic. When marked toxemia is associated with neutrophilic
proliferation some of the cells may show abundant senile traits while other
cells show marked evidences of immaturity or even of atavism.
The staining reactions of the nuclei as well as the
number of nuclear lobes or lobules vary with changing physiological conditions.
In pathological conditions these variations may be extreme. When there
is increased outpouring of neutrophiles from the red bone marrow under
physiological conditions, such as the increase which occurs as a result
of rapid traveling to high altitudes, many young forms are found in the
peripheral blood. These young forms show larger nuclei with fewer lobes,
simpler forms and more delicate nuclear structure than do the older forms.
The cells thus thrown into the peripheral circulation are so speedily produced
that they must have been already formed and held in reserve in the sinuses
of the bone marrow. They do not differ from the younger forms of the cells
previously in the circulation, the only difference being that there are
many more of the younger forms than is ordinarily the case. Within a day
or at most a few days the cells become older and the blood picture is practically
that of the individual before his journey.
Under certain abnormal conditions the neutrophiles
are manufactured more rapidly than is normal, and very immature cells may
be thrown into the general circulation. These include myelocytoid forms
and myelocytes. The nucleus is very large and occupies more than half the
entire area of the cell; it is round or roundish, is eccentric as in its
position and is often bare of protoplasm upon one side. It has one to three
nucleoli which stain deeply. The chromatin is fine and deeply staining
and is arranged in irregular masses. These cells are abundant in cases
of myeloid leukemia and may be found in considerable numbers in cases of
severe, acute, pyogenic infection.
With still more rapid formation of leucocytes, especially
when the hematopoietic areas approach exhaustion, atavistic types are occasionally
found. These cells are not present in normal adult human blood or marrow.
Atavistic forms are occasionally found in abnormal embryonic human blood
and in abnormal adult marrow, but they are characteristic of the cells
of mammals below human, or of vertebrates below mammals. The neutrophiles
of human blood are not exactly like those of other mammals, and no cells
which can properly be called neutrophiles are present in the blood of animals
below mammals. For this reason it is easier to recognize atavistic forms
among the neutrophiles than it is to find them among the hyaline cells,
because the latter are found in about the same forms in all mammals and
in nearly all vertebrates. (Plates V, VI, XII)
EFFECTS OF VERTEBRAL LESIONS
Bony lesions affect the structure of the neutrophilic
cells recognizably. Any bony lesion is associated with a disturbance of
the circulation through the red marrow of the bones concerned in the lesion
and, in the case of small bones, those in the immediate vicinity of the
bones actually concerned in the lesion have also some circulatory disturbance.
For example, when one rib is lesioned there is some edema of the tissues
around the joint or joints concerned in the lesion. This edema frequently
extends beyond the nutritive foramina of neighboring ribs as well as those
of the rib which is lesioned and often also to the foramina of adjacent
vertebrae. The nerves and blood vessels passing through these nutrient
foramina are subjected to the pressure due to the edema. The nerves, especially
those which are non-medullated, are subjected to the chemical changes in
the edematous tissue juices. Because of these physiological relations,
the red marrow of one or several bones has some circulatory disturbance
whenever there is a bony lesion anywhere in the body. The red marrow thus
affected produces blood cells which are not quite normal in structure;
such cells are usually immature or myelocytoid in type; the nuclei are
roundish, somewhat vesicular in form, show larger and paler chromatin masses
and occasional nucleoli. Their protoplasm shows granules of irregular size
and irregular staining reactions. The intergranular hyaline protoplasm
is more abundant. These cells flatten to a thinner layer on the slide than
do normal cells, and their pseudopodia are less regular in form, are protruded
from two or several parts of the circumference of the cell simultaneously
and are less efficient in the ingestion of bacteria or of foreign particles
than are normal pseudopodia.
The presence of these immature or myelocytoid forms,
in blood which shows no other cause for this abnormality, indicates the
existence of some conditions causing inefficient circulation through the
red bone marrow somewhere in the skeleton. Bony lesions are the most common
cause of such nutritional defect of the red marrow.
ARNETH’S INDEX AND THE NUCLEAR AVERAGE
Arneth’s index is the result of computations based
on nuclear structures. It is supposed that those neutrophiles which have
a single nucleus, round or only indented, are the younger forms. Those
with two lobes are younger than those with three lobes. In the older neutrophile
the nucleus is almost or quite divided into several lobes. Arneth’s index
is a method of estimating the relative age of the neutrophile by means
of a study of these variations in the nuclear structure. While the nuclear
lobulations may not be altogether accurate as a basis for the calculation
of age, still this study gives useful results under certain conditions.
In our laboratories Arneth’s index has been superseded by a study of the
“neutrophilic nuclear average” which we find much more useful. (Plates
XIV, V, IV)
Arneth divided the neutrophiles into five groups,
Class I having a single nucleus which is round or indented; Class II having
two nuclei, and so to Class V which has five or more nuclei. Each class
is subdivided according to the form of the nucleus. In Class I are three
groups, M cells which are really myelocytes and are not found in normal
blood; W cells which are mononuclear neutrophiles or myelocytes and have
nuclei which are slightly indented or reniform, and T cells which have
nuclei rather deeply indented but which are still definitely single in
structure. The W cells may or may not be found in normal blood and, if
present, are very scanty. T cells may make up 5% of the total neutrophile
count. Classes II, III, IV, and V are subdivided into different groups
according as the nuclei show definite knob-like lobes, or are ribbon-like
with grouping of chromatin in such a manner as to form lobules. Both forms
of nucleus may be present in a single cell, so that Arneth describes in
Class II cells with two knob-like projections, cells with two S-shaped
masses, and cells with one S-shaped lobe and one knob-like lobe. Class
II has, altogether, about 35.5% of all neutrophiles, in normal blood. Class
IV has four subdivisions, based on different combinations of the knob-like
and the S-shaped nuclei, and this class makes up about 36% of all neutrophiles
of normal blood. Class IV has five subdivisions and makes up about 2% of
all neutrophiles in normal blood. These percentages are given from various
laboratories and they are practically identical with our own figures. According
to Arneth, the neutrophiles are greatly increased during infections and
hence immature forms are found in the circulation; the index is then said
to “shift to the left,” that is, there are many more cells in the first
and second classes than is the case with normal blood. After an infection
has been present the younger cells are no longer being formed so rapidly,
there is an accumulation of older forms, and an increased number of cells
in the fourth and fifth classes. However, the effect of toxins on the white
cells also increases the number of nuclei, causes the nuclei to become
pyknotic and the chromatin to become arranged in irregular masses. Fragmentation,
vacuolization and cloudy swelling of the protoplasm, with a loss of the
distinctive granules, lead to great difficulty in estimating Arneth’s index
in many cases, and especially in those cases in which the diagnostic value
of the method is of most importance.
Modifications of the method of determining the index
of Arneth have been devised by Cooke, Schilling, Ponder and others. After
considerable study of normal and abnormal bloods we have discarded all
of these in favor of the study of the neutrophilic nuclear average. In
making this computation true myelocytes are disregarded and only typical
mononuclear and polymorphonuclear neutrophiles are included in the count.
The myelocytes, if present in any considerable numbers, are separately
estimated. In this method the myelocytes which are present as a result
of imperfect circulation through the red bone marrow, or of developmental
abnormalities, or in the blood of leukemic patients, are not allowed to
affect the nuclear average. Thus the nuclear average represents only the
relative ages of the neutrophiles. In this connection it must be remembered
that toxemias often increase the nuclear average and cause, in other ways,
an appearance of senility in neutrophiles.
