Paper - The first lymph glands in rabbit and human embryos

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Lewis FT. The first lymph glands in rabbit and human embryos. (1909) Anat. Rec, 3: 341-353.

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This historic 1909 paper by Frederic Thomas Lewis (1875—1951) describes human embryonic lymph gland development using the Harvard Collection embryos. See the links below for current notes of development of the lymph gland.

This paper uses models based on the Harvard Embryological Collection.

Also by this author: Lewis FT. On the cervical veins and lymphatics in four human embryos, with an interpretation of anomalies on the subclavian and jugular veins in the adult. (1909)

Modern Notes: Lymph Node Development | Rabbit Development

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The First Lymph Glands in Rabbit and Human Embryos

Frederick Thomas Lewis
Frederick Thomas Lewis (1875-1951)


Frederic T. Lewis.

Harvard Medical School, Boston, Massachusetts

In 1896 Sa;xer stated that the lymph glands in sheep and cow embryos arise from a plexus of lymphatic vessels.‘ “The connectivetissue between the lymphatic vessels of the plexus has at first a trabeeular arrangement, but later one or more compact masses or islands are formed within it. From the beginning, the connective tissue which makes the traboculae, or masses, is narrower meshed than that which surrounds it, and contains many blood vessels.” However, he adds: “There can be no doubt that there are many plexus formations in embryonic tissue, having exactly the appearance of those from which lymph glands arise, which simply degenerate.”

Kling, in 1904, emphasized the importance of the plexus stage and modelled the lymphoid trabeculae.” Although they connect with one another so as to form a continuous mass, his model has “an extremely irregular appearance.” It shows that these structures have little resemblance to the future glands. Kling stated that from such a general mass portions were separated by constriction to form the basis for individual glands. But “lymph glands which have an isolated position appear from the first as solitary formations; each one arises independently.”

A year later Miss Sabin wrote 1°‘ “All of the nodes of the early

‘Saxer, F., I'el:er die Entwickelung und den Bau der normalen Lymph(lriisen. Annt. Hefto, 1896. vol. 6, pp. 349-532.

’Kling_. (‘. A., Studien iiher die Entwicklung der Lyinplidriisen heim Menschen. Arch. f. mikr. Anat., 1904, vol. (33, pp. 575-610.

Sabin, F. R., The development of the lymphatic nodes in the pig and their relation to the lymph hearts. Amer. Jonrn. of Anat., 1905, vol. 4, pp. 355-389.

embryos, the primary 11odes in the sense of Gulland, pass through this (plexus) stage. Lymphatic nodes which develop later in the life of the embryo, after lym-phocytes occur, hurry through the primary process and show a considerable modification of it.” Recently‘ Dr. Sabin published the figure of a section through the ugular lymph sac in a human embryo of 30 mm., “to show the simple bridging of the sac which is the anlage of the first lymph node.” In the pig she found that “the first node to appear develops from the lymph heart, which is in the supra—elavicular triangle behind the sternocleidomastoid muscle.”

Thus, Saxer, Kliug and Miss Sabin agree that the. first lymph glands arise from trabeculae in a plexus of lymphatic vessels.

The plexus of lymphatics i11 relation with the internal jugular vein is a conspicuous feature in human embryos measuring from 30 to 40 mm. It is shown in Figs. 1 and 2 from an embryo of 42 mm. A portion of the vein is seen in the lower right corner of each photograph. in places the connective tissue trabceulae are broad and pale, as shown in Fig. 1. Elsewhere they are more slender and deeply stainiiig, as in the left part of Fig. 1 and in Fig. 2. The latter is a section through the structure which Miss Sabin has described as the primary lymph gland.

The cells in the similar trabeculae of a 31 mm. human embryo are described by Kling as having “chiefly, if not exclusively, the char ‘Sabin, 14‘. R., The lymphatic system in human embryos. with a consideration ot’ the morphology of the system as :1 whole. Amer. Journ. of Anat., 1909, vol. 9, pp. 43-91.

Explanation of Figures 1-6

Figs. 1 and 2.—I'lexus of lymphatic vessels in relation with the internal jugular vein. From a human embryo of 42 mm. X 45 dimns. (Harvard Embryological Collection, Series 841, Section 432, and Series 838, Section 153, respectively).

