Toxicologic Pathology, 34:455–465, 2006

Copyright

C by the Society of Toxicologic Pathology

ISSN: 0192-6233 print / 1533-1601 online

DOI: 10.1080/01926230600867743

Normal Structure, Function, and Histology of the Spleen

MARK F. CESTA

Integrated Laboratory Systems, Inc., Durham, North Carolina 27713, USA

ABSTRACT
The spleen is the largest secondary immune organ in the body and is responsible for initiating immune reactions to blood-borne antigens and for
filtering the blood of foreign material and old or damaged red blood cells. These functions are carried out by the 2 main compartments of the spleen,
the white pulp (including the marginal zone) and the red pulp, which are vastly different in their architecture, vascular organization, and cellular
composition. The morphology of these compartments is described and, to a lesser extent, their functions are discussed. The variation between species
and effects of aging and genetics on splenic morphology are also discussed.
Keywords. Immunopathology; lab animal; marginal zone; morphology; red pulp; spleen; white pulp.

INTRODUCTION (Figure 10). These trabeculae also contain blood and lymph
The spleen is a dark red to blue-black organ located in the vessels and nerves. The lymph vessels are efferent vessels
left cranial abdomen. It is adjacent to the greater curvature of through which lymphocytes migrate to the splenic lymph
the stomach and within the omentum. It is an elongated organ, nodes.
roughly triangular in cross section. The gross appearance and Being a blood filter, it follows that the spleen is a highly vas-
size of the spleen are variable, depending on the species and cular organ. Blood flow through the spleen is rather complex,
the degree of distension; nonetheless, spleen weights can be but is an important and sometimes controversial concept.
important in its evaluation. The ratio of splenic weight to Blood enters the spleen at the hilus via the splenic artery. The
body weight remains fairly constant regardless of age and, in splenic artery divides into trabecular arteries located within
rats, is typically around 0.2% (Losco, 1992). the trabeculae entering the splenic parenchyma. Small arte-
The functions of the spleen are centered on the systemic rioles branch from the trabecular arteries and enter the red
circulation. As such, it lacks afferent lymphatic vessels. It pulp where they become central arterioles which are sur-
is comprised of 2 functionally and morphologically distinct rounded by lymphoid tissue. Smaller arterioles branch from
compartments, the red pulp and the white pulp (Figures 1 the central arterioles and feed the white pulp capillary beds
and 2). The red pulp is a blood filter that removes foreign (Satodate et al., 1986; Valli et al., 2002). Some of these ter-
material and damaged and effete erythrocytes. It is also a minate in the marginal sinus at the junction of the white pulp
storage site for iron, erythrocytes, and platelets. In rodents, it and the marginal zone, others terminate within the marginal
is a site of hematopoiesis, particularly in fetal and neonatal zone, and a few extend beyond the white pulp to terminate
animals. The spleen is also the largest secondary lymphoid in the red pulp (Dijkstra and Veerman, 1990; Schmidt et al.,
organ containing about one-fourth of the body’s lymphocytes 1985a). Blood entering the marginal sinus and marginal zone
and initiates immune responses to blood-borne antigens (Ku- percolates through the marginal zone in the direction of the
per et al., 2002; Nolte et al., 2002; Balogh et al., 2004). This red pulp. Once through the marginal zone, the blood either
function is charged to the white pulp which surrounds the flows directly into adjacent venous sinuses whose open ends
central arterioles. The white pulp is composed of three sub- are continuous with the marginal zone, the so-called “fast
compartments: the periarteriolar lymphoid sheath (PALS), pathway,” or enters the reticular meshwork of the red pulp,
the follicles, and the marginal zone. the “slow pathway” (Schmidt et al., 1993). As much as 90%
The spleen is surrounded by a capsule composed of dense of the total splenic blood flow travels through the adjacent
fibrous tissue, elastic fibers, and smooth muscle. The outer- venous sinuses, bypassing the reticular meshwork of the red
most layer of the splenic capsule is composed of mesothelial pulp (Schmidt et al., 1993). As the central arterioles continue,
cells, which may not be evident on histologic section. Irreg- the white pulp wanes and they become the penicillar arteries
ularly spaced trabeculae of smooth muscle and fibroelastic surrounded by red pulp. These give rise to the arterial capil-
tissue emanate from the capsule into the splenic parenchyma laries, which terminate in the reticular meshwork of the red
pulp in rodents (open circulation; Mebius and Kraal, 2005).
Blood from the red pulp collects in the venous sinuses which
Address correspondence to: Mark F. Cesta, Integrated Laboratory Sys- enter the trabeculae and merge into the trabecular veins (Fig-
tems, Inc., 601 Keystone Park Drive, Suite 100, Durham, NC 27713, USA; ure 9). The trabecular veins then converge at the hilus to form
e-mail: [email protected] the splenic vein which drains into the hepatic portal system.
This work was supported by NIEHS contracts N01ES35513 and
N01ES95435. The author wishes to acknowledge the assistance of the staffs Red Pulp
of Integrated Laboratory Systems Inc., Experimental Pathology Laborato-
ries Inc., and the National Institute of Environmental Health Sciences with The red pulp is composed of a three dimensional meshwork
preparation of photographs included in this paper and the helpful comments of splenic cords and venous sinuses. The splenic cords are
from Dr Jerrold Ward. composed of reticular fibers, reticular cells, and associated
455
456 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 1.—Cross-section of the spleen. C57Bl/6 mouse. Relative to the rat (see Figure 2), the mouse spleen typically has a slightly blue tint due to the increased
amounts of extramedullary hematopoiesis in the red pulp. In general, the marginal zones are much smaller and more variable than those of the rat and the white pulp
is more prominent. H&E stain. 2—Cross-section of the spleen. Wistar rat, female. Compare to Figure 1.

