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The transformation of lymphocytes into erythroblasts in a lymph node of a rabbit.

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THE TRANSFORMATION O F LYMPHOCYTES INTO
ERYTHROBLASTS IN A LYMPH NODE
OF ,
4 RABBZT
H. 3:. JORDAN
Laborator?/ of Histology and Embryology, M d i c a l School, Unkversity of V i r g W
THREE PLATES (EIXVEN FIGURES)
The material of this investigatioll was obtained under the
following circumstances : A full-grown albino rabbit was
secured from the animal pen of the Department of Pharmacology for the purpose of studying fresh areolar connective
tissue in the course in histology. After the laboratory period
the submaxillary salivary glands and some femoral marrow
were removed and fixed in Helly’s fluid. These tissues were
subsequently given to the laboratory technician with instructions to prepare sections stained with hematoxylin and eosin
for the student loan collection of slides. When the sections
were submitted for examination I noticed a peculiarly altered
lymph node attached to one of the salivary glands. More
careful study with higher magnification revealed a t once that
this particular lymph node was undergoing extensive
erythroblastic metaplasia. Subsequently, other sections
were stained with the Giemsa mixture and with the ironhematoxylin eosin combination.
The present report concerns itself primarily with the m i equivocal evidence relating to the direct transformation of
lymphocytes into erythrocytes. Moreover, this lymph node
reveals suggestive evidence in regard to the specific differential factor underlying red-cell development and the manner in
wliich extravascularly differentiating erythrocytes may subsequently enter the medullary vascular channels. It is, of
369
wiirse, iuifortunate that there are no data on record
coiicerniiig the previous treatment or experience of this
rabbit, that a careful postmortem examiiiatioii of the viscera
was not made, arid that other tissues, especially other lymph
110(1cs aiitl the spleen, were not removed f o r liistological examination. However, tlie rabbit appeared well nourished
a i d in good health, and there is no reason to suspect that lic
Iiacl Iicen ill or used f o r experimciital purposes. Luckily,
stv+tionsof l,oiie-marro\i- aiid of hloocl vessels in tlie submasillary glands are available for comparison with the crythrocyt opoietically active lymph node.
Ti1 R iiiiinlm- of previous joint communications I have urged
that the lymphocyte represents a rclativcly nndiffereiitiated
( * ~ lenclo\-vccl
l
with multiple developmental capacities, one of
wliich is the ability to differentiate iuider favorahle circumstances directly into a n erythrocyte. 1 have suggested,
further, as a reasonable working hypothesis that the
lympliocytcs normally perform a large portion of their total
fuiic*tion by diffcreritiatiiig into erythrocytes after they arc’
filtered out of the blood stream in the red bone-marrow. I f
it (2111 be demonstrated, as in the case of the lymph node here
to he described, that lymphocytes do under certain conditions
differentiate into erythrocytes, then tlie hypothesis just mc’iitioned reccives weight)- additional support, a n t 1 the question
of the normal fate of the lympliocyte may receive its proper
and complcte answer.
I)EA(*HIi w o s
lliis lymph iiotle has an 01-a1 sliape, measui*ing apl)roui-
f l
mately 5 mm. in length and 2 mm. in thickness (fig. 1). The
available sections show- no distinct hilum. The largest
arterial vessel lies along the inner border of the altered
cortex. A smaller vein leaves tlie node from tlie opposite
surface. Apparent I)-, the blood vessels ciiter and leave tlic
iiodc over a wide area. The node is covered with a thin capsule of loose areolar connective tissue continuous with the
st roma of tlie submaxillary salivary gland. Longitudinal
371
TRANSFORMATIOS O F LYMPHOCYTES IXTO ERYTHROBLASTS
scbctioiis present vague evidence of a division into a cortical
aild a medullary portion.
The cortical portion comprises a thin oval discoid mass of
more compact ‘lymphoid’ tissue orer one surface of the node.
This cortical disc measures approximately 2 mm. in its
longest diameter, and lias an average depth of approximatel)one-third of a millimeter (fig. 1). Peripherally, it presents
a sharp contour; iiiternally, its boundary is very irregular and
more or less vague in certain areas (fig. 2 ) . No definite peripheral sinus is discernible. The disappearance of this sinus
is presumably the result of an intense proliferative activity
of the (*ortical l;vmphocytes, tlic new-formed lymphocytes
having become crows-ilcd into the original peripheral 4nus.
Whether this lymphocyte increase preceded, followed, o r accompanied the atrophy of the afferent lymphatics remains
uncertain. Theoretical considerations outlined helots. would
seem to favor the primary atrophy of the suppl:+ng
lymphatics.
The lympliocytes of the cortex arc 1)reclomiiiaiitl;v of thcl
small variety. Only re1ativel-i- few large lymphocytes and
erythroblasts occur within this area. The differentiating
erptlirocvtes are in general in the close vicii1it;v of the blood
vessels. The latter are of relatively large caliber and comprise both arteries a i d veiiis. The red blood corpuscles iii
some of the cortical vessels and many of the meclullary vessels stain only very faintly except with iron-hematox~lin,
appearing mostly as rings resembling ‘blood shadows’ of
laked blood. The laking of the blood in many of the vessels
presumably indicates stagnation. The iiitranodal blood vessels contain very few of the specific cells of this altered node,
namely, differentiating erythroblasts.
The differentiating lymphocytes are more compactly aggregated immediately about the blood vessels. The latter are
largely of the thin-walled sinusoidal type. Large portions of
the cortex stain very lightly (fig. 1). This differential staining reaction follows from a peculiar character of the lymphocytes. The small lymphocytes of these lighter areas have
L
372
H. E:. JORDAX
\rcsicular nuclei, and their cytoplasm also stains only faintlv.