Figs. 3, 4, and 5.—Lymph glands from a human embryo of 42 mm. X 60 diains. Fig. 3 shows the submental (“subinaxillary”) gland (Series 841, Section 589); Fig. 4 shows the external jugular gland (Series 841, Section 524) ; and Fig. 5, the circumflex scapular gland (Series 838, Section 321).

FIG. 6.—Subs(-apular lymph gland from a rabbit of 20 days, 29 mm. X 60 diauns. (I-I. ll}. 0, Series 170, Section 1080.) ‘u:



FIG. 6.

FIG. 5.

acter of fixed connective tissue cells.” At 70 mm. “we find among pale oval nuclei, others of rounder form and darker stain which already suggest adenoid tissue.” Similarly, in pigs of 80 mm. Miss Sabin fo1111d large, faintly staining, oval nuclei belonging to connective tissue, and small, round, deeply staining nuclei with coarser chromatin granules and a more distinct membrane, which belong to lymphocytes. “Between the connective tissue cell, especially the young forms, and the lymphocyte one can see every possible transition” (1905, p. 371). Saxer likewise found that “the lymphocytes, which later form the bulk of the lymph glands, arise in lace.”

The examination of the bridges in the 42 mm. eiubryo shows the pale oval cells and the darker round ones apparently derived from‘ them, and indicates that these trabeeulae contain lymphoid tissue. They do not, however, constitute a lymph gland, but represent the material from which the chain of deep cervical lymph glands is to be derived. A sufficiently detailed study of the later stages of the plexus has not yet been made. Bonnet“ believes that it produces the “interseapular gland” of Ilatai, which seems to be a collective term for the cervical fat and lymph glands.

Almost simultaneously with the lymphoid transformation of trabeeulae among the ugular lymphatics, distinct lymph glands appear in the superficial tissues. These do not pass through a plexus stage, but from the first they resemble the glands of the adult. The striking difference in the arrangement of the deep and the superficial lymphoid tissue seems due to the fact that the deep tissue is molded about an involved pre—existing plexus; but the superficial glands develop freely in the loose subcutaneous tissue. The plexus stage may therefore be regarded as a complication in the development of the glands, rather than a fundamental condition which is sometimes hurried through, modified, or omitted.

In the human embryo of 42 mm. two superficial glands were found on either side of the head. Their position is indicated in Fig. '7. The smaller gland is in intimate relation with the submental branch of the anterior facial vein. A section through it is shown in Fig. 3.

“Bonnet, E... The interseapular gland. Journ. of Anat. and Phys., 1908, vol. 43. pp. 4358. l,}y111pl1 Glands in Rabbit and l[u111an E111l11'yos. 345

At the upper l1o1'd(=.1' of the phot.og1'apl1 a part of Meckel’s cartilage is seen on the left, and the bone of the lower jaw on the right; the lower border of the photograph passes through the suh1naxilla1'y gland. Between the subniaxillary gland and the mandible the s11l)n1ental vein appears, surrou11ded by dense tissue. This dense lymphoid tissue is chiefly on the upper side of the vein, and it. is bounded by a lymphatic

V3.7'ua.- ceph.

FIG. 8.

Fm. '1'.—'1‘he head of at 11111111111 e111l11'yo of 42 111111.. to show tl1e position.ot' tl1e suhinental (“suhn1axi11a1'y”) and external jugular glamls. X 2-2/5 diams. (H. E. (1., 841.)

F10. 8.—'1‘he head of :1 rabbit e111l11'_\'o of 29 111111. to show the position of the posterior facial gland. X 4 diams. (H. E. C-., 170.)

The veins shown are the anterior and posterior facial, the linguo—fa(~iuI, the external and internal jugular, and the jugulo-(‘e1)halic. (The external jiigular of man corresponds with the juguIo-ceplmlic of the rabbit and not with the linguo—faclal; the latter in the rulnhit l1o\ve\‘er. 11s1111lly called the external jugular. (If. Lewis, A1ne-1'. Joni-11. of A11at., vol. 9, 11. 33.)

vessel, crescentic in section. The sul1111e11ta.l vein sends branches into and through the lymph gland.