Arneth’s index shows marked shift to the left (predominance
of youthful and immature forms) when there is efficient reaction to acute
infections; pneumonia and pyogenic infections generally cause extremely
marked shifting. During an infection to which the myeloid tissues do not
make adequate response, toxemia is severe, the neutrophiles show abundant
senility and there are relatively very few young cells being thrown into
the circulation; the index is shifted to the right in such a case. After
an infection and during recovery there is also a shift to the right, due
to the fact that young cells are not being thrown into the circulation
and the cells already present are somewhat affected by the toxemia of the
infectious processes. There is a marked shift to the right in jaundice,
in toxemias due to malignant neoplasms, the absorption of old pyogenic
foci or degenerating benign neoplasms, in intestinal toxemia due to putrefaction
and in many other conditions associated with disturbances in putrefactive
products anywhere in the body.
The changes in the nuclear average are of similar
import. The normal adult neutrophili nuclear average varies from 2.45 to
2.55. During the early stages of an acute infection this decreases to below
2 and occasionally to 1.5. The nuclear average is below 2.3 in normal young
children and may be below 1.3 during an acute infection in childhood.
In chronic toxemia and during convalescence from
an acute infection the nuclear average often exceeds 3.0 and in senility
it is normally above 2.7.
In severe infections to which hematopoietic tissues are unable to react
efficiently, there is no leucocytosis and may be leucopenia; in such cases
the nuclear average may be 3.5 or even 4.0.
The lower the neutrophile nuclear average, the greater
the proportion of newly-formed, young neutrophiles; the higher the average,
the greater the proportion of worn-out and elderly neutrophiles.
FUNCTIONS OF NEUTROPHILES
The functions of the neutrophiles have not been
adequately determined. That they are important factors in protecting the
body against certain types of bacteria is evident, though they are not
efficient in other infections. They ingest and digest and render harmless
injured tissues and many foreign substances within the body. The fact that
they increase and diminish so rapidly at different times of the day and,
under certain circumstances, during the digestion of food leads to the
view that they may have a nutritive function.
In their own metabolism they take up nitrogenous
substances and, probably, certain forms of carbohydrate related to glycogen.
When they die and are digested and absorbed and, perhaps as a result of
their own living metabolism, these substances are given off again into
the blood plasma. They represent a storehouse of food materials and are
very efficient in this relation, since substances so stored do not affect
the composition of the blood plasma, and since they are so thoroughly scattered
over the body that they are immediately at hand for every demand. They
carry tiny globules of fat in their protoplasm, and this also is an efficient
method of storage.
They elaborate an enzyme which is efficient in the
digestion of necrotic tissues resulting from injury of the body cells and
from exudates, transudates or hemorrhages within the body. After pneumonia,
for example, the processes of resolution are due chiefly to the activities
of the leucocytes and of the enzymes formed by them.
DEVELOPMENT OF NEUTROPHILES
The neutrophiles are normally formed, during adult
life, only in the red bone marrow. From the “stem cell” arise myeloblasts
which show differentiation by the development of individual cells and as
a result of the unequal division of the mother cells. The myelocyte of
the neutrophilic series is a large cell with its nucleus occupying much
more than half the mass of the cell. The protoplasm is very finely granular
and many contain mitochondria; it is feebly basophilic. With further differentiation
the nucleus becomes smaller and the protoplasm more abundant; the nucleus
loses its nucleoli and becomes lobed; the protoplasm loses its nucleoli
and becomes lobed; the protoplasm loses its mitochondria and developes
more abundant granules which become more and more definitely neutrophilic.
The protoplasm is pushed or grows toward the endothelium of the blood vessels
of the marrow, and finally it enters the blood vessel through the endothelial
wall. In human marrow there are many spaces in which no endothelial wall
can be seen; the cells are simply pushed out into the blood stream.
Under normal circumstances only the myelocytes of
almost adult type seem to be concerned in reproduction; at any rate karyokinesis
is seen only in those cells in normal, or almost normal, human marrow.
In the leukemias and in pernicious anemia karyokinesis is abundant among
the earlier myeloblasts and also among the “stem cells.”
The length of life of the neutrophiles cannot be
estimated in any satisfactory manner. The rise of the nuclear average during
a few hours after an acute leucocytosis due to acute infections would seem
to indicate that the development of young to senile forms is rather a hasty
process under such conditions, which are, of course, distinctly abnormal.
Neutrophiles containing carbon particles may be found several weeks, even
several months after such particles have been injected into the veins,
but these same particles may have been ingested and left behind at the
death and digestion of many cells in the interim.
Cells which appear to be senile are found constantly
in normal blood. They fail to show normal movements on the warm slide;
they do not stain distinctly; they have swollen and fragmented nuclei and
swollen and fragmented protoplasm. Naked or almost naked nuclear masses
of distinctly neutrophilic type are found and the occasional ragged fragments
of protoplasm which may occasionally be found clinging to such nuclei are
of neutrophilic structure. In the blood of a normal young woman such cells
were found to be present, in the early morning, 25 senile cells or naked
nuclear masses to 230 normal neutrophiles. At nine o’clock at night 25
senile cells or naked nuclei were present in 150 normal neutrophiles. Other
estimations of this relation in several other apparently normal persons
gave similar results; in some cases the differences between morning and
evening blood were much greater. Based upon these studies, the life of
the neutrophile in circulation can scarcely be more than a week. Estimations
based upon the increase present in infections give one day or two days
as the probable life period of the neutrophiles.
DISPOSAL OF LEUCOCYTES
Fragments of leucocytes are found in the endothelial
cells of the spleen and the liver, and, to some extent, of the bone marrow.
These are, no doubt, utilized as food by these and perhaps other cells
of the body. The molecules of which they are composed seem to be very well
adapted to serving as food for other cells, and it is quite probable that
in building up the food materials brought into the body into these more
complicated molecules they serve their most important physiological function.
Eosinophiles are, as the name indicates, intensely
eosinophilic or acidophilic. A typical eosinophile is about 9 microns in
diameter on the warm slide. From .5% to 1.5% of the total leucocyte count
are eosinophiles in normal adult human blood. In children the number of
greater both relatively and absolutely. Under certain abnormal conditions
of adults and children the number may be very greatly increased, even to
80% of the total leucocyte count. Nearly all animal blood contains higher
eosinophile counts than human blood, and young animals show higher eosinophile
counts than do older animals.
Eosinophiles show hyaline protoplasm filled with
very large granules. These are conspicuous objects on the warm slide. When
they are stained with eosin they are very brilliant and noticeable. In
younger cells and in eosinophilic myelocytes the intergranular, hyaline,
basophilic protoplasm is visible. In older cells this protoplasm can sometimes
be demonstrated by very delicate staining methods. The granules seem to
be definitely alive; they are the active elements in the movements of the
Very often no other protoplasm is visible even with the most careful
staining of smears and the most exhaustive study of living cells.
In lower mammals the granules are often definitely
oval or rod-shaped. The rod-shaped form occasionally appears in human blood
when other atavistic characteristics are present. The oval form has not
been reported in human blood.
The nuclei vary in form, but are always roundish
in outline. Reniform and saddle-shaped nuclei are common forms. They are
never ribbon-like, nor are they so markedly polymorphic as are neutrophile
nuclei. The nuclei have rather a coarse structure. The chromatin masses
and net-knots are larger than in hyaline cells and are not so deeply basophilic.