macrophages (Saito et al., 1988). The reticular cells are con- by the reticular cells and their processes (Saito et al., 1988).
sidered to be myofibroblasts and may play a role in splenic The reticular fibers are composed of collagenous and elastic
contraction (Saito et al., 1988). With electron microscopy, fibers, microfibrils, reticular cell basal laminae, and unmyeli-
it is apparent that the reticular fibers are actually ensheathed nated adrenergic nerve fibers (Saito et al., 1988). For more

FIGURE 3.—B6C3F1 mouse, female, 20 weeks old (left) and F344/N rat, male, 12 weeks old. (right). Relative to the mouse spleen, the rat spleen has a larger and
more uniform marginal zone (MZ) and a more pronounced marginal sinus region (MS). The follicle (F) in the rat spleen is better demarcated from the PALS (P).
Hematopoietic tissue is more prevalent in the red pulp (RP) of the mouse. A = central artery, T = trabeculus, H = hilus.
Vol. 34, No. 5, 2006 STRUCTURE OF THE SPLEEN 457

FIGURE 4.—White Pulp. C57Bl/6 mouse. The germinal centers (G) are prominent, highlighting the number and location of the normally inconspicuous follicles
(F) in the mouse spleen. A = central artery, P = PALS, MZ = marginal zone, RP = red pulp. 5.—White Pulp. C57Bl/6 mouse. Higher magnification view of the
white pulp from Figure 4. G = germinal center, F = follicle, A = central artery, P = PALS, MS = marginal sinus, MZ = marginal zone, RP = red pulp.
458 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 6.—F344/N rat, male, 12 weeks old. The marginal sinus (MS) of the rat and its sinus lining cells are readily apparent. The marginal zone metallophilic
macrophages can occasionally be seen on the PALS side of the marginal sinus. The outer ring of the marginal sinus is composed of marginal zone macrophages,
dendritic cells, B-cells, and reticular cells and blends with the red pulp (RP). Erythrocytes percolate through the marginal zone (MZ). OP = outer PALS.