The appearance is somewhat that of the peripheral portion
of the cortical nodules of very active lymph nodes. But there
is nothing in this cortical area t o suggest definite lymph
nodules or germinal centers. The greater bulk of the anomalous cortex apparently corresponds in regard to its predominating cells to the peripheral portions of the cortical nodules
of normal lymph nodes. However, many of these cells are
clearly in process of degeneration, as indicated by a considerable amount of karyorrliexis or a partial resorption of
the nucleus. Some of the cells apparently represent abortivo
erythrocytes, incapable of elaborating hemoglobin.
The most plausible interpretation of the modified cortex
would seem to he in terms of an initial intense proliferation
in original cortical nodules, effecting secondary fusions and
an invasion of the peripheral sinus, followed by a gradual
tlrainage a i d erythroblastic differentiation of lympho<*ytes
iilong the medullary border. However, mitotic figures art’
cantirely lacking, and evidence even of amitotic proliferation
is meager. Reconciliation of this contradictory fact with the
interpretation suggested on other grounds may be effected
011 the assumption that the period of lymphocyte multiplieation considerably antedated the time when this node was
removed. This assumption receives support from the fact of
widespread regressive changes in the medulla, as will be
described below. The further apparently contradictory fact
of an abnormally thin cortex may be explained as the result
of a central drainage of lymphocytes following the closure
of the afferent lymphatics and preceding the later atrophy of
the efferent lymphatics.
The medulla consists of wide irregular areas of very diffuse
lymphoid tissue and variable narrow cords of compact
lymphoid tissue (figs. 2 and 3 ) - The former most probably
represent original medullary sinuses, secondarily enlarged
by gradual reduction of the medullary cords, both periplieral
and central. The reticular stroma of the altered sinuses is
wide-meshed. The reticular cells have for the most part an
T E A N ~ F O l 1 M X T l O K OF LYMPHOCYTES Ih’TO ERYTHROBLASTS
373
unhealthy atrophic or liydropic vacuolated appearance (figs.
7 and 8). I n certain small areas near the ends of the node
the intercellular spaces appear filled with a mucoid substance.
The parenchyma of the medullary sinuses includes predominantly scattered erythroblasts at various stages of
differentiation (fig. 6) , an occasional apparently unaltered
lymphocyte, numerous cells with budding (fragmenting)
nucleus (fig. 6, f ) , and certain larger mononuclear and
binucleated cells with vacnolated cytoplasm, probably representing free reticular cells, and of the nature of plasma cells
(figs. 6, 7, and 8). Obviously, the conditions here are those
largely of regression and beginning degeneration. There is,
however, no evidence of phagocytosis, nor are erythroplastids
to be seen in these areas. The interpretation that the histologic conditions suggest is disconnection of afferent lymphatics, followed by almost complete drainage of the sinuses
of their original lymphocyte content, and subsequent atrophy
of the efferent lymphatics. Certain of the persistent lymphocytes of the isolated medullary sinuses differentiate into
erythroblasts (fig. 6, c, d, and P ) . The node contains no
fat-cells.
The central point of interest in this anomalous lymph node
concerns the histology of the medullary cords (figs. 4, 9, 10,
and 11). Many of these contain an axial blood vessel (figs.
4 and 9), others lack all trace of a vessel (fig. ll), and a few
are in a condition of transition, showing a phase of the process of obliteration of tlic central vessel through disruption of
the endothelium and cellular invasion of the original lumen
(fig. 10).
The predominating cell in most of these cords is the young
erythroblast, the normoblast (fig. 5, h ) , with a relatively small
graiiular spheroidal nucleus, and a considerable envelope of
slightly acidophilic cytoplasm. With the hematoxylin-eosin
staining technic the cytoplasm of these cells colors a variable,
but generally deep shade of red, with a variable bluish tinge.
111 terms of the amount of hemoglobin, as indicated progressively by the loss of bluish tinge and a deepening pink color
of tlie c;\*tol)l;ism,tlie iiormo1,last has appareiit1~-mi approxiiriately iioi.ma1 coiiteiit. Oiilp ixhlatiwly f c v cells, homeoer.,
p a s s Iw;\-oiitl this stage of cliffcreiltiatioii a s regards hemogIoI)iii elaboration, though iiuclcar cliaiigcls pmceecl i n many
c ~ l l sto late erytlirohlast coiiditioiis (fig. t5, c a n d (1). 0cc;i,sioiiul t~r;\~tlii~ol)lnsts
coiitrast sliarpl?- ivitli tlie snrroniitlirig
(*ells,1):~ i*ewsoii of tlicir hriliiaiit rcd color, iiitlicati\-e of ;I
large amoiuit of 1icmogiol)iii (fig. 11, cell
). IIitcrrnodiato
stagcs lwtwcleii tlic latter a i i t l the slightly sopliilic younger
iioimol)lasts a r e reliitiTeiy numerous (figs. 10 and 1I, cells x)
111 the (+iemsa-staiiictl 1)reparatioiis the majority of the cortlwl
wlls staiii T-nrions sliades of 1)liic ; oiily tlir oltler erytliroI~1:ist-ssliow a piiikisli cytoplasm. F r o m amoiig tlie ctblls of
almost aiiy cord ;I calosel?- graded series of traiisitioii stagcis
rnay be ari.:iiig,.ed leadiiig from a typical medium-sized lymplioc.:-tcl (fig. 5, 0 ) through typical iiormoblast stages (fig. 5, h )
t o oldel* t~i*>-tlirobiasts
iii wIii(*li tlie nucleus is iiiidergoiiig
t'ragmeiitatioii aiid resorptioii (fig. 5, d ) .
Ll t y p e of cell wliicali w a s at first coiifusing is one in lvliicli
lias sproiitetl small sphciroidal buds which wemaiii
c.oiiiicctecl with tlic ceiitral cliromatic. mass h;v delicate thrrads,
giving to the stwactnuc as a wliolc w radiate appearaiice (fjg.