Dividing forms are not seen in normal human blood, but under abnormal conditions
in human blood, in the blood of embryos and in lower vertebrates dividing
eosinophiles are occasionally found. Nuclear pseutopodia are never seen
in normal blood, either animal or human, and are rarely found in abnormal
ACTIVITY OF EOSINOPHILES
Eosinophiles move with considerable celerity on
the warm slide. They die within twenty or thirty minutes. The large granules
are the active element. One granule usually begins to roll over; this may
be near the nucleus or at the periphery. It rolls over and over, between
or over other granules but not necessarily causing these to move. Other
granules then begin to move and these tend to follow one another in curving
lines. Very often these curved lines of granules are discernible in the
stained cell. The hyaline part of the protoplasm, when it is visible, usually
follows the granules. Occasionally, especially in the blood of fasting
patients or those with severe malnutrition from any cause and in very young
or animal blood, the hyaline substance may precede the granules and the
granules may even, sometimes, seem to be carried along by the streaming
protoplasm without displaying any intrinsic activity of their own. The
nucleus follows the protoplasm sometimes, and it seems to be carried along
as if it were heavy or reluctant. In many cases the nucleus does not move
at all; the granules flow away in long masses, sometimes leaving the nucleus
almost or quite naked, then they return to surround the nucleus almost
evenly; they may then flow out in another direction only to repeat the
process. This phenomenon is most commonly seen in blood which has been
taken from a feverish patient, or in blood which has been under observation
upon a slide whose temperature is one or two degrees above that of normal
blood. Phagoytosis has not been observed in eosinophiles though their ameboid
movements are so rapid.
Very little is known of their functions, and a study
of the conditions associated with their increase and their decrease add
little to our understanding. The granules contain iron and copper and they
seem to be concerned in iron and copper metabolism. They are very abundant
in the sputum under certain conditions. The formation of Charcot-Leyden
crystals and crystals of the seminal fluid is usually associated with their
Eosinophiles are diminished in nearly all uncomplicated
acute pyogenic infections. A differential count of 5,000 leucocytes made
for one of our cases with lobar pneumonia included no eosinophiles.
After the crisis in pneumonia and after the fall
in fever in most acute infections the eosinophiles increase rapidly, often
considerably exceeding the normal numbers.
Pyogenic and other acute infections in which the eosinophiles remain
in almost or quite normal numbers, or perhaps somewhat above normal numbers,
are osteomyelitis, ovaritis, orchitis, prostatitis, measles, scarlet fever
and acute articular rheumatism. In malaria they are increased the day after
Eosinophilia, or marked increase in the eosinophiles,
occurs under many different physiological and pathological conditions.
Eosinophiles above 2% should be considered a relative increase and above
200 per cubic millimeter an absolute increase, but the term eosinophilia
is usually employed only when the eosinophiles rise above 3%, relatively,
and above 300 per cubic millimeter, absolutely.
Eosinophiles are increased physiologically during
and for a day after physiological congestion of the reproductive tissues,
that is, after sexual excitement in both sexes, and before menstruation
in women or at the time of heat in female animals.
They are also increased as a result of vertebral
lesions which cause congestion of the reproductive glands; this is more
marked in the female with congestion of the ovaries produced by lesions
than in the case of the male with congestion of the testes as a result
of lesions. Correction of lesions concerned is followed by decrease in
the eosinophiles within three days, in human subjects.
They are increased in diseases of the spleen, including
the congestion of the spleen due to lesions of the ninth thoracic vertebra,
and, in less marked degree, of neighboring vertebrae and ribs. Diseases
of other lymphoid tissues do not cause eosinophilia in the same degree,
nor is it always present. After splenectomy and after destruction of considerable
splenic tissue by neoplasms eosinophiles are increased also. In cases of
splenomegaly the eosinophilia may reach tremendous heights. Counts exceeding
80% of the total leucocyte count and 130,000 per cubic millimeter absolute
count have been reported by several workers.
Diseases of the bone marrow, including myelogenous
leukemia, usually show high actual counts of eosinophiles, often exceeding
20,000 per cubic millimeter. In osteomyelitis, osteomalacia, sarcoma and
carcinomatous metastases and in less common diseases of the bone marrow
the eosinophiles may be greatly increased. In pernicious anemia they are
relatively increased and they may be absolutely increased even though leucopenia
may be extreme.
The absorption of the toxic products of degeneration
of animal proteins causes eosinophilia, but the absorption of degeneratiang
vegetable proteins does not. In intestinal putrefaction the eosinophiles
are increased if the patient is on a diet high in meat or eggs, but not
if he is on an exclusively vegetarian diet. Mild eosinophilea is present
in malaria, syphilis and during the absorption of exudates, transudates,
and pus, and during resolution after pneumonia. It is often present when
degenerating benign neoplasms or rapidly growing malignant neoplasms are
present in the body. Eosinophilia may be marked during the fever of scarlet
fever, measles and acute articular rheumatism. In cases of mumps with overitis
or orchitis the eosinophiles are increased, and this rise may precede recognizable
symptoms of the spread of the inflammation to these tissues by a day or
even two days. The value of this reaction is evident.
Eosinophilia may be marked after the use of any of
the animal substances used in the treatment of disease, such as tuberculin,
antitoxin and vaccines. They are not increased after the injection of vegetable
proteins unless anaphylaxis or definite irritation of the skin is associated
with the injection. They are occasionally diminished immediately after
the injection of animal products, then rise to a surprising degree within
a few hours; counts of 40% and of 45,000 per cubic millimeter have been
Eosinophilia in bronchial asthma is useful in differentiating
bronchial asthma from symptomatic dyspnea. It must be remembered that the
eosinophiles are also usually increased in emphysema. In uncomplicated
bronchial asthma eosinophilia is always present, usually above 8% of the
total leucocyte count and above 1,000 per cubic millimeter of blood in
Diseases affecting the sympathetic nervous system
may cause marked eosinophilia; this is especially noted in cases in which
the solar plexus is invaded by carcinomatous metastases.
Any irritation of the skin causes increase in the
eosinophile count, whether this be mere mechanical or chemical irritation
or whether inflammation of the skin is present (as by poison oak). Even
rather small burns may cause marked eosinophilia; it may be that the absorption
of the proteins from the injured tissues is a factoring this case. Counts
up to 60% of total leucocyte count, and to 4,000 eosinophiles per cubic
millimeter of blood have been reported in urticaria; with relief of the
hives the eosinophile count returns to normal within a few days. Any skin
disease associated with itching or other sensory irritation increases the
eosinophiles to some extent, and this increase may be surprisingly high
for mild cases. There seems no relation between the area of skin involved,
the severity of the disease or of the sensory irritation and the height
of the eosinophilia.
Animal parasites usually cause definite or high eosinophilia.
Amebic infections frequently cause no eosinophilia at all, and in uncomplicated
cases there is never more than a slight increase in eosinophiles. Filaria
sanguinis hominis usually is associated with mild eosinophilia. Darling’s
hisoplasma capsulata caused slight eosinophilia in the one case studied
in our laboratories. Hydatid cysts of the liver may cause little or high
eosinophilia, usually less than 20% of the total count. Trichinae cause
eosinophilia which may be of diagnostic value in obscure cases of muscular
Worms in the intestinal tract often cause very high
eosinophilia, to 70% or even more, and to 8,000 eosinophiles per cubic
millimeter of blood; commonly the count runs from 15% to 25% for the ordinary
pinworms, round worms and tapeworms.