information on the ultrastructure of the red pulp, see Saito the red pulp, and sometimes in the white pulp as well, are
et al. (1988) or Schmidt et al. (1993). Within the spaces be- a typical finding (Figure 9). In fact, iron pigments (i.e.,
tween the cords are blood cells, including erythrocytes, gran- hemosiderin and ferritin) are the most common pigments in
ulocytes, and circulating mononuclear cells. Also associated the macrophages of the red pulp (Losco, 1992). Iron from
with the splenic cords, are lymphocytes and hematopoietic the hemoglobin of phagocytized erythrocytes is converted to
cells as well as plasma cells and plasmablasts that migrate hemosiderin for storage in the spleen. According to historical
from the follicles and the outer PALS after antigen specific control data from the National Toxicology Program (NTP),
differentiation (Matsuno et al., 1989; Mebius and Kraal, hemosiderin pigmentation is more prevalent in females than
2005). The red pulp macrophages are actively phagocytic in males (Ward et al., 1999). Ceroid and lipofuscin derived
and remove old and damaged erythrocytes and blood-borne from oxidation of lipids is also typically found in the spleen,
particulate matter. Extra medullary hematopoiesis is common though they are less abundant than hemosiderin (Ward et al.,
in rodent red pulp, especially in fetal and neonatal animals. 1999). Melanocytes containing melanin may be present in the
Any combination of erythroid, myeloid, and megakaryocytic spleen, particularly in black mice, usually in the trabeculae
cells may be evident (Figure 10). or focally in the red pulp (Ward et al., 1999).
Venous sinuses can be found throughout the red pulp, in-
cluding, as mentioned previously, directly adjacent to the White Pulp
marginal zone (Figure 8). They are lined by loose network of The white pulp is subdivided into the PALS, the follicles,
endothelial cells which sit on a basement membrane that is and the marginal zone (Figures 3, 4, and 5). It is composed
sandwiched between the endothelial cells and reticular fibers of lymphocytes, macrophages, dendritic cells, plasma cells,
of the red pulp (Saito et al., 1988). The penicillar arteries and arterioles, and capillaries in a reticular framework similar to
arteriolar capillaries are also located in the red pulp, though that found in the red pulp (Saito et al., 1988). As the cen-
they are more difficult to identify light microscopically. tral arterioles enter the red pulp, they are surrounded by the
Various pigments may be present in the spleen. PALS which are composed of lymphocytes and concentric
Hemosiderin deposits in the cytoplasm of macrophages in layers of reticular fibers and flattened reticular cells (Dijkstra
Vol. 34, No. 5, 2006 STRUCTURE OF THE SPLEEN 459

FIGURE 7.—B6C3F1 mouse, female, 20 weeks old. Two examples of the marginal zone (MZ) of the mouse showing the variation in thickness. The marginal
zone is thicker in 3b than in 3a. Note that the marginal sinus (MS) is sometimes obscured in the mouse as opposed to the rat where it is more readily apparent (see
Figure 6). F = follicle, RP = red pulp.