6, f ) . Tliese cells, which occur especially numerously among
the more peripliei*al erythroblasts of some of the meclullal*y
cords, suggest in the moi*e irregular coiiditioiis (fig. 5, P )
ciithcr poll\.rnory>iioliuclea~lcucocytcs o r cells iii mitosis.
rI1 heir cytoplasm, however, lacks granules ; their rcsemhlancc
to ampiiophii pol~morpliorincleargranulocytes is only snperficial. Moreover, the complete almence of snch (*ells wit11
c*liromaticimasses a ~ * r a n g e in
d the form of diasters (aiiapiiase
of mitosis) malies it quite clear. that the col~ditioilis not indica tive of indirect division. The slight degree of proliferative
capacity persisting at tlie time this node was removed was of
tlie direct tvpe, a s suggested by occasional biiiixcleatetl erytllroblasts (fig. 5, f ) .
Nor a r e these cells properly interpreted a s phases of t l l c h
enucleation process by which the er:-throhlast hccomes a11
TBANSFOHMATIOS OF L P B I P H O C Y T E S 1NTO EI:YTHI1OBLASTS
375
er;vthroplastid. This process is practically exclusively one
of intracellular resorption (fig.3, c, and cells below P ) , sometimes preceded by a previous nuclear fission (fig.5, d ) . The
cells in question are unmistakably in process of degeneratioii,
accompanied hy karyorrhesis. S o unequivoral instances
either of erythroplastids or graiiulocytes occur anywhere
within this lymph node. Occasional cells like that of figure 7
with a few small spheroidal granules are puzzling, but most
likely also represent a phase of degeneration. I n Giemsastained preparations these granules have a red color and the
cells have the appearance of eosinophilic granulocytes. The
coiiditioiis in this node are such as to support erythrocyte
differentiation practically exclusively ; and this only inadecluatel)-, as indicated by the slowness and f reyuently abortive
issue of the process, in the case of only a very few cells leading to a normal hemoglobin content and complete enucleation.
The medullary cords are without exception enveloped by
what appears to be a typical eiiclotlielial membrane (figs. 4,
9, 10, and 11). This is obviously derived from the reticulum,
possibly largely tlirough tlie operation of the mechanical factor of pressure. ‘fhe occurrence of transition stages (fig.lo)
between cords with an axial blood vessel (figs. 4 and 9) and
such as lack any trace of blood vessel (fig. 11) indicates
either that the cords were originally solid and became seeondarily invaded by a blood vessel or that the original blood
vessel of the cords suffered obliteration. In either event, as
sliowii by tlie transitioii stages (fig. lo), the endothelium is
locally feiiestrated to permit the entrance to its lumen of
the peripherally differentiating lymphocytes. The evidence
farors more the interpretation that the endothelium of the
central vessel suffers disruption and that its lumen becomes
obliterated through erythroblast invasion. I n this manner
the new-formed reticulum-endothelium becomes continuous
proximally with the proper endothelium of the cordal blood
vessel, and the cells of this distal ‘sinusoid’ are placed in
direct communication with the terminal blood channels. Eve11
in figure 9 there is apparently a small gap in the endothelium
at the right, through which several erytlirohlasts have entered
Iumeii. The evidence from normal histology, i i s regards
the blood supply of lymph nodes, also favors the interpretation that these medullary cords were originally vascnlarizrd
cdumns of lymphocytes. The lymphocytes evident1;v differontiated slowly into erythroblasts under the stimulus of somc
hpecific transidstion product from the plasma of the iiic1udt.d
1)lood vessel.
111 t h e C4icnisa-stained sections only some of the m o w
I)eripheral medullary blood vessels contain deep-red-stained
voiyuscles : olsewhere the corpuscles appear lakecl of thcir
’Iicnioglobiii. Obviously, the blood circulated veq7 poorl3through this node. This condition of essential blood stasis
ol)wated t o produce a local accumulation of carbon diositle.
I ii the resulting relativelv high concentration of carbon
clioxide most, prolitil~lyi ~ i I i ~ rtlic
( ~ sspecific stimnlns for hernogl o hi n ela 110 ra t ion.
1 tic.
DISCUsSION
‘I’hv onlJ- plausible iiiterpretation of this structure, as the
a1)ove description suggests, is in terms of mi altered lymph
iiode. The modification obviously consists primarilp in an
ii tropliy of the afferent lymphatics and a subseqntwt cl~~aiiiagq~
of the lymph sinuses, involving the deeper portions of tlic
vortex and the more peripheral portions of the mednllary
(wrds, followed by atrophy of the efferent, lymphatics. The
I h o d supply has largely remained intact in spite of certain
regressive changes consequent to the drainage and isolation
of the lymph sinuses. It apparently spread some\vhat
originally, stiniulating thus proliferatioii of lymphocytes,
especially in the cortex, which caused obliteration of the
Iwripheral lymph siiius. Subsequently, certain vessels
suffered partial 01-complete isolation, as indicated by the
stagnation of their blood current, presenting t h i s the specific
cvuiditions cleterminiiig ail ei*ytliiwl)lasticmetaplasia of t l i p
cm-eloping I ymphoc y t es.
TRAXSFORMATXON O F LYMPHOCYTES INTO ERYTHROBLASTS
377
Three possibilities present themselves in explanation of
the alteration of this lymph node : First, it might conceivably
represent a transition stage between a lymph node and a
hemal node; secondly, it might represent a compensatory reaction of potentially hemopoietic tissue to a defective or
inadequate bone-marrow ; thirdly, it might represent a regressive phase of a transient lymph node. The last possibility
involves the further alternative of complete degeneration and
ultimate removal or partial degeneration to be followed by
complete regeneration.