Several drugs may cause eosinophilia, usually moderate
and transitory. Camphor is of interest in this connection and persons whose
occupation causes the inhalation of camphor fumes may show persistent eosinophilia.
Diagnosis is sometimes difficult in such cases.
It is evident from this review of the changes in
eosinophile counts that the biology of these peculiar cells is extremely
complicated and that much further study must precede our satisfactory understanding
of their behavior under normal and abnormal conditions.
FATE OF EOSINOPHILES
Normal human adult blood occasionally shows eosinophiles
in which the nucleus stains feebly and the granules are separated widely.
These cells are undoubtedly disintegrating. Such cells are much more abundant
in abnormal blood.
Fragments of these cells can be found within the
cells of the spleen and the liver, and in other areas of the reticulo-endothelial
system. In abnormal blood they are occasionally found within the endothelial
There seems to be no doubt that these cells die in
the circulation, are ingested by phagocytic cells and are used as food
by the tissues of the body.
BASOPHILIC GRANULAR CELLS
Basophiles, or mast cells, are scanty in normal,
adult, human blood, but are more common in embryonic blood, in the blood
of animals and during the course of certain diseases, especially the leukemias.
In normal adult human blood one or two mast cells may be found in a differential
count of 2,000 to 5,000 cells. Occasionally a specimen of normal adult
human blood is found which contains no basophiles at all, even when several
students make simultaneous differential counts of the same blood taken
at the same time, each student counting 500 to 1,000 cells. If the basophiles
exceed 1% or 100 per cubic millimeter of blood, some explanation of the
excess must be sought.
A basophile is eight to ten microns in diameter on
the warm slide. It has a nucleus which may be roundish but is usually lobate.
The nucleus stains feebly and chromatin masses are usually very dimly visible.
There is a very scanty hyaline, feebly,
N. N. normal neutrophiles.
Ac, Neutrophile from blood
showing acidosis and toxemia of the fatigue type.
Al, Neutrophile from blood
with high alkalinity and toxemia due to excessive use of soda as a drug.
M. Neutrophile from blood
of patient with late cancer.
B. Immature neutrophile
from patient with developmental anemia.
S. Senile neutrophile.
BT. Immature neutrophile
showing effects of acidosis.
Basophilic protoplasm which
may not be visible at all in normal blood but is usually visible in leukemic
blood. The granules are variable in size usually including a few which
are very large. Like eosinophile granules, these seem to be the more active
part of the protoplasm when ameboid movements occur. In living blood basophiles
are recognized with difficulty, being distinguished from eosinophiles chiefly
by the larger and more varying size of the granules and their less marked
activity. The granules are absolutely basophilic and are left unstained
by all acid dyes. Those found in normal blood are not easily soluble in
water, so that they stain easily with suitable dyes in watery solutions.
Those found in leukemia are more easily soluble in water, so that watery
solutions of stains are not suitable for them unless they have received
special methods of fixation.
Mast cells, or basophiles, give the oxidase reaction.
They are formed in the red bone marrow. Cells which are indistinguishable
from these except that they may not give the oxidase reaction, are present
in the tissues of the body, and these are increased during inflammatory
states, especially those of traumatic origin. These cells are known to
enter the blood stream and it seems very probable that they wander into
and out of the blood vessels according to the changing tensions of the
various gases and other substances in solution in the blood plasma and
in the tissue juices. They are more abundant in the tissues when absent
in the blood, and vice versa.
It is not yet known whether they have any functions
different from those of other granular cells or not. They are increased
in the leukemias. In gonorrheal pus and in pleural exudates they are often
very abundant; these abnormal accumulations of basophiles differ somewhat
from the basophiles found in normal blood and also from those of leukemia.
In abnormal blood amphophilic cells are sometimes
found. Only rarely do they appear in the blood of healthy individuals.
These have usually a single round, vesicular, eccentric nucleus, often
lobate, rarely notched or polymorphic, feebly staining with ordinary nuclear
stains, and often very eccentrically placed. The granules are vividly stained,
some with basic and some with acid stains. These, lying over the paler
nucleus, offer a brilliant spectacle. By washing the smear with a feebly
acid or feebly alkaline solution, the amphophilic granules can usually
be induced to stain as eosinophiles or as basophiles at will. In general
appearance the amphophile resembles the basophile, with which it is usually
THE HYALINE CELLS
Hyaline cells form from one-fourth to one-third
of the white cells of normal adult human blood. Of these the lymphocytes
are the most numerous. Monocytes are present in small numbers. Under abnormal
conditions plasma cells, hyaline myelocytes and a few other less common
forms may appear. In the discussions of these less common forms there have
been great differences in the terminology employed by different authors.
The developmental relations of different types have also been a matter
of considerable discussion, and many disputed points must await further
study. In this connection the differences of opinion between the Unitarians,
who hold that the “stem cell” is the progenitor of all blood cells, and
the dualists, who believe that there is a limitation of the developmental
potentialities of the stem cells, is of some temporary interest. With further
study the actual facts will terminate the discussions.
The development of certain forms of hyaline cells
from certain other forms is well known. Defibrinated blood containing no
plasma cells, placed in tubes and kept in moist air in an incubator, was
found to contain plasma cells after five days, in our laboratory. In other
laboratories cultures of blood cells have shown various instances of a
changing cell type, apparently due to metaplasia. Studies made of inflamed
tissues indicate that certain cells may become transformed into other forms
under abnormal circumstances.
Normal adult human blood contains small lymphocytes,
which make up about 25% of the white cells; large lymphocytes, which make
up about 4% of all the white cells; and, occasionally, a cell is found
which is intermediate in size between the large and the small lymphocytes.
In the lymph nodes there are hyaline cells of very much larger size, the
progenitors of the lymphocytes of the blood. These may enter the blood
under abnormal conditions and they are then called large endothelial cells
or giant lymphocytes according to their stage of development. Lymphocytes
are found in relatively larger numbers in the blood of young individuals,
whether human or other mammalian blood is studied; and the lower mammals
have larger proportions of lymphocytes than the higher. Normal adult human
beings have a smaller percentage of lymphocytes than is to be found elsewhere
among mammals. (Plates X, XIII)
The functions of the hyaline cells are not well
known. The large hyaline cells are phagocytic for certain pathogenic organisms,
epecially for protozoa (malarial parasites; histoplasma capsulata). Since
they are increased during certain infections it may be supposed that they
exert some protection against either bacterial invasion or bacterial poisons.
The phagocytic activity of the lymphocytes seems
to be an important factor in the absorption of fats from the intestinal
tract. In this way particles of fat are carried into the lymph spaces without
the necessity of first being broken up into soluble substances. They also
are concerned in providing conditions necessary for growth and repair.
This last function is not well understood. They may neutralize poisons
or they may elaborate needful nitrogenous materials for building or they
may perform other services.
Lymphocytes and other large hyaline cells from the
blood are able to live and to multiply in blood serum, in vitro. Fibroblasts
are unable to grow in blood serum alone, but when cultures of lymphocytes
and large mononuclears grow near cultures of fibroblasts, the latter become
able to live and to multiply. Apparently the lymphocytes produce from the
serum albumins or globulins the substances required by the fibroblasts
for their nutrition. An important function of the lymphocytes is the utilization
of proteins absorbed from the intestinal tract in the manufacture of the
peculiar proteins necessary for the feeding of the other cells of the body.