and Veerman, 1990; Satodate et al., 1986). The PALS are which is surrounded by a mantle zone or corona composed of
divided into the inner PALS and the outer PALS (Matsuno small to medium lymphocytes (Ward et al., 1999). Follicles
et al., 1989; Nicander et al., 1993; Van Rees et al., 1996). may contain germinal centers, which form upon antigenic
The inner PALS, a T-cell dependent region, may stain slightly stimulation, that stain less intensely due to the presence of
more intensely than the outer PALS due to its cellular com- fewer cells and contain tingible body macrophages and apop-
position of predominantly small lymphocytes (Dijkstra and totic B-cells.
Veerman, 1990; Matsuno et al., 1989). The difference, how-
ever, is not uniformly present and is generally very subtle and Marginal Zone
difficult to detect by light microscopy (Stefanski et al., 1990). The marginal zone is a unique region of the spleen situated
The cells of the inner PALS are largely CD4+ T-cells, though at the interface of the red pulp with the PALS and follicles
smaller numbers of CD8+ T-cells may also be present, as well (Figure 6). Considered by many to be a separate compartment
as interdigitating dendritic cells, and migrating B-cells (Van rather than part of the white pulp, it is designed to screen
Rees et al., 1996). The outer PALS is populated by small and the systemic circulation for antigens and pathogens and
medium lymphocytes (both B- and T-cells), macrophages, plays an important role in antigen processing (Kuper et al.,
and, upon antigenic stimulation, plasma cells (Matsuno et al., 2002; Mebius and Kraal, 2005). A band of macrophages, the
1989; Van Rees et al., 1996). It is an important site of lym- marginal zone metallophilic macrophages, and the marginal
phocyte traffic where the formation of plasma cells occurs sinus (Dijkstra and Veerman, 1990; Mebius and Kraal, 2005;
(Dijkstra and Veerman, 1990; Matsuno et al., 1989). Satodate et al., 1986), separate the marginal zone from
The follicles are continuous with the PALS and are typi- the PALS and follicles. The marginal zone metallophilic
cally found at bifurcation sites of the central arterioles (Ward macrophages are a unique subset of macrophages at the
et al., 1999). They are composed primarily of B-cells with inner margin of the marginal zone adjacent to the PALS
fewer follicular dendritic cells and CD4+ T-cells but typi- and follicles (Dijkstra and Veerman, 1990; Matsuno et al.,
cally do not contain CD8+ T-cells (Van Rees et al., 1996). 1989; Mebius and Kraal, 2005). They can be visualized by
The follicles have larger lymphocytes at the follicular center silver staining and with the monoclonal antibody MOMA-1
460 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 8.—F344/N rat, male, 12 weeks old. Several venous sinuses are readily apparent in the red pulp, particularly the 3 largest ones (VS) at the margin of the
marginal zone (MZ). Aggregates of erythropoietic cells (EP) are scattered throughout the red pulp. MS = marginal sinus, F = follicle. 9.—F344/N rat, male, 12
weeks old. A venous sinus (VS) can be seen penetrating a trabeculus (T) to merge with a trabecular vein (TV). Granulocytes, erythropoietic cells, lymphocytes, and
hemosiderin-laden macrophages are present amid the splenic cords.
Vol. 34, No. 5, 2006 STRUCTURE OF THE SPLEEN 461

FIGURE 10.—B6C3F1 mouse, female, 20 weeks old. Hematopoietic cells are prevalent in the red pulp of the mouse. Granulopoiesis can be seen in the center of
the photo immediately adjacent to the capsule. Erythroid cells and megakaryocytes are also present. A trabeculus arises from the capsule and enters the red pulp.
11.—NIH Nude rat, 9 weeks old. The PALS are sparsely populated by T-cells, particularly the inner PALS (IP). The marginal zone (MZ) and red pulp (RP) are
relatively normal. MS = marginal sinus, OP = outer PALS, A = central artery.
462 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 12.—BALB/cA nude mouse, 9 weeks old. As with the rat, the PALS (P) are depleted of T-cells. The B-cell follicle (F), marginal zone (MZ), and red pulp
(RP) are relatively normal. MS = marginal sinus, A = central artery. 13.—CB-17 SCID mouse, 9 weeks old. The white pulp region is small and both B- and T-cell
regions are affected. The PALS (P) and the follicle (F) are markedly depleted of lymphocytes. The marginal zone is nearly nonexistent (the asterisk indicates where
the marginal zone should be). As with the nude animals, the red pulp (RP) appears relatively normal. A = central artery, MS = marginal sinus.
Vol. 34, No. 5, 2006 STRUCTURE OF THE SPLEEN 463