The altered vascular conditions in this lymph node are
exactly those which von Schumacher ('12) believes lead to the
transformation of an ordinary lymph node into a hemal node,
namely, atrophy of the afferent lymphatics. Under such circumstances the blood vessels are believed to effect connections
with the original lymph sinuses and to cause these to become
filled with blood. I n the lymph node here under discussion
such result did not follow. The blood is limited to the blood
vessels. Moreover, the differentiating erythroblasts are passing into the blood vessels, not into the almost empty lymph
sinuses. The latter contain only scattered erythroblasts, differentiation products of lymphocytes trapped within the
sinuses after atrophy of the efferent Iymphatics. Meyer ('17)
denies that transitions occur between lymph nodes and hemal
nodes. He defines a hemal node as a mass of lymphoid tissue
intercalated from the beginning in the venous blood system
arid lacking both primitively and definitcly any lymphatics.
Conceivably, this node might yet have developed into a hemal
node, but regressive changes within the medullary sinuses
appear t o me t o have proceeded too far to render such a
developmental outcome at all likely. A single exception does,
of course, not disprove the hypothesis of hemal node derivation from lymph node, but this particular node, in which
the chief theoretical conditions are met as regards the vascular and lymphatic supply, offers no support. However,
certain hemal nodes in my collection give rather clear evidence
of lymph-node derivation. Also, in these altered nodes, at.
tacliecl to sections of tlie human parotid, there occur regioiis
of 1;vmphocyte traiisformation into erythrocytes. Since a
complete description of these hemal nodes involves very
immerous peculiar giant cells here present, tlie entire matter
will hc rcserred for a separate study.
Consideration of the second explanatory possibility of this
iiocie involves A description of the bone-marrow. The specimt’n of marrmv from this individual available f o r comparison
with tlie lymph node is from the femur. It differs from the
same marrow of a niimber of control specimeiis in its complete absence of fat. Noreover, it is predominantly granulocytopoietic. The g1~11ulocyte~
are almost exclusively of the
amphopbil variety. The complete absence of fat might signify
vornpensatory reaction to a severe anemia. The predomi11an(~~
of amphophilie grarinlopoietic activity may indicate
extensive bacterial infection. The presumed infection 15-oulil
most probably entail anemia. These suggestions may explain
the peculiar conditions of this marrow. Assuming that all of
tlie lymph nodes of this individual, and possibly also the
hpleeri, were in furictional coiitlitions similar to that of the
altered submaxillary lymph node, as indicated by its histology, then the conclusion would 1ogicall~-follow that this
motiific>itionof the I?-mphoicl tissue was compensatory to tlic
primary condition of an abnormal bone-marrow. I n other
words, given the contlitions imposing a predominantly granulopoietic function upon the bone-marrow, the regulatory
capacity of the body would force an erythrocytopoietic activity upoi; the uninvolved potentially hemopoietic tissue,
namely, the spleen and lymph nodes. Absence of the pertinent
iiiformatioii regarding other portions of the lymph-adenoicl
hystem greatly invalidates ally explanations attempted from
this approach. If erythrocytopoietic compensation to a
defective myeloid tissue were the correct interpretation of
the condition of this lymph node, then one would expect the
node in questioii to be packed with erythropoietic tissue rather
than with merely scattered islands of erythroblasts. However, this objection assumes that all of the lymph nocies are
TRANSFORRIATIOX O F LYMPHOCYTES INTO ERYTHROBLASTS
379
in essentially the same condition as the specimen removed.
On the contrary, other nodes, and perhaps the spleen, may be
much more active in red-cell production ; this submaxillary
node may have arrived at a stage nearing exhaustion. Xoreover, the marrow may just be entering upon a more near1:normal hemopoietic function, as suggested by the presence
of some erythroblasts among the granulocytes.
Ignoring f o r the moment the striking, and assuredly significant, division of the two chief aspects of hemopoiesis
between this lymph node and the specimen of femoral
marrow-the former being exclusively erythrocytopoietic, the
latter predominantly granulocytopoietic-we may next consider the third possibility above listed regarding the explanation of this submaxillary lymph node. This possibility interprets this structure as a regressive phase of a transient lymph
node. I f we accept Gulland's ('94) view of lymph nodes as
unstable and evanescent structures, which appear and disappear as needed, then this node could take a very definite
place in the series of alleged stages leading t o complete or
partial disappearance. Whatever the actual status of this
view may be, this particular node, judged by the apparent
degree of degenerative changes within the medullary sinuses,
and even portions of thp cortex, represents a relatively late
phase in the regression of a transient lymph node. It is difficult for me to conceive of the restoration of this structure
t o a typical lymph node, and it seems more in accord with
the histological data to consider it doomed to final resorption.
However this may be, the central point of our present
interest is not materially affected. This point concerns the
transformation of lymphocytes into erythrocytes under the
peculiar structural, chiefly vascular, conditions of this node.
This material is of prime value and importance in that it
demonstrates erythrocytogenic capacity of lymphocytes, given
favorable conditions, and gives very suggestive evidence concerning the specific differential factors mediating hemoglobin
elaboration.
380
H. E. J O R D S S
a joiut commmiicatioii with Doctor ; I l a ~ s h d l( ' 2 5 ) ' 1
reported a condition of myeloid metaplasia of lymph nodes
in a case of atypical ancmia (lenkemia?) in ~ - h i c hlymphocytes differentiate directly into erythrocytes ~t-ithinthe nodes.