The lymphocytes of normal adult human blood are
formed in lymph nodes and in the spleen, tonsils and other lymphoid structures.
These derived from the red bone marrow are from small lymphoid masses within
the marrow and not from those areas of the marrow which produce the red
cells and the granular cells.
A short review of the structure of the lymphoid tissue explains the
manner in which lymphocytes are formed and are enabled to enter the blood
In the spleen, tonsils and all other lymphoid tissues
the structures present similar characteristics. There is a delicate framework
of connective tissue trabeculae, and associated with this are the reticular
cells. These are stellate, oval, spindle-shaped or elongated cells with
a nucleus which is roundish, oval or elongated, and has scanty, feebly
basophilic chromatin. These reticular cells are abundant in many organs
of the body; they are phagocytic and moderately motile. They are part of
the reticulo-endothelial system and share in the general functions of that
Associated with the reticular cells is a group of
cells, usually syncytial, with smaller, paler nuclei, less differentiated
protoplasm, and no apparent motile or phagocytic activity. Between the
reticular cells and the syncytial cells are all intermediate forms, and
the syncytial cells seem able to change into reticular cells or to produce
lymphocytes on demand. They are not found in the circulating blood in typical
form. The connective tissue traveculae with the histiocytes and the syncytial
cells form the reticulum of the lymphoid tissue. In the interstices of
this reticulum there are abundant masses of lymphocytes and a varying number
of reticular cells (histiocytes or macrophages) which have become removed
from the immediate vicinity of the traveculae. The lymphocytes include
Cells apparently identical with the large lymphocytes
of the circulating blood are present. These have been called lymphoblasts
or lymphoidocytes in this situation. They are most abundant in proliferating
lymphoid tissue and are rather scantily found in resting lymph nodes. They
divide by karyokinesis and thus are formed the small lymphocytes.
Cells identical with the small lymphocytes of the
blood stream and of the tissue spaces generally are most abundant in the
lymph nodes. These do not divide. They may be the only cells present in
the spaces of the reticulum of a resting lymph node.
Very large lymphocytes, never found in circulating
normal human blood, apparently are the daughter cells of the lymphoblasts
grown to several times their original diameter. They often show karyokinetic
figures and their daughter cells are smaller in size; small lymphocytes
may be derived from these cells also, especially in rapidly proliferating
lymphoid tissue. These very large lymphocytes are never found in circulating
normal human blood but under abnormal conditions may reach the blood stream.
They are not identical with the giant lymphocytes of the blood of certain
lower mammals, sometimes found in the atavistic blood of morons or other
imperfect human beings.
Cells showing karyokinesis are not found in the blood
stream normally, but when lymphoid tissue is seriously inflamed or in lymphatic
leukemia dividing forms may be found in the circulating blood. Cell division
of lymphoid tissue is always by karyokinesis. Direct division and building
have never been reported for them.
The tonsils and spleen as well as other lymphoid
tissues show peculiar pale, roundish areas called nodules or germinal or
germ centers. The general structure of these areas is about the same as
that already described, but these centers undergo marked variations in
activity, both normally and in answer to unusual demands made upon them
by toxic or inflammatory conditions.
Each such nodule has its own blood supply and this
may be the only visible indication of such a nodule in the resting lymph
node. No such nodules are present at birth or for some weeks thereafter;
they increase rapidly during childhood and youth, then diminish very slowly
until, in old age, they disappear altogether. They show considerable variations
in activity even under normal conditions, and they react to toxic and inflammatory
states with very rapid proliferation.
ACTIVE PHASE OF LYMPHOID TISSUE
During a period of increased proliferation the blood
supply becomes increased. Vasomotor nerves for these tissues have not been
demonstrated nor are secretory nerves known to exist for them. The impetus
to increasing proliferation seems to be in the character of the blood or
the lymph reaching the nodes. The node of stimulation is not yet understood.
The outlines of the nodule become very definite and they are paler in tint
than the rest of the section of a lymph node in all ordinary methods of
staining. The reticulum is relatively less abundant but it has the same
structure as in other parts of the section. The lymphocytes are usually
chiefly of the lymphoblast type and these show abundant karyokinesis. The
very large lymphocytic cells are also present; very frequently these are
grouped in threes to sixes; rarely in larger groups. Many intermediate
sizes are present. Small lymphocytes are occasionally very abundant. Very
large reticular cells, macrophages containing fragments of blood cells
and lymphocytes, are often present; these are derived from the reticulum
in this location as in other parts of the lymph node. They may reach a
diameter of twenty or more microns, especially in the lymphoid proliferation
due to acute pyrogenic inflammation.
A comparison of the resting lymph follicle with those
in various stages of activity indicates that the reticular cells in the
immediate vicinity of the arteriole supplying the nodule first show karyokinesis
and that the cells so produced show consecutive changes and differentiation
with succeeding divisions and growth until the lymphocytes are produced
they tend to assume positions at the periphery of the nodule. As they are
small cells with relatively large deeply basophilic nuclei they form a
dark ring which seems to surround the nodule. They pass from this peripheral
location into the lymph stream and the venous blood. As they increase slightly
in size in this passing they become the adult small lymphocytes of the
blood and the tissues. As the period of activity wanes the peripheral zone
of small lymphocytes forms a smaller and smaller ring around the diminishing
numbers of larger, actively dividing cells until these have almost disappeared
and the nodule again assumes its resting stage.
SMALL LYMPHOCYTES IN THE BLOOD
The small lymphocyte has about the size of an erythrocyte,
in life, but it may spread out to eight or nine microns in diameter in
a thin, stained smear. The protoplasm as seen in the living cell is almost
or quite structureless. By special methods of staining a few azur granules
and a delicate cytoplasmic reticulum can be made visible. The cytoplasm
varies from deeply to faintly basophilic. There is no cell wall and the
limiting layer is of the sol type. In many cells there is so thin a layer
of protoplasm that the nucleus may seem to be almost or quite naked. Mitochondria
are small and lie near the nucleus. The protoplasm is somewhat more abundant
upon the side of the cell opposite the crease in the nucleus.
The nucleus has a limiting layer which is quite distinct,
and a nuclear wall is sometimes discernible. The nuclear structures are
deeply staining. One rather large and two or three smaller nucleoli are
usually visible. The chromatin is arranged in rather large irregular masses
presenting something of a tiger-skin arrangement. Wheel-like arrangements
are rare. The nucleus usually shows a shallow or deep groove or infolding
upon one side.
The large hyaline cells of normal, adult, human
blood are ten to twelve microns in diameter, in the living state, and they
make up from four to eight per cent of the white blood cells. They are
relatively increased by those physiological conditions which diminish the
neutrophiles, but are not actually increased by physiological conditions.
Under certain abnormal conditions they are considerably increased. They
are relatively decreased by those conditions which cause actual increase
in the neutrophiles and other cell elements but are not actually diminished
appreciably under any normal conditions.
In large lymphocytes the protoplasm varies in basophilia
and granules are stained with more difficulty. The cytoplasmic reticulum
is more easily demonstrated. The edges are even more definitely of the
sol type and the periphery of the cells seems to pass indefinitely into
the blood plasma in cells which seem to be older. These cells are phagocytic
and they ingest animal parasites of the blood with avidity. The nucleus
is not often moved about by the ameloid activity present on the warm slide.