(Mebius and Kraal, 2005). Adjacent and peripheral to the capillaries both terminate in the reticular meshwork (open
marginal zone metallophilic macrophages is the marginal circulation) and empty directly into the venous sinuses with
sinus. It is continuous with vessels that feed the capillary no interruption of the endothelial lining (closed circulation)
beds of the PALS and follicles and is lined by MADCAM1+, (Schmidt et al., 1982, 1983, 1993). In dogs, but not rats,
sinus-lining endothelial cells (Mebius and Kraal, 2005). the arterial capillaries are surrounded by dense, circumfer-
Peripheral to the marginal sinus, is the thick outer ring of the ential clusters of macrophages known as ellipsoids or peri-
marginal zone, composed of reticular fibroblasts, marginal arterial macrophage sheaths (PAMS) (Blue and Weiss, 1981;
zone macrophages, dendritic cells, and medium sized Satodate et al., 1986). In dogs, there are very few capillar-
marginal zone B-cells (Dijkstra and Veerman, 1990; Mebius ies within the PALS, as opposed to rats and mice where the
and Kraal, 2005). The marginal zone blends into the red pulp. PALS have abundant capillaries (Schmidt et al., 1983, 1985a,
The marginal zone macrophages are another population of 1985b, 1993).
splenic macrophages that stain with the monoclonal antibody Extra medullary hematopoiesis is more prevalent in
ERTR-9 (Van Rees et al., 1996). While all the potential spleens of mice than rats. In dogs, hematopoietic tissue is
functions of the marginal zone metallophilic macrophages present in the spleen in pathologic conditions such as neo-
are not known, the marginal zone macrophages are im- plasia and anemia, but may be present in the absence of un-
portant in clearance of microorganisms and viruses. They derlying disease (HoganEsch and Hahn, 2001). When the
express a number of pattern recognition receptors such as hematopoietic tissue is predominantly myeloid, the term
toll-like receptors (TLRs) and the macrophage receptor with myeloid hyperplasia may be applied. The incidence of splenic
collagenous structure (MARCO), which are important in the myeloid hyperplasia in the absence of underlying disease was
uptake of various bacteria (Mebius and Kraal, 2005). The 4% in beagle dogs in one study (HoganEsch and Hahn, 2001).
marginal zone B-cells are a unique subset of noncirculating Though there is a lot of individual variation, mice tend
B-cells that have an IgM+/IgD- phenotype as opposed to to have a greater proportion of white pulp than rats, but the
follicular B-cells which are IgM+/IgD+ (Van Rees et al., follicles and marginal zone of mice are less distinct than those
1996). of rats (Figures 1, 2, and 7) (Ward et al., 1999). In rats, the
marginal zone comprises up to 28% of the splenic volume
Factors Affecting Splenic Morphology and is the largest B-cell region in the spleen (Dijkstra and
Species: There are a number of species differences in the Veerman, 1990; Schmidt et al., 1993). Approximately one-
gross and histologic appearance of the spleen. In dogs, for third of the B-cells in the rat spleen have the marginal zone
example, the spleen is somewhat dumbbell shaped, while in B-cell phenotype, whereas in the mouse, only 15% of the
mice and rats, it’s more uniform along the longitudinal axis. splenic B-cells have this phenotype (Van Rees et al., 1996).
The spleen in dogs is able to expand to store large numbers Though the region where the marginal sinus is located is more
of erythrocytes, but it is also capable of rapid contraction. consistently discernible in rats, electron microscopic studies
Therefore, its gross appearance is quite variable, ranging from show that the marginal sinus is up to 6 times larger in mice
large and dark red to blue-black to smaller and lighter red. (Schmidt et al., 1993).
The capsule and trabeculae of dogs contains more smooth
muscle than that of mice and rats, so the spleens of rodents Age: In the fetus, the spleen begins as a collection of
do not contract as rapidly and tend to vary less in their gross primitive reticular cells in the dorsal mesogastrium. The first
appearance (Valli et al., 2002). The splenic artery also differs cells to appear are hematopoietic, which are evident by ges-
among species. In dogs, it branches into as many as 25 smaller tation day 17 in the rat (Losco, 1992). In the mouse, splenic
branches prior to entry into the spleen (HoganEsch and Hahn, tissue can first be identified, light microscopically, at gesta-
2001), while in the rat, there are as many as eight branches tion day 12.5 and the first hematopoietic cells can be seen
(Satodate et al., 1986). at gestation day 15.5 (Seymour et al., 2006). In the dog,
Vascular arrangements are perhaps the greatest source of lymphocytes first appear in the spleen at gestation day 52,
species variation in splenic architecture. Species variation in while the rodent spleen contains little or no white pulp at
the structure and morphology of the venous sinuses forms birth (HoganEsch and Hahn, 2001; Van Rees et al., 1996).
the basis for the classification of spleens into two groups, si- The first lymphocytes to appear are T-cells that accumulate
nusal spleens and nonsinusal spleens (Schmidt et al., 1985a). in the PALS regions (Losco, 1992; Van Rees et al., 1996).
Sinusal spleens are found in rats and dogs and nonsinusal In rats, this begins by 2 days of age, by day 5, dendritic cell
spleens are found in mice (Schmidt et al., 1985a). The ve- precursors appear, after which B-cell follicles begin to de-
nous sinuses of sinusal spleens are larger, more abundant, velop, and immunologic function begins at 14 days of age
make numerous anastamoses, and have a characteristic wall when cell to cell contact of antigen presenting dendritic cells
structure relative to the venous sinuses of nonsinusal spleens becomes apparent (Losco, 1992). The spleen reaches peak
(for an in depth description of these differences, see Snook development at puberty, in rats, followed by gradual involu-
(1950) and for more detail on the wall structure of each ves- tion (Losco, 1992). In dogs, the spleen increases in weight
sel type, see Blue and Weiss (1981) (Schmidt et al., 1985a). during the first 6 months of life (HoganEsch and Hahn, 2001).
The venous sinuses of nonsinusal spleens are so different, in Numerous references discuss the effects of aging on
fact, that some investigators use the term pulp venules rather lymphocyte function and changes in the distribution of
than venus sinuses (Schmidt et al., 1985a). The larger venous lymphocyte subsets. Lymphocyte numbers, however, may
sinuses of the rat spleen are far more conspicuous than those also decrease with age. One study showed a greater than
of the mouse spleen. 80% decrease in lymphocyte numbers in the white pulp
There are also species differences in the arterial vascula- of Fisher rats between 4 and 30 months of age (Cheung
ture. Schmidt et al. have reported that, in dogs, the arterial and Nadakavukaren, 1983). This change corresponded, light
464 CESTA TOXICOLOGIC PATHOLOGY