The other lymph gland in the head is in relation with the external jugular vein. It. is shown in section in Fig. 4. Lymphoid tissue, enclosing small blood vessels, forms a rounded mass attached to the lower part of the vein. Its f1'ee_surface is in relation with a crescentic, lymph sinus. No other lymph glands were found in the head of this embryo.

In a human embryo of 30 mm. the submental“ and external jugular glands were not found. They are not mentioned in four embryos of 46-50’ mm. described by Miss Sabin, but she has recorded that in an

FIG. 9.— Reconstruction of the arteries -in the axilla of the human embryo of 42 mm., to show the position of the first axillary lymph gland. X 10 diains. (H. 14}. C., 838). The suhscapnlar branch of the axillary artery is seen to divide into the circumflex scapular and thoraco—dorsal arteries. The lymph gland is along the latter. The brachial and lateral thoracic arteries are also shown.

80 mm. embryo “there are st-uondary lymph nodes along the veins of the neck; for example, along the external jugular vein next the parotid gland and along the facial vein at the angle of the jaw."

‘It seems desirable to name the early lymph glands for the veins which they accompany and this has been done. It is to be noted, however, that in the adult there are several glands along the submental vessels, the anterior ones forming the submental group. and the posterior ones the submaxillary group. The snhmental gland of the 42 mm. embryo belongs evidently with the submaxillary group of the adult.

Since the early lymph glands develop with such regularity in the rabbit, it seems quite possible that these glands noted in human embryos of 80 mm. are the ones appearing at 42 mm.

The Harvard collection includes three rabbits of 29 mm. (20 days) cut in the transverse, sagittal and frontal planes respectively.

Flu. 1U.——A, 1-ex-mush-m-lion of the arteries in the axilla of the 2!) mm. ruhhit. lo Show the position of the first axillary l_\'nIph gland. x 10 diams. (H. E. (3., Series 170). B, 1-e<-onstruction of the arteries in the pelvis of the same en1b1',\'o, to show the Iirst pelvic gland. x 10 (lituns.

The arteries labelled are the axillary, b1'zu-liial, st1hscapula1', aorta, illoluiuhar and h_\'pogast1'ic.

These embryos all show a lymph gland near the junction of the anterior and posterior facial veins (Fig. 8). Except at this point, no lymph glands were found in the head.

The most distinct lymph gland in the body, in these.rabbit.s and in the human embryo of 42 mm., is in the".1Xillar_y region. In the huinan elnllryo it is an accumulation of lyinphoid tissue surrounding the circumflex scapular artery and vein, and forming a lenticular mass bulging into the accompanying lymphatic vessel. lts position is shown in Fig. 9, and a section through it is photographed in Fig. 5. It lies next the muscle in the deep subcutaneous tissue. This gland was not found in a 30 nun. embryo, although at that‘ stage the circumflex scapular vessels are accompanied by lymphatics. it is not specifically mentioned by Miss Sabin, and if it occurred in the embryos studied by Kling it was overlooked. At 70 mm. he found all of the axillary groups represented except the subscapular group (p. 588).

Flo. 11.—Wax l'et'0l]Sll'l]('lil))) of the human axillary glam] shown in Figs. 5 and 9. X 40 diauls. A. (air. xv. I’. vir. x('.. circumflex scapular artery and vein; :0. 1/. ::., small blood vessels. of which .1: is so surrounded by lymphatic vessels, V. I1/m., that it seems to perforate them; 1..~gI., L.-gl'., nodules of lymphoid tissue. '

A corresponding gland occurs in rabbit embryos. I t can be identified in a specimen measuring 25 mm. (18 (lays), and it is well dofined in all three of the 29 mm. embryos. lt is in relation with the siibscapiilar vessels, which are relatively large in the rabbit (Fig. 10A). A section through the gland is shown in Fig. 6.