The cytoplasm contains azur granules and occasionally, a few basophilic
granules of varying degrees of basophilia. Mitochondria are somewhat more
abundant than in small lymphocytes. On the warm slide the protoplasm may
form bud-like pseudopodia which become detached from the cell completely.
The nucleus is almost spherical and it has a fold
or crease actor one side. In some cells this fold may divide the nucleus
into two almost separated parts; in other cells the nucleus is only notched,
creased, reniform or saddle-shaped. The chromatin masses are arranged much
as is the case with the small lymphocyte nuclei, and they are about the
same size; there are clear spaces between the chromatin masses and fine
linen threads pass between the chromatin masses. In cells which appear
to be older nuclear vacuoles and canaliculi are often present; these are
filled with a clear fluid which does not take any of the ordinary stains.
VARIATIONS IN LYMPHOCYTES
The proportion of hyaline cells is increased under
many pathological conditions. Physiologically, the hyaline cells are relatively
increased by fasting and relatively diminished by the factors which cause
an increase in the neutrophiles. They are actually increased at fairly
regular intervals corresponding to the periods of increased proliferation
during the active phases of lymphoid tissues.
EFFECTS OF SUDDEN EMOTIONAL STATES
Emotional states suddenly produced increase the
leucocytes, especially the hyaline cells, temporarily. This reaction does
not occur in animals or human subjects who have undergone splenectomy.
Animals which have been subjected to injury of the splanchnic nerves or
the solar plexus do not show the reaction. Under the influence of emotions,
especially fright and anger, the splenic capsule contracts, thus forcing
many hyaline cells into the blood stream. The biological significance of
this increase in the hyaline cells lies in the fact that these cells have,
as one of their important functions, the healing of wounds.
Lymphocytosis, or abnormal increase in the lymphocytes,
occurs more frequently in children than in adults. It is usually marked
in ordinary gastro-intestinal diseases of children, in rickets, mumps,
whooping-cough, bronchopneumonia and cervical adenitis. The lymphocytes
are increased also during the reaction to tuberculin used for diagnosis.
In severe pyrogenic infections to which the hemotopoietic tissues are unable
to react efficiently there may be a great increase in the hyaline cells.
They are increased in several adult diseases, such as malaria, typhoid,
relapsing fever and a few less common conditions. The large hyaline cells
and especially the monocytes are greatly increased in agranulocytic angina,
kala azur, Malta fever and also in severe pyrogenic infections when ordinary
granular leucocytosis does not occur. The large hyaline cells are increased
in tetrachlorethane poisoning. Chronic diseases which are usually characterized
by lymphocytosis are syphilis, whether acquired or inherited; tuberculosis
of all parts of the body except the meninges and brain, and several other
chronic diseases. During the digestion of a meal rich in carbohydrates
and in patients whose diet includes an excessive proportion of carbohydrate
and hydrocarbon foods, the lymphocytes are relatively and absolutely increased.
During starvaton the lymphocytes are relatively and sometimes absolutely
increased as long as the glycogen and fats are being utilized as foods.
During lysis in pneumonia and during convalescence in scarlet fever the
hyaline cells are increased. After injury to the spleen or to any great
area of lymphoid tissues the large hyaline cells are usually considerably
Relative or absolute lymphocytosis is usually present
in scurvy, pernicious anemia, chlorosis, general debility, late typhoid
hemophilia, exophthalmic goiter, and sometimes associated with malnutrition.
In lymphatic leukemia the increase in hyaline cells
may be tremendous. The small hyaline cells are most abundant in the less
malignant and chronic lymphatic leukemia, the larger forms in the more
malignant acute lymphatic leukemia and in the terminal stage of the chronic
type. In the terminal stage of myeloid leukemia the hyaline cells may predominate
and may seem to be exclusively present but in this case the hyaline cells
are really of the myelocytoid type and are derived from bone marrow. The
oxidase reaction may or may not be present in these hyaline myelocytes.
In the presence of inflammation involving lymphoid
tissues the hyaline cells are increased and this increase is associated
with many structural changes in large and small lymphocytes and endothelial
cells. The small lymphocytes then show less distinct nuclear structures,
the nuclear limits are less well defined, there is less intensely basophilic
protoplasm, the protoplasm is more abundant, and basophilic granules appear
occasionally in the protoplasm. The large lymphocytes include some which
are smaller than normal, though still distinctly larger than the small
lymphocytes. These show less intensely basophilic protoplasm and occasional
The large hyaline cells occasionally contain a few fine granules which
are neutrophilic or feebly eosinophilic, and their protoplasm is occasionally
vacuolated and at the periphery of the cell the prptoplasm presents a frayed-out
or a ragged outline. These large lymphocytes then have more irregular nuclei;
notched, reniform, saddle-shaped and occasionally double or even polymorphic
forms are much more abundant than are the normally rounded nuclei. In severe
inflammations of lymphoid tissue the large and the small lymphocytes may
often show karyokinetic figures and dividing forms are not rare.
The endothelial cells present nuclei larger than
normal, with less marked affinity for basic stains. The protoplasm presents
a swollen appearance and it flattens out on the warm slide very noticeably.
The cell outlines are indistinct and often ragged. Granules do not appear,
though sometimes there may be inclusions of fragments of other cells, of
bacteria or of foreign particles.
Lymphopenia is of much less common occurrence. During
the digestion of fats and proteins, in some cases of tuberculosis and in
some cases of lymphosarcoma the lymphocytes may be reduced to a few hundred
in number per cubic millimeter of blood. They are relatively diminished
in all conditions associated with marked neutrophilic leucocytosis but
are often actually slightly increased in these diseases.
EFFECTS OF BONY LESIONS
Direct effects of vertebral lesions upon lymphoid
tissue have not been observed, but indirectly very marked changes in lymphoid
tissues may be due to such lesions. Space permits only a few references
to these conditions.
Lesions of the cervical and upper thoracic vertebrae
affect the cirulation through the mucous membranes of the head and throat.
A mild, chronic congestion of these tissues results. With this congestion,
there is a moderate but persistent edema and some lessening of the alkalinity
of the tissue juices. The lymph from tissues so affected passes into the
lymph nodes, and these are stimulated into increasesd activity. The small
normal lymphoid tissues of the nasopharyngeal region are often so affected
and adenoid growths result. Moderate non-infectious enlargement of the
tonsils is another such result of cervical or upper thoracic lesions. Enlargement
of the cervical chain of lymph nodes results from longer existence of the
same lesions. Immunity is diminished in all tissues affected by lesions
as well as by the engorgement and hyperplasia of the lymphoid tissues.
Infection of the tonsils is a later result of the lesions. Tubercular infection
of the cervical lymph nodes is partly due to local lowering of the immunity
of these glands and partly to systemic conditions, themselves often due
to mid-thoracic lesions. The common infectious agents are almost universally
Lesions of the ninth thoracic vertebra cause dilatation
of the splenic blood vessels and decreased tone of the muscles of the splenic
capsule. With the congestion thus produced there is inevitably some hyperplasia
of the splenic lymphoid tissue.
Lesions of the lower thoracic vertebrae cause mild
chronic congestion and some loss of tonicity of the intestinal walls. With
the resulting mild, chronic stasis, there is a mild but constant edema
and a constant, mild poisoning due to the stasis. Hyperplasia of the lymph
nodes of the intestinal tract is very common under such conditions.