Tliese nodes contain great numbers of nucleated red cells
and abundant examples of closely graded series of transition
s t i i g p s hrtweeii typical small and medium-sized lymphocytes
mid typical norrnololssts. The conclusion of in sitin cliffercntistion of crpthroc-yt es from the lvmph-node lymphocytes
was the more definite by reason of the clearly degenerate
contiition of the marrow, the fiinctional incapacitation of the
spleen b j - radium irradiation, and the almost complete absence
c)f nucleated red cells from the circulation. Similarly, in the
vase of certairi fishes and amphibia, Jordan and Speidel ( '23,
'24, '35) describe direct transformation of lyrnpliocytes of
the spleen into erythrocytes. Laguesse ('90) also derives
thc cqdhrocytes of fishes from splenic lymphocytes. Raclertscher ('15) describes a similar transformation of large and
medium-sized lymphocytes into erythrocytes in pig fetuses
from 55 mm. to full term.
The studies of Alder and Huber ('23) present strong cotifirniation of our claim that the lymphocytes of amphibians
function as hemocytoblast s. They describe this same cell
in t h c h spleen, lirer, and bone-marrow of various amphibians
m d reptiles in its process of tliffereritiatioii into both
erythrocytes and granular lencocytes. However, they dc
uot interpret this cell as a true lymphocyte. The)- name it
'Iiemoc;vtoblast,' and give it as their opinion that genuine
lymphocytes clo not occiir in forms below birds. Rut this is
simply a matter of terminology, and their descriptions and
illnstratioiis only seem to me further to support the vicw of an
crythrocytogenic capacity of the lymphocyte.
.\foreover, Chlopin and Chlopin ( '25) have very recently
shown in tissue cultures of the spleen of axolotl that even
under these conditions the splenic lymphocytes differentiate
into both erythrocytes and granular leucocytes. To be sure,
as regards the erythrocyte, the? describe its dcrivation
111
1 ILA4SSFOII
>
M.4TTOS
I (
OF LYMPHOCYTES I S T O ERYTHRORIJAS‘TS
381
directly from a ‘hemoliistioblast,’ a slightly differentiated
reticular cell. But at the same time they derive also the small
and large lymphocytes from a reticular source. Judging from
their illustrations, the larger lymphocytes and the later hemohistioblasts (early erythroblasts) are essentially identical. I n
the case of the special and eosiiiophilic granulocytes they
derive these cells from both lrmphocytes and reticular
sources, and in my opinion their data should have led them to
the same conclusion regarding the erythrocytes.
The atypical, possibly pathologic, lymph node above
described gives even more unequivocal evidence that under
certain conditions lymphocytes differentiate in situ into
erythrocytes. The close structizral similarity, amounting in
certain cases to an apparent identity, as in the case of
Amphilbia, between the ancestral blood cell of the marroviand the lymphocytes of the spleen, and the similarity of
structural conditions, as regards particularly the character
of the blood supply, in the various hemopoietic loci (yolk sac,
liver, spleen, mesonephros, and red bone-marrow ) suggest
that lymphocytes of mammals arc normally in large part
filtered out of the blood stream within the bone-marrow to
functioa here as the ancestors of both erythrocytes and leucocytes. This suggestion receives indirect support from the
fact that as yet no other hypothesis regarding the fate of
the lymphocyte has been able to meet the objection of
numerical disparity between the enormons numbers of
lymphocytes known to leave the Hood stream daily and the
relatively small number whose disappearance can be accounted f o r on the basis of actual observations. This matter
is more fully discussed in a previous paper (Jordan and
Speidel, ’24).
Nuchl of the recent work on leukemias also leads to the
conclusion that, under the conditions prevailing in this type
of disease, lymphocytes of lymph nodes differentiate into
‘myeloid cells.’ Under the latter term is usually understood
t o be included only granulocytes at various stages of development. Though the term ‘myeloid’ should properly include
383
H. R. JOEDAK
also erytliI.oblasts, statements that these same lymphocytes
tiitferentiate also into red cells are generally given only in
nnccrtain ancl qualified terms. Citron ( ’15), in liis discussion
of a case of ‘micromyeloblastic leukemia,’ states his helief
that in some C B S C S a direct autocellular change of lymphatic
follicular lymphocytes into myeloid cells may take place ill
both spleen and lynipli nodes. Fineman ( ’22), in his caw
of microlymplioidocytic leukemia, notes tlie abundance of
transition forms between lymphocytes and hemoblasts
(‘atypical cells’) both in the peripheral blood and in the
lymph nodes, but is unable to determine whether the lymphocyte is the mother cell of the atypical cell or vice versa (p. 5).
Logefeil (’24) finds evidence in a case of ‘mised leukemia’
of a “direct transition from lympliocytes to myelocj-tes, without going through the stage of tlie stem cell” (hemoblast).
Ilc tiotes also evidence of local development of myelocytes
from lymphocytes in the areas of leukemic infiltration in the.
pancreas, kidneys, and lungs. Furthermore, both in the lymph
nodes arid the spleen he found immature lymphocytes anti
myelocytes diffusely arranged without evidence of segregation. He states also that many of the eosinophils, both
immature and adult, had nuclei identical 11-ith adjacent
lymphocytes. H e quotes Turk ( ’08) as having reported many
nilcleated reds in the lymph nodes in a case of mixed leukemia.
Rut no definite statement appears a s to whether these reds
are believed to be the result of congestion, infiltration, or
local in situ differentiation. Finally, Downey ( ’24) states
that under pathological and experimental conditions which
cause myeloid metaplasia the deyivation of myeloid cells from
lymphocytes without the intervention of the mpclo1)last may
I)e an extensive process. He admits further that the blood ill
lymphatic leukemia may shorn all transition forms from the
‘my?loblast’ (hemoblast) to the ordinary lymphocyte, without,
Iiow~ever,committing himself as to which cell is the progenitor.