Since the axillary glands seem to be the largest and most clearly defined, they were ree(mstrn(-ted in wax. The gland in the human embryo is shown in Fig. 1]. Along the top of the model the circumflex scapular artery and vein pursue a parallel course, accompanied by the lymphatic vessels, V. lg/m.. As the blood vessels approach the gland the mesenchyma around them becomes condensed and forms an intensely staining mass of lymphoid tissue, L-gl'. Both artery and Lymph Glands in Rabbit and Human Embryos. 349

vein are surrounded by this tissue, but the vein seems more deeply embedded. The lymphoid tissue extends for some distance along these vessels and forms a second nodular swelling, L.-gl. The position of these swellings may be determined by the small branches of the blood vessels, y and z, which they accompany. The n1ai11 mass of lymphoid tissue, L.—gl., forms a lenticular nodule bulging into the pcrivascular lymphatics; it has been exposed by removing a part of the wall of the lymphatic vcsscl. In the photograph, Fig. 5, the dark

Fm. 12.—-VVnx reconstruction of the axillary gland of the rabbit shown in Figs. 6 and 10 A. X 56 diams. A. subsc-., 1'. 311030.. suhscapular artery and vein; V. I1/m.. peri\'usc1i1ur l_vmphati('-s; L. gI., lymph gland; (1, b, c, (I, the blood vessels correspondingly lettered in Fig. 10 A.

oval area is L.-gl. of the model, and the somewhat triangular mass above it is L—gl'; in the midst of the latter the vessel z may be seen. Fig. 5 is therefore a horizontal section of the model. The fact that there are two nodular masses of lymphoid tissue connected with one another suggests the twin glands (Zwillingsdriisen) which Kling regarded as malformations due to incomplete subdivision. The bulging of the lymph gland L.—gl. into the lymphatic vcsscl recalls the follow ing observation by Ranvierz‘ “Whenever I have observed a Vascular nodule on a lymphatic, the latter has appeared to be interrupted.

‘Rmivier, I... Morpliologie et dévelnppeincnt du s_\'stf=1ne 1yn1p1m1’iq\1c. Arr-h. d'annt. mic., 1897, vol. 1, pp. 137-152.

Thus, the lymphatic, divided at the level of the nodule, forms two trunks, of which the inferior becomes an afferent and the superior an efferent. If a new gland forms along the course of the efferent the latter will become the afferent for the second gland. The efferent for one gland may be the afferent for another.”

The subscapular gland of the rabbit is shown in the model, Fig. 12. The subscapular vein and artery are spun about with perivascular lymphatics, which extend along the branches of the blood vessels, at, D, c and (1. (Compare with Fig. 10A.) The lymph gland L.-gl. is seen through a window cut in the lymphatic vessel. It rests upon the subscapular vein and bulges into the lymphatic, pushing the endothelium before it. That the gland is more intimately related to the vein than to the artery is shown in Fig. 6. The upper portion of the gland is irregularly subdivided, so that in one or two sections there is a suggestion of the plexus formation ; lower down it forms a single rounded mass.

In addition to the well—defiucd gland in each axilla, other glands were found in the thoracic region of both the human and rabbit embryos. In the human embryo tl1e1'e is indication of lymphoid tissue along the dorsalis seapulae vessel and a somewhat diffuse gland near the anterior end of the internal mammary vein. Where the pleurapericardial septum joins the diaphragm a branch of the internal mammary vein passes inward, accompanied by a large lymphatic. Near the unction of the septum and diaphragm lymphoid tissue is found in relation with these vessels. The left pleuro-pericardial septum is thinner and farther from the median line than the right and has no corresponding lymphoid tissue. In the rabbit there is a developing gland along the thoraeo-epigastrie, or external mammary vein, nearly opposite the elbow.

The glands of the head and thorax have now been described; the abdominal and pelvic regions remain to be considered. In four rabbit embryos of 29 mm. a gland was found along the ilio—lumbar vein on either side of the body. It appears to be smaller than the axillary gland, b11t has essentially the same features. It is more deeply placed than the other glands. The ilio—lumbar vessels (Fig. 1013) have extensive subcutaneous branches, f, f, f, and a branch, e, to the abdominal musculature. As noted by Krausc, the ilio—lumbar vessels are highly developed in the rabbit. The lymph gland is found, as shown in Fig. 10B, where the subcutaneous branches join the main stem.