Lesions of the third lumbar and neighboring vertebrae
cause mild and chronic congestion of the uterus. With this congestion there
is edema and diminished alkalinity of the tissue juices. The weight of
the edematous membranes increases with the persistent congestion though
this may not be severe in degree at any one time. A serous polyp may result
or an area of lymphoid tissue in the immediate vicinity of the edematous
region may proliferate and form a lymphoid polyp of the cervix. In other
cases there may be marked connective tissue proliferation and a fibrous
polyp is produced The character of a polyp produced by upper lumbar lesions
may pass through these three stages in order, in experimental animals,
and a similar progression is quite possible in the human subject.
In many areas of the body similar relations in pathogenesis
may be observed. Such relations are suspected when the blood cells include
immature or other abnormal forms of lymphocytes associated with a few granular
myelocytes and other evidences of disturbed circulation through the red
bone marrow of the bones concerned in the lesion.
OTHER HYALINE CELLS
A few other large hyaline cells may be found in
very small numbers in normal adult human blood; these are found in considerable
numbers under abnormal conditions. Turck cells are somewhat like ordinary
large hyaline cells. The origin of Turck cells is not certainly known;
they are increased under certain pathological conditions, and they are
considered identical with plasma cells by several writers.
Turck cells are hyaline cells with intensely basophilic
protoplasm and deeply staining nucleus. The spongioplasm is usually distinctly
visible and vacuoles are frequently present in the cytoplasm. Fatty material
may be stored in vacuole-like areas, thus producing the “foam” cell type.
The protoplasm presents a somewhat granular appearance but contains no
real granules. These cells are ten to fifteen microns in diameter. They
are ameboid and phagocytic, and often contain fragments of red cells. This
is particularly true in those diseases associated with blood destruction,
such as malaria. The nucleus is often eccentric and may be altogether free
from a cytoplasmic covering upon one side. They are certainly concerned
in the healing of wounds, and they seem to be derived from the adventitial
Plasma cells are like Turck cells except that they
are often angular on account of pressure conditions; the nucleus is eccentrically
placed, and very often the nucleus contains more definite chromatin masses
which may show a wheel-like arrangement. The nucleus often lacks any recognizable
protoplasmic covering for half or even more of its surface. The protoplasm
is often vacuolated in the vicinity of the nucleus. The protoplasm is intensely
basophilic at its periphery and very rarely can fine neutrophilic or basophilic
granules be demonstrated in the region farthest from the nucleus. These
cells are not found in normal blood. They may be abundant in inflammatory
conditions and seem to be concerned in regeneration. They are derived from
small lymphocytes, probably those of adjacent tissues.
Myeloplaxes are very large hyaline cells which are
very rarely found in the circulating blood. They are identical with the
megakaryocytes of the red bone marrow.
During pregnancy a few cells derived from the placenta may appear in
the maternal blood. These are very large hyaline cells, with feebly eosinophilic
or basophilic protoplasm and round nuclei, not deeply staining and without
marked nuclear structures. They are often not found at all though repeated
examinations of the blood are made, and they may appear in considerable
abundance in other cases. They‘re of little diagnostic significance for
this reason, and also because the diagnosis of pregnancy is usually easy
before the placental cells can be expected. In three of our cases in which
pregnancy had not been suspected the finding of these cells led to further
study of the patient with this possibility in mind, and, in one case, an
X-ray plate showed a normal fetus which went on to normal birth. In another
case proposed surgical interference for uterine fibroids was postponed
and a normal baby was born. In one case the fetus was dead at the time
the pregnancy was first suspected. The diagnosis was made as a result of
finding these cells in the blood.
Hyaline myelocytes are not found in normal blood.
They are present in very large numbers in late stages of chronic or in
rapid and severe acute leukemias. They may be found in small numbers when
the bone marrow is invaded by malignant disease, especially in cancer metastases.
They are then associated with other types of myelocytes and myeloblasts.
Hyaline myelocytes have very large, spherical nuclei,
usually feebly staining, and a very narrow rim of protoplasm, usually with
very marked affinity for basic stains. No granules are found by the ordinary
staining methods. They vary in size, the smaller being distinguishable
with difficulty from small lymphocytes and the larger having a diameter
of forty microns or more. Every size between these may be found in severe
cases of either lymphatic or myeloid leukemia. (Plates XII, XIII)
THE FATE OF HYALINE CELLS
The relations of the cells of the reticulo-endothelial
system to the large phagocytic monocytes of the blood has been the subject
of much study, yet many problems remain unsolved. That certain of the phagocytic
monocytes found in the blood stream under abnormal circumstances are derived
from the endothelium of the sinuses of the bone marrow, spleen and other
lymphoid tissues, and probably from the liver and from certain glands of
internal secretions is fairly well demonstrated by experimental and by
Large, hyaline, mononuclear, phagocytic cells are
found in the blood stream, a few normally, and many under abnormal conditions.
Their presence in more than 1%, or in abnormal forms, indicates some definitely
abnormal condition in the body. If they are merely increased in number
but present no definitely abnormal forms, it may safely be concluded that
there is some circulatory disturbance affecting the spleen and the liver.
If they show vacuoles or inclusions, the significance depends upon the
nature of these abnormalities. If they are immature and are derived from
lymphoid tissue, it may be concluded that there is a chronic infectious
process present in the body and that this affects a considerable area of
lymphoid tissue. If many myelocytoid forms of granular cells or if a few
immature red cells are present without other evidences of anemia, then
there is some marked disturbance of the red bone marrow; if there is no
evidence of serious disease of the red marrow the disturbance may be merely
circulatory. If excessive numbers of the endothelial cells are present,
with high red cell and rather high white cell counts, without other evidence
of visceral disease, then it may safely be concluded that there is some
very considerable area of the vascular bed in which the circulation is
inefficient. Cardiac inefficiency is suspected in such conditions.
The endothelial cells which normally remain within
the lymphoid tissues are found in the circulating blood when there is any
chronic inflammatory state which affects these tissues. These cells also
may be found in the blood stream of an individual who suffers from the
effects of ninth thoracic or neighboring lesions; in this case the cells
are derived from splenic sinuses. The cells are often called splenocytes
because they are so commonly derived from the spleen but they may be derived
from any lymphoid tissues which have been affected by inflammatory conditions.
They are not commonly derived from lymphoid tissues other than the spleen
as a result of the direct effects of bony lesions, on account of the anatomical
peculiarities of the tissues concerned.
Large mononuclear phagocytes containing fragments
of erythrocytes and particles of hemoglobin or of hemoglobin derivatives
are found in the circulating blood under several quite different conditions.
Such cells are often found in the blood after an attack of pneumonia, and
are undoubtedly derived from the adventitial cells of the lungs. Occasionally
such cells are found in the blood of persons with mitral lesions; in this
case they are also from the pulmonary adventitial cells and they are a
result of the excessive pulmonary congestion They may also be found, less
frequently, in persons with bony lesions which affect the heart and thus
the pulmonary circulation, or which interfere directly with the pulmonic
vasomotor centers in the upper thoracic spinal centers.
Endothelial cells containing fragments of erythrocytes
or the brownish granules of one of the hemoglobin derivatives are usually
present in the blood during an attack of malaria and for some time afterward.