and electron microscopically, to a decrease in lymphocyte Cheung, H. T., and Nadakavukaren, M. J. (1983). Age-dependent changes in
density in the white pulp (Cheung and Nadakavukaren, the cellularity and ultrastructure of the spleen of Fischer F344 rats. Mech
1983). There was also an increase in the number of retic- Ageing Dev 22, 23–33.
Custer, R. P., Bosma, G. C., and Bosma, M. J. (1985). Severe combined immun-
ular cells and macrophages in the same regions (Cheung and
odeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms.
Nadakavukaren, 1983). Some degree of white pulp atrophy is Am J Pathol 120, 464–77.
also a common aging change in Sprague–Dawley rats (Losco, Dijkstra, C. D., and Veerman, A. J. P. (1990). Normal Anatomy, Histology,
1992). The spleens of older dogs and rodents typically have Ultrastructure, Rat. In: Monographs on Pathology of Laboratory Animals:
fewer germinal centers (HoganEsch and Hahn, 2001; Losco, Hemopoietic System (T. C. Jones, J. M. Ward, U. Mohr and R. D. Hunt,
1992). eds.), pp. 185–93. Springer-Verlag, Berlin.
Extra medullary hematopoiesis tends to be decreased in Hanes, M. A. (2005). The Nude Rat. In The Laboratory Rat (M. A. Suckow, S.
adult animals, but can increase in any animal when there is Weisbroth and C. L. Franklin, eds.), pp. 733–59. Academic Press.
increased demand for these cells as in cases of anemia, in- HoganEsch, H., and Hahn, F. F. (2001). The Lymphoid Organs: Anatomy, Devel-
flammation, decreased production by the bone marrow, or in opment, and Age-related Changes. In Pathobiology of the Aging Dog (U.
Mohr, W. W. Carlton, D. L. Dungworth, S. A. Benjamin, C. C. Capen
cases of neoplasia (Losco, 1992). The amount of hemosiderin
and H. F. F., eds.), Vol. 1, pp. 127–135. Iowa State University Press,
present in the spleen tends to increase with age in both ro- Ames.
dents and dogs (HoganEsch and Hahn, 2001; Losco, 1992; Kuper, D. F., de Heer, E., Van Loveren, H., and Vos, J. G. (2002). Immune
Van Rees et al., 1996) and, in mice, is more prevalent in System. In Handbook of Toxicologic Pathology (W. M. Haschek, C. G.
females than males (Ward et al., 1999). Rousseaux and M. A. Wallig, eds.), Vol. 2, pp. 585–646. Academic Press,
Genetics: Genetic mutations in rats and mice, either San Diego.
spontaneous or engineered, resulting in immunodeficiency Losco, P. (1992). Normal Development, Growth, and Aging of the Spleen. In:
Pathobiology of the Aging Rat (U. Mohr, D. L. Dungworth and C. C.
markedly affect the morphology of the spleen. Among the im-
Capen, eds.), Vol. 1, pp. 75–94. ILSI Press, Washington, D.C.
munodeficient strains, nude rats and SCID (severe combined Matsuno, K., Ezaki, T., and Kotani, M. (1989). Splenic outer periarte-
immunodeficiency disease) mice are perhaps the best known rial lymphoid sheath (PALS): an immunoproliferative microenvironment
and most commonly used in scientific studies. Nude rats are constituted by antigen-laden marginal metallophils and ED2-positive
congenitally athymic and so are deficient in T-lymphocytes. macrophages in the rat. Cell Tissue Res 257, 459–70.
The spleens of nude rats (and mice) are smaller than those Mebius, R. E., and Kraal, G. (2005). Structure and function of the spleen. Nat
of their wild-type counterparts. They have sparsely popu- Rev Immunol 5, 606–16.
lated PALS regions and, since T-cell activity is required for Nicander, L., Brown, E. M., Dellmann, H. D., and Landverk, T. (1993). Lym-
the formation of germinal centers, lack secondary follicles phatic Organs. In: Textbook of Veterinary Histology (H. D. Dellmann, ed.),
(Figures 11 and 12) (Bell et al., 1987; Hanes, 2005). SCID pp. 120–135. Lea and Febiger, Philadelphia.
