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Normal Structure, Function, and Histology of the Spleen

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

Correspondence: Address correspondence to: Mark F. Cesta, Integrated Laboratory Systems, Inc., 601 Keystone Park Drive, Suite 100, Durham, NC 27713, USA; e-mail:mcesta{at}ils-inc.com

	Abstract

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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.

Key Words: Immunopathology • lab animal • marginal zone • morphology • red pulp • spleen • white pulp

	Introduction

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The spleen is a dark red to blue-black organ located in the left cranial abdomen. It is adjacent to the greater curvature of the stomach and within the omentum. It is an elongated organ, roughly triangular in cross section. The gross appearance and size of the spleen are variable, depending on the species and the degree of distension; nonetheless, spleen weights can be important in its evaluation. The ratio of splenic weight to body weight remains fairly constant regardless of age and, in rats, is typically around 0.2% (Losco, 1992).

The functions of the spleen are centered on the systemic circulation. As such, it lacks afferent lymphatic vessels. It is comprised of 2 functionally and morphologically distinct compartments, the red pulp and the white pulp (Figures 1 and 2). The red pulp is a blood filter that removes foreign material and damaged and effete erythrocytes. It is also a storage site for iron, erythrocytes, and platelets. In rodents, it is a site of hematopoiesis, particularly in fetal and neonatal animals. The spleen is also the largest secondary lymphoid organ containing about one-fourth of the body’s lymphocytes and initiates immune responses to blood-borne antigens (Kuper et al., 2002; Nolte et al., 2002; Balogh et al., 2004). This function is charged to the white pulp which surrounds the central arterioles. The white pulp is composed of three sub-compartments: the periarteriolar lymphoid sheath (PALS), the follicles, and the marginal zone.

View larger version (138K): [in this window] [in a new window]   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.

View larger version (916K): [in this window] [in a new window]   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.

View larger version (916K): [in this window] [in a new window]   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.

Venous sinuses can be found throughout the red pulp, including, as mentioned previously, directly adjacent to the marginal zone (Figure 8). They are lined by loose network of endothelial cells which sit on a basement membrane that is sandwiched between the endothelial cells and reticular fibers of the red pulp (Saito et al., 1988). The penicillar arteries and arteriolar capillaries are also located in the red pulp, though they are more difficult to identify light microscopically.

Various pigments may be present in the spleen. Hemosiderin deposits in the cytoplasm of macrophages in the red pulp, and sometimes in the white pulp as well, are a typical finding (Figure 9). In fact, iron pigments (i.e., hemosiderin and ferritin) are the most common pigments in the macrophages of the red pulp (Losco, 1992). Iron from the hemoglobin of phagocytized erythrocytes is converted to hemosiderin for storage in the spleen. According to historical control data from the National Toxicology Program (NTP), hemosiderin pigmentation is more prevalent in females than in males (Ward et al., 1999). Ceroid and lipofuscin derived from oxidation of lipids is also typically found in the spleen, though they are less abundant than hemosiderin (Ward et al., 1999). Melanocytes containing melanin may be present in the spleen, particularly in black mice, usually in the trabeculae or focally in the red pulp (Ward et al., 1999).

White Pulp
The white pulp is subdivided into the PALS, the follicles, and the marginal zone (Figures 3, 4, and 5). It is composed of lymphocytes, macrophages, dendritic cells, plasma cells, arterioles, and capillaries in a reticular framework similar to that found in the red pulp (Saito et al., 1988). As the central arterioles enter the red pulp, they are surrounded by the PALS which are composed of lymphocytes and concentric layers of reticular fibers and flattened reticular cells (Dijkstra and Veerman, 1990; Satodate et al., 1986). The PALS are divided into the inner PALS and the outer PALS (Matsuno et al., 1989; Nicander et al., 1993; Van Rees et al., 1996). The inner PALS, a T-cell dependent region, may stain slightly more intensely than the outer PALS due to its cellular composition of predominantly small lymphocytes (Dijkstra and Veerman, 1990; Matsuno et al., 1989). The difference, however, is not uniformly present and is generally very subtle and difficult to detect by light microscopy (Stefanski et al., 1990). The cells of the inner PALS are largely CD4+ T-cells, though smaller numbers of CD8+ T-cells may also be present, as well as interdigitating dendritic cells, and migrating B-cells (Van Rees et al., 1996). The outer PALS is populated by small and medium lymphocytes (both B- and T-cells), macrophages, and, upon antigenic stimulation, plasma cells (Matsuno et al., 1989; Van Rees et al., 1996). It is an important site of lymphocyte traffic where the formation of plasma cells occurs (Dijkstra and Veerman, 1990; Matsuno et al., 1989).

View larger version (1518K): [in this window] [in a new window]   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.

View larger version (1084K): [in this window] [in a new window]   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.

Marginal Zone
The marginal zone is a unique region of the spleen situated at the interface of the red pulp with the PALS and follicles (Figure 6). Considered by many to be a separate compartment rather than part of the white pulp, it is designed to screen the systemic circulation for antigens and pathogens and plays an important role in antigen processing (Kuper et al., 2002; Mebius and Kraal, 2005). A band of macrophages, the marginal zone metallophilic macrophages, and the marginal sinus (Dijkstra and Veerman, 1990; Mebius and Kraal, 2005; Satodate et al., 1986), separate the marginal zone from the PALS and