The claim that lymphocytes function in part as erythrocyte
ancestors within the bone-manww does not exclude other
soiIrces of origin. No (Ionht, ciitlotl~elinnifiinctions in part
TRANSFORMATION O F LYMF'HOCTTES
IKTO E1:YTHROBLhSTS
383
in the same manner. That yoiing enclothelium has a potential
erythr~ocytogeniccapacity is demonstrated in the case of the
so-callod aortic cell-clusters of mammals ( '16, '17). Similar
endothelial hlood islands were seen by Sabin ('17) in the
aorta of the living chick emhryo of the second day. Furthermore, Doan ( '23) has described an intravascnlar endothelial
origin of erythrocytes in tlie bone-marrow of the adult pigeon ;
arid Ciclnniiigham and Doan ( ' 2 3 ) liave arrived at the same
conclusion regarding the bone-marrow of tlie adult rabbit.
The double facultative origin of erythrocytes from lymphocytes and endothelium is readily explicable on the basis of
tlte close genetic relationship hetween the two types of cells
and their common only slight degree of differentiation from
the anc-estral mesenchyme. The pluripotential developmental
capaci tjr of tlie meseiichj-me includes direct blood-cell production, lymphocyte production, and endothelium production.
The intercliangeahle functional capacity of these tissues accordingly inheres in the maintenance of a considerable degree
of original polyvaleiicy. Moreover, the development of a
membrane about the mctlnllary cords above described, indistinguishable in these sections from endotheliam, demonstrates
again the close genetic relationship between reticulum cells
and endothelium, and emphasizes tlie need for extreme caution
in interpreting eiidotlielium-liiiecl spaces of marrow as
originally continuous ivith the blood capillaries.
Another matter of primary interest in this peculiarly modified lymph node relates to the specific coitditions of hemopoiesis and t o the essential identity of the process of
erythrocytopoicsis here and tliat described hy Latta ('21) in
the iliac tonsil (Peyer's patches) of young rabbits. This
imporiant work of Latta has not yet received the attention
that its results ~ v o u l dseem to merit. Latta shows that the
fate of tlie 1Tmpliocytes in the primary iliac patches is
dependent upon tlie blood supply and the closeness of their
relatiom t o the blood vessels. If the relation is remote, development proceeds in a random fashion and diffuse lymphatic
tissue results. If the hlood supply of any focus is particularly
3-34
H. E. JORDAS
good, the lymphocytes proliferate rapidly and aggregate
atwnt tlic hloocl vessels, forming dense lymphatic tissue. The
further differentiation of the lymphocytes is dependent upon :
I ) tlio c*Iosoness of association with the blood vessels, 2 ) the
slowness of the current in the blood stream, and, 3) the thinness of the vascular walls. If these three conditions are
\-erp good, erythrocyt opoiesis results ; if poor, granulocyt opoiesis occurs.
In the altered submaxillary lymph node the three conditions
specified by Latta as requisite for erythrocytopoiesis are all
adequately met. The lymphocytes have obviously undergone
cistensire proliferation about the blood vessels of the cortex ;
those of the medullary cords especially are closely associated
wit11 the axial blood vesscls; the blood current is relatively
stagnant, as indicated by the pale character of the crythroplastids in certain of the channels, and the vessel walls are
imiformly thin. The primary factor involved in stimulating
erj-throc;rtopoiesis under these conditions, as pointed out bv
Latta, is probably a transudation product of the blood plasma.
Elsewhere we have given the evidence in support of the conclusion that the specific erythrocytogenic factor or hormone
i*rsiclesprimarily in a relatively high concentration of carbon
ciioxide in the regions of hemopoietic tissues (Jordan and
Spcidel, '24 ; ,Jordan, '24). Dallwig, Kolls, and Loevcnhart
( '1 5) ha\-e demonstrated that oxygen lack and carbon-dioxide
ex(ws in the respired air arc both efficient stimuli f o r increase
of crytlirocytc production in red bone-marrow, but they regard
the decrease of oxygen tension as the primary and more
cff'cictive stimulus. However, a fall in oxygen tension of the
respired air would secondarily effect an accumulation of carhoii dioxide in the tissues, and an increase of carbon dioxide
in the respired air, unless excessive, mould be ineffective as
a hemopoietic stimulus until after saturation of the buffer
suhst;-lnccs of the circulating blood. The specific structiiral
features of this lymph node, as pertains especially to the
stagnant blood current and the regressive degenerate conclitioti of the medullary sinuses, give further support to the
TKASSFOI~3IIaTION O F LYXPH0CPTF:S INTO EKTTEIROBLASTS
385
hypothesis which locates the specific erythrocytogenic factor
iii the relatively increased concentration of carbon dioxide.
SUMMARY
1. An altered submaxillary lymph node of an adult albino
rahbit is described. The principal modifications of the node
consist in the atrophy of the lymphatics, the almost complete
drainage of the medullary sinuses, and the erythroblastic differentiation of the lymphocytes of the medullary cords and
certain perivascular areas of the thin cortex.
2. The predominating cell type of the medullary cords is
a typic,al normoblast. Occasional older erythroblasts with
conside rahle amounts of hemoglobin also occur. The
various cells include closely graded series of transition stages
IietmTeei-t typical small and medinm-sized lymphocytes and
eiiucleating erythroblasts.
3. The majority of the cords contain a thin-walled axial
blood vessel. A few are in transition stages to avascular
conditions, and show a disruption of the endothelium and an
iiivasion of the lumen by diff creiitiating erythroblasts. The
cords are enveloped by an endothelioid layer derived from the
recticular stroma. This layer becomes continuous proximally
with the endothelium of the intact portion of the involred
blood vessel. The phenomenon suggests the mode by wliich
extravascularly differentiating erythrocytes may enter the
vascular capillary terminals of hemopoietic tissues.