Nolte, M. A., Hamann, A., Kraal, G., and Mebius, R. E. (2002). The
mice are homozygous for the Prkdcscid mutation, a muta-
strict regulation of lymphocyte migration to splenic white pulp
tion in the gene encoding the catalytic subunit of DNA- does not involve common homing receptors. Immunology 106, 299–
dependent protein kinase (DNA-PKcs) (Perryman, 2004; 307.
Seymour et al., 2006). This results in a defect in V(D)J Perryman, L. E. (2004). Molecular pathology of severe combined immunodefi-
recombination of T-cell receptors and B-cell immunoglob- ciency in mice, horses, and dogs. Vet Pathol 41, 95–100.
ulin receptors and a lack mature B- and T-cells (Perryman, Saito, H., Yokoi, Y., Watanabe, S., Tajima, J., Kuroda, H., and Namihisa, T.
2004). The spleens of SCID mice are smaller than those of (1988). Reticular meshwork of the spleen in rats studied by electron mi-
wild-type mice and all three regions of the white pulp con- croscopy. Am J Anat 181, 235–52.
tain few lymphocytes but do contain macrophages (Custer Satodate, R., Tanaka, H., Sasou, S., Sakuma, T., and Kaizuka, H. (1986). Scan-
et al., 1985). The follicles are variable in size and contain oc- ning electron microscopical studies of the arterial terminals in the red pulp
of the rat spleen. Anat Rec 215, 214–6.
casional plasma cells, however, follicular dendritic cells are
Schmidt, E. E., MacDonald, I. C., and Groom, A. C. (1982). Direct arteriovenous
absent since B and T cells are required for the development of connections and the intermediate circulation in dog spleen, studied by
these cells (Custer et al., 1985; Seymour et al., 2006). The scanning electron microscopy of microcorrosion casts. Cell Tissue Res
marginal zone is markedly decreased in size and is poorly 225, 543–55.
demarcated from the PALS and follicles (Figure 13). In both Schmidt, E. E., MacDonald, I. C., and Groom, A. C. (1983). Circulatory path-
the SCID and nude mutants, the reticular framework of the ways in the sinusal spleen of the dog, studied by scanning electron mi-
sparsely populated white pulp is intact (Custer et al., 1985; croscopy of microcorrosion casts. J Morphol 178, 111–23.
Hanes, 2005). Schmidt, E. E., MacDonald, I. C., and Groom, A. C. (1985a). Microcirculation in
mouse spleen (nonsinusal) studied by means of corrosion casts. J Morphol
186, 17–29.
REFERENCES Schmidt, E. E., MacDonald, I. C., and Groom, A. C. (1985b). Microcircula-
Balogh, P., Horvath, G., and Szakal, A. K. (2004). Immunoarchitecture of dis- tion in rat spleen (sinusal), studied by means of corrosion casts, with
tinct reticular fibroblastic domains in the white pulp of mouse spleen. particular reference to the intermediate pathways. J Morphol 186, 1–
J Histochem Cytochem 52, 1287–98. 16.
Bell, E. B., Sparshott, S. M., Drayson, M. T., and Ford, W. L. (1987). The Schmidt, E. E., MacDonald, I. C., and Groom, A. C. (1993). Comparative aspects
stable and permanent expansion of functional T lymphocytes in athymic of splenic microcirculatory pathways in mammals: the region bordering
nude rats after a single injection of mature T cells. J Immunol 139, 1379– the white pulp. Scanning Microsc 7, 613–28.
84. Seymour, R., Sundberg, J. P., and HogenEsch, H. (2006). Abnormal lymphoid
Blue, J., and Weiss, L. (1981). Electron microscopy of the red pulp of the dog organ development in immunodeficient mutant mice. Vet Pathol 43, In
spleen including vascular arrangements, periarterial macrophage sheaths Press.
(ellipsoids), and the contractile, innervated reticular meshwork. Am J Anat Snook, T. (1950). A comparative study of the vascular arrangements in mam-
161, 189–218. malian spleens. Am J Anat 87, 31–77.
Vol. 34, No. 5, 2006 STRUCTURE OF THE SPLEEN 465