These same cells ingest and probably destroy the malarial plasmodium. The
organism of histoplasma capsulata was found within endothelial cells and
large lymphocytes in the blood of one of our patients, and the blood of
inoculated guinea pigs contained many endothelial cells containing the
organism. (Plates X, XI)
During the course of pernicious anemia, the endothelial
cells of the sinuses of the spleen, lymph nodes, bone marrow and hemolymph
glands ingest great numbers of the abnormal red cells, and the endothelial
cells found in the blood stream which contain fragments of red cells are
probably derived from those areas. Whether the Kupffer cells commonly gain
entrance into the blood stream is not known; that they do pass into the
blood stream under experimental conditions seems definitely verified by
Sabin and others. The Kupffer cells are abundantly filled with fragments
of red blood cells during relapse in pernicious anemia, and this is true
also of sickle-cell anemia and of other diseases characterized by abnormal
fragility or abnormal structure of the red blood cells.
Endothelial cells carrying granules of melanin are
often found in the circulating blood when melanotic tumors are present
anywhere in the body, and are more abundant when there are metastases in
the liver, lungs, spleen or bone marrow.
The amyloid substance is first found in the Kupffer
cells of the liver when that gland undergoes amyloid degeneration. Endothelial
cells containing granules of amyloid or a precursor of that substance are
often found in the circulating blood under such circumstances.
Endothelial cells often carry indophilic granules
and such endothelial cells are rather abundant when there is an abnormal
condition of the liver. When the neutrophiles as well as the endothelial
cells of the blood carry indophilic granules some disturbance of sugar
metabolism is suspected and a determination of the sugar tolerance curve
is indicated. While patients with marked indophilia occasionally show no
further evidence of disturbances in sugar metabolism, yet the relation
is sufficiently common to warrant further investigation.
The large phagocytic cells carrying iodophilic granules
are also found when there is a marked disturbance in protein katabolism.
Such conditions occur during the absorption of chronic pus foci, during
the period of absorption after pneumonia, during the absorption of the
products of degeneration of a tumor of any kind or of the absorption of
any degenerating tissues of the body, or during rapid loss of weight after
the fat has been absorbed during fasting, or even when a patient with intestinal
atony is for some time on a heavy protein diet.
The endothelial cells seem to have some especial
affinity for fat, and droplets of fat are occasionally found in these cells
in the blood stream. When there has been any injury to the shaft of a long
bone, or when the fatty marrow has been invaded by infectious processes
or by metastases of any malignant neoplasm, fatty globules are often found
within the phagocytes of the circulating blood, including the endothelial
cells. Fatty globules of small size may also be found free in the plasma
under these conditions. Endothelial cells containing fatty globules are
also found, occasionally, in disease or abnormal circulatory conditions
affecting the liver, even though the hepatic disorder may not be very severe.
When the fat of the body is undergoing rapid disintegration endothelial
cells carrying fat are present; this is significant in patients who are
reducing weight too rapidly. During the rapid absorption of pus, rapid
degeneration of tumors, rapidly growing cancer, rapidly progressing pulmonary
tuberculosis, and similar states these fatty inclusions within endothelial
cells are occasionally found. When the cells are stained by ordinary methods
the fatty globules appear as vacuoles. When stained by osmic acid or Sudan
III their fatty nature is clearly shown.
Metallic poisons are often stored in the endothelial
cells and occasionally these cells are found in the blood stream. Mesotherium
is so stored, and this may be one cause of obscure anemias. Lead particles
also are so stored and these have been found in the circulating blood in
cases of chronic lead poisoning. In an obscure case in our laboratory in
which pernicious anemia was strongly suspected the finding of metallic
particles in several large phagocytic monocytes in the blood smears led
to the correct diagnosis of chronic lead poisoning.
The endothelial cells of the peripheral blood are
increased after emotional excitement, especially after fright and anger.
Human beings who have undergone splenectomy do not show this reaction.
From these and other related facts it may be concluded that during emotional
states the contractions of the spleen force these cells out and into the
blood stream. After removal of the spleen or of all or part of the sympathetic
ganglia from the abdominal region the reaction does not occur in animals.
Human subjects and animals with lesions of the ninth
thoracic vertebra (and, in less marked degree, neighboring vertebrae and
ribs) show higher than normal numbers of large hyaline cells in the peripheral
blood; no doubt this is due to the chronic slight congestion and the chronic
slight atony of the spleen due to the lesions.
Under experimental conditions the cells derived from the reticulo-endothelial
system may be found in the circulating blood. By injecting certain colloidal
or particulate substances into the blood of an animal the endothelial cells
may be stained in such a manner as to be easily recognizable wherever they
are found. Blood examinations made at any subsequent time, after any selected
manipulations planned to show some chosen relationship either show or do
not show the stained endothelial cells in the blood. By selecting stains
for which certain endothelial or reticular cells have special affinities,
it is possible to determine whether those cells do or do not gain entrance
into the blood stream. To some extent these experimental procedures involve
relationships which may occur during pathological or physiological processes
and the finding of cells from the endothelial system reported by various
hemotologists is thus justified.
A very brief review of the studies made of the reticulo-endothelial
system may be useful. The discussions by Aschoff first aroused general
interest in the subject. Very many histologists and pathologists have made
reports; unfortunately the cells have received many names and many descriptions
because the methods employed have produced so many reactions on the part
of cells which were essentially, of the same class and of similar, if not
The descriptions of the phagocytes of the blood and
the tissues given by Metchnikoff are classical. In his reports the neutrophiles
of the blood are called microphages and the larger cells of the tissues
macrophages. The macrophages are phagocytic and are usually found lying
free in the meshes of the connective tissues around the smaller blood vessels
and the capillaries. Because they are especially abundant in that location
they have been called adventitial cells. Because they were observed by
Ranvier to present peculiar budding processes he called them clasmatocytes.
With ordinary staining methods they are not distinguished from the fibroblasts
of the connective tissues.
The sinuses of the bone marrow, the spleen and other
lymphoid tissues, the hemolymph glands and perhaps the tissue spaces of
certain of the glands of internal secretions are lined with cells which
resemble the endothelium of ordinary capillaries to some extent, but which
are definitely phagocytic and which are able to store both particulate
and colloidal dyes in such a manner as to prove them distinctly different
from ordinary endothelium. The Kupffer cells of the liver, the podasteroids
of the brain, the adventitial cells of nearly all the body, the plasma
cells of the loose connective tissues and of the omentum as well as the
cells of the sinuses of the bone marrow, spleen and other lymphoid tissues
may, under certain physiological or pathological conditions be carried
from many viscera in the blood stream. They may reach the blood by way
of the lymph channels and the thoracic duct under certain circumstances.
They can be cultivated in vitro and their development watched. There is
very good reason for supposing that the words tissue macrophage, blood
monocytes, clasmatocyte, fibroblast, hemohistioblast, wandering adventitial
cell, endothelial cell and other terms less commonly employed are really
different names for the same cell which presents somewhat different appearances
under differing circumstances. These cells are capable of developing from
one form into certain others according to the needs of the body at any
given time. Their developmental potentialities are still a subject of considerable
discussion and of intensive experimentation. The endothelial cells are
important in the protection of the body against foreign substances and
infections and they are concerned in the development of tubercles, together
with the lymphocytes. In tuberculosis the blood often contains a marked
increase of these cells. The blood of children with tuberculosis usually
shows these cells abundantly.
Further study of these cells should be made. With a definite
understanding of their functions more adequate methods of diagnosis and therapy
should become possible.