4, The specific structural and functional conditions of this
node under which the lymphocytes are stimulated to differentiate in to erythrocytes involve the close association betwecn
lymphocytes and thin-walled blood vessels with relatively
stagnant blood flow. These conditions represent the optimum
for the diffusion of transudation products of the blood plasma
among the surrounding lymphocytes. These vascular conditions also are such as provide for a relativelv high concentration of carbon clioxide.
5. The bone-marrow also of this rabbit is peculiar in that
it lacks f a t entirely, and the hemopoietic activity is pre-
386
H. E. JORDAS
tiomiiiantly of the amphopliil granulocytic type. The
exclusively erythrocytopoietic activity of the lymph nod(>
and the predominantly granulocytic activity of the marrow
may have causal relationship.
6. The data derived from the microscopic study of this
anomalous, perhaps pathologic, lymph node support the
hypothesis of an erythrocytogenic capacity of the lymphocyte
under certain conditions, comparable to those which normalljolkain in red bone-marrow and the fetal spleen. They support
also the hypothesis which locates the specific crythrocytogenic stimulus in a relatively increased carbon-dioxide
concentration within liemopoietic tissues.
I ~ I T E R A T U H EClTE1)
A L D ~ R , A., UND HUIIER,E. 1923 Untersucllungen ueber Bluteellen und
Zellhildung hci Amphibien und Rrptilien. Folia IIaematologica,
Bd. 29, S. 1-22.
HIDERTSCHER,J . A . 1!115 Development of thymus in the pig. 11. Histogenesis.
Am. Jour. Anat., vol. 17, pp. 4 3 7 4 9 3 .
('HLOI'IN,
N. G., END CHLOPIN, ANNA L. 19.8
Studien ueber Uewebskulturrn
im artfremden Blutplasma. 111. Die Histogenese der Zellformen in
den Explantaten der blutbildendern Organe des Axolotls. Areh. fur.
exp. Zellfors., Rd. 1, 8. 193-260.
c*ITROS, J .
191.5 Ueber zwei hemerkenswerte Fsllr ron (akntvr)
Leukinlie.
Folia Ifaematologica, Bd. 20, S. 1.
CI-SSINGHAM,R. S., AND DOAN, C. A. 1923 On the intravnscu1:tr development
of erythrocytes in the bone marrow of the adult rabbit. Z'roc. Sor.
Esp. Biol. and Med., vol. 20, pp. 262-264.
DAI,I,W-IG,
li. C., KOLLB,A. C., AND LOEVENHART, A. S. 192.5 The meclianism
adapting thc oxygen capacity of the hlootl t o the rquircnients of tlic
tissues. Am. Jour. Physiol., rol. 39, pp. 77-108.
Doax. C. A. 1923 On the intrav:iscul;tr dei <>lOl)nieiitof carytllrocytes in the
bone niarrow of the adolt pigeon. I'roc. Soe. Exp. S i o l . and Med.,
VUI. 20, pp. 260-262.
~ ) O W N E Y , 11. I909 The lyrnpliatic tissue of tlicl kithicy of I'olyodon spathula.
Folia Hitematologica, Bd. 8, S. 70-74.
- - ____1924 The occurreuce and significaiice of the ' mgclob1:rst ' undvr
normal and pathologic conditions. Archives of Internal Medicine, vol.
33, pp. 301-313.
osis
with
DOWNEY,11 ., AND MPKINLAI~,
C. A. 1923 Acntr l ~ m ~ ~ l i n ~ l e r t(wn~p:tred
acute lympliatic leukemia. Archives of 1ntcrn:il Mrrlicinr, vol. 32,
1'1). 82-11?.
F"ISI.:MAN,8. 1923 A study of inic,rolymplioitloc.\.tic Irukemia. Archives of
1nterii:il Medicine. vol. 29, pp. 168-220.
TRASSFQRMdTlON O F LYMPHOCYTES INTO ERYTHKOBLASTS
CUI,I,.~WD,G. L.
387
1894 The development of tlie IFmphatic glands. Jour. Path.
and Ract., 7-01. 0, p. 447.
JORDAK, H. E. 1916 Evidence of hemogenic wpacity of endothelium. Anat.
Rec., vol. 10, pp. 417-420.
____
1917 Hemopoiesie in the mongoose embryo, with s]iecial referenre
t o the activity of the endothelium, including that of the yolk-sac.
Pub. 251, Carnegie Institution of Wash., pp. 291-312.
_____1918 A study of a 7-mni. human embryo; with special reference
to its peculiar spirally twisted form, an d its large aortic cell-clusters.
Anat. Rec., vol. 14, pp. 479-492.
1924 The significance of the spleen, in the light of embryological,
evolutionary a n d experimental data. Virginia Medical Xonthly, vol.
31, pp. 537-544.
JORDA4N,H. E., AND MARSHALL,11. T. 1923 Metnplastie development of erythrorytes in lymph nodes. (Abstract, Proc. Am. Assoc. Anat.) Anat.
liec., vol. 29, pp. 363-363.
Jomas, H. E., AND SPEIDEL,
C. C. 1924 Studies on lymphocytes. I. Effect of
splenectomy, experimental hemorrhage and a hemolytic toxin. Am.
Jour. Anat., vol. 33, pp. 135-187.
1924 The fundamental erythroeytopoietic stimulus. Proc. Sop. Exp.
Bid. and Med., 1701. 21, pp. 339-404.
1924 The f a t e of the mammalian lymphocyte. Anat. Ree., vol.
26, pp. 223-23-2.
____- 1924 Studies on lymphocytes. 11. The origin, function, and f a t e
of the lymphocyte in fishes. Jour. Morph., vol. 38, pp. 529-548.
-1924 Studies o n lymphocytes. 111. Uranulocytopoiesis in the salnmiinder, with special reference t o the mouophyletic theory of blood-cell
origin. Am. Jour. Anat., vol. 23, pp. 4 8 5 5 0 5 .