Stefanski, S. A., Elwell, M. R., and Stromberg, P. C. (1990). Spleen, Lymph Van Rees, E. P., Sminia, T., and Dijkstra, C. D. (1996). Structure and Develop-
Nodes, and Thymus. In Pathology of the Fisher Rat (G. A. Boorman, S. L. ment of the Lymphoid Organs. In: Pathobiology of the Aging Mouse (U.
Eustis, M. R. Elwell, C. A. Montgomery Jr. and W. F. MacKenzie, eds.), Mohr, D. L. Dungworth, C. C. Capen, W. W. Carlton, J. P. Sundberg
pp. 369–83. Academic Press, San Diego. and J. M. Ward, eds.), Vol. 1, pp. 173–187. ILSI Press, Washington,
Valli, V. E., McGrath, J. P., and Chu, I. (2002). Hematopoietic System. In: D.C.
Handbook of Toxicologic Pathology (W. M. Haschek, C. G. Rousseaux Ward, J. M., Mann, P. C., Morishima, H., and Frith, C. H. (1999). Thymus,
and M. A. Wallig, eds.), Vol. 2, pp. 647–679. Academic Press, San Spleen, and Lymph Nodes. In Pathology of the Mouse (R. R. Maronpot,
Diego. ed.) pp. 333–60. Cache River Press, Vienna, Illinois.