In the abdominal part of the human embryo of 42 mm. no distinct glands were found, but along the femoral vessels, in the inguinal region, there is a suggestion of lymphoid tissue. At 50 mm. Miss ‘Sabin describes the posterior lymph sacs as lying in the side of the pelvis opposite the first three sacral vertebrae, and states that “the entire dorsal wall of the sac is occupied by a lymph node” (190%), p. 87). A gland which extends over three sacral vertebrae is clearly unlike any gland in the adult. The structure referred to seems to be the plexus of deep lymphatics, among which lymphoid tissue has appeared, but has not yet formed glands. At this stage Miss Sabin speaks of “secondary nodes” developing near the sacs along the femoral and sciatic groups of veins. In an 80 mm. embryo she describes a true lymph gland which, from its structure and position, as shown in a figure, strikingly sitggests the ilio-lumbar gland of the rabbit ; it is not stated along what vessels it occurs. The description of the gland is as follows: “In Fig. 19 is a tiny lymph node . . . which illustrates well the sirnplest form of a lymph node, a central mass of lymphocytes with a plexus of lymph ducts around it. This plexus of duets is so close that it may already be termed a sinus, so that the node consists of a single follicle with its peripheral sinus.” It may be noted that Miss Sabin has figured such a simple gland in the lung of an adult pig (1905, p. 385), and Kling has described them in the axilla of an adult man.

From the preceding study the conclusion may be drawn that the first definite lymph glands are superficial. They appear with surprising regularity, as shown by comparing the three rabbit embryos of 29 mm. They are situated along the large cutaneous veins, and there is a well-developed pair for the head, thorax, and abdomen respectively. In addition to these, the rabbit embryo of 29 mm. gives evidence of gland formation along the thoraco-epigastric vein. The human embryo of 42 mm. dif'fers from the rabbit of 29 mm. by the absence of the ilio-lumbar gland and the presence of the submental gland, together with indications of glands along the internal mammary and femoral veins. Doubtless, bot.h in man and the rabbit the development of additional glands proceeds rapidly.

At the time when the superficial glands are distinct the deep ones are represented by lymphoid trabeeulae, which are said to be transformed into chains of glands by the accumulation of the lymphoid tissue i11 nodules. Something of this sort must occur, but models showing the development of such a chain have not yet been made. It seems undesirable to speak of an extensive plexus of lymphatic vessels, even when associated with diffuse lymphoid tissue, as a lymph gland.

At the time when the lymph glands and trabeeulae arise—that is, in the embryos which have now been (lescribe(l———the1'e is apparently no lymphoid tissue elsewhere in the body. The spleen is well developed, but the compact tissue of which it. is composed does not appear like that of the lymph glands. The thymus at this stage, in the rabbit at least. is clearly an epithelial organ. This is contrary to the statement of Gullan<l,3 that “the thymus in mammalian embryos is the first place where true adenoid tissue is formed, and it is an active center for the production of leucocytes long before lymphatic glands are formed at all.”

The question of the origin of lymphocytes can be answered only by examining thin and ‘specially stained sections. The embryos here described were prepared for general study, and the sections are 10 microns or more in thiclmoss. They Sllg{.’,‘(‘St, however, that the lymphocytes are forming in the glands and that they are absent from the blood. Maximow, who has studied the embryonic development of the blood with faultless technique, has unfortunately not examined the earliest lymph glands.” He considers that “the first leucoeytes, the lymphocytes, arise at the same time and from the same source as the primitive erythroblasts. The latter l‘t‘pI'eS("1lt a specially (lifferentiated form of cell, but the lymphocytes always remain unclii’ferentiated.

'Gn1land, G. I... The development of lymphatic glands. Jgurn. of Path. and Bach, 1894, vol. 2, pp. 447-485.

'Maxlnow. A.. Untersuchung fiber Blut uud Blndegewebe. I. Die frtlhesten Entwlcklungsstadien der Blut. etc. Arch. 1!. mlk. Anat.. 1909. vol. 73. pp. 444-561.

Therefore, like the primitive blood cells from which they directly proceed, they are undifferentiated rounded amoeboid mesenchymal cells.” He states that these lymphocytes of the embryo “have nothing to do with lymphoid tissue”—they develop in the yolk sac.

The lymphocytes of the lymph glands are, indeed, round 1nesenchymal cells, but, except for an occasional cell in the lymph sinus, apparently detached from the gland, they are unlike the forms of corpuseles in the adjacent vessels. It seems probable that the lymph glands, arising in rabbit embryos of 25-30 mm. and in human embryos of 30-45 mm., are the source of a special form of round mesenehymal cell, which is the true lymphocyte. This opinion can be established or disproved only by a cytological study of the early lymph glands, the position of which has been indicated.