___-1925 Studies o n lpmpliorytes. IV. Further observations on the
effects of splenectomy in the frog. .Jour. Morph. and Physiol., vol.
40, pp. 461-477.
IdAGUESSE:, E. 1890 Recherclies 8111’ l e development de la rate chez les Poissons.
Jour. de 1’Anat. et de la Pliyiol., T. 26, pp. 34.5406; 425-495.
L-YlT-4, J. 8. 1921 The histogenesis of dense lymphatic tissue of the intestine
( L r p u s ) . A ~ontril)utionto the knowledge of the devclopmnit of
lymphatic tissue a n d blood-cell formation. Am. Jour. Anat., 1-01. 29,
1)p. 159-212.
LOGEFEIL,
R. C. 1924 A study of mixed leukemia with the report of a case.
Archives of Internal Medicine, 1701. 33, pp. 659-700.
MEYER, A. N. 1917 Studies on hema1 nodes. VI. Hems1 nodes in bovincs :ind
goats. Am. Jour. Anat., vol. 21, pp. 3.59374.
SABIN,F. It. 1917 Preliminary note on the differentiation of angioblasts and
the method by wliich they produce 1)lood vessels, ldood plasma, and
red blood-cells as seen in the living chick. Anat. Rec., vol. 13, pp.
199-204.
v. SCHITMACHER,
VON S . 1912 Bau, Entwicklung unil systenidtische Stollung drr
Blutlymphdriisen. Arch. mikr. Anat., Bd. 81, S. 92-150.
PLATE 3
EXMAXATlOK OF FIGUKES
Longitndinal section, approximately medial, of altered submaxillary lymph
TIN!
capsule is thiu and loosc. The dark iriegular areas within the node represent
rcwmnnts of cortex (above) and medullary cords. The lighter spaces seen near
tlit’ center of these dark compact areas are blood vessels. Zenker-formol fixation :
Iic~iii;cto.iylin niid eosin stain.
2 Nore highly magnified area from figuro 1, showing cortex (above) and
portion of the medulla. Note the blood ressel in ninny of the compact areas and
the relatirely wide and very loose intereordal areas of the medulla.
3 Highly magnified area from medullary portion shown in figure 2. The
cord shown below, at the left, contains a relatively Large, thin-walled blood vessel.
The cord at the right, near tho midpoint, is solid; its original hlood ressc,l liiih
Iwonic obliterated through tho proliferation and sulisequent invasion of the
P I I \ eloliiiig cells. the differentinting erythi oblasts.
1
node of rabbit, showing general shape and gross internal arrangement.
33s
TRANSFORMATION
OF LYMPHOCYTES INTO ERYTHROBLASTS
H. E. JORDAN
389
PLATE 1
PLATE 2
EXPLANATION OF FIGURES
4 't'r:~nsirrse section of a small medullary cord, sliowing a ceutral a p i l l a r y
I,lood \ rssel n i i t l ii peripheral endothelioid reticulum membrane. The cells of the
cord include er~tli+ohlastsat rarious stages of differentiation. X 1200.
.i \7:trions wlls from a medullary cord. a, 15 mpliocyte (lymphoid heniol~lsst):
b , norniobl;~sts; r . erythroblasts; d, early stage i n nuclear fragmentation and
rcsorptioit of er? tliro1)lnst ; the cytoplasni roiltailis relatively much hemoglobin,
:Nyparcntly Jargel? in the form of globules ; e, abortive erythroblasts in karyorrliexis. 8 u i rounding c :ire six relatively small eiythroblasts (rnicrocptes) at
r:irions stages of differentiation.
ti Various types of cells from the intercordul areas of tlie medulla. a, large,
lrinucleated, modified reticular cell; h, free r e t i c u h r cell (monocgte?) ; r , normo),last ; tl, youiig erpt1rrol)last; e , two older erytlirohlasts; j , abortive erfthroblast,
showing kargorrlresis.
7 Smnll typical i ~ r e :of
~ less extensivelv inodified i n t e r c o r h l nieilullary area,
showing thrrc reticwlar cells a n d two er,ytlirobl:ists.
8 T?pica1 iiitercordal medullary wen. l'lie modified reticular cells a r e e1i;tr:icterizd 1)y irregular s1r:ipe and p:rle-st;tining v:iwol:it4 cytoplauni.
390
TRANSFORMATION
OF LYMPBOCTTES INTO ERYTHROBLASTS
H. E. J O R D A N
391
T E E ANATOMIC.4L RECORD, VOL. 32, X O . 4
PLATE 2
PLATE 3
EYI’LANATION OF FIGURES
9 Transrerse section of a medullary cord. The central blood vessel is defective
a t the right, permitting the entrance of differentiating erythroblasts.
The
periphery of the cord is fairly sharply outlined by a secondary endothelium
derived from the reticular stroma. The cells of the cords include various transition
stages in the differentiation process of eryt1iroc)-tes. X 1200.
10 Similar transverse section of a medullary cord in which the central blood
vessel j s largely obliterated by disruption of the endothelium and invasion of
lumen by erythroblasts. The two erythroblasts, x, stain a deeper pink color,
indieatire of a greeter content of hemoglobin, contrasting thus with the bluish-red
color of most of the cells.
11 Transection of a larger medullary cord. The original central blood vessel
has become completely obliterated and the enveloping reticular tissue has become
differcntinted into endotheliurn. This cord is essentially a wide sinus filled with
differentiating erytliroblasts. Erythroblasts, r, contain somewhat more hemoglobin tlinn most of the cells, and m contrasts still more sharply with the surrounding (.ells bp reason of a very deep pink color, the result of relatirely more
hemoglobin.
TRANSFORMATION
OF LYMPHOCYTES INTO ERYTHROBLABTS
H. E. JORDAN
393
PLATE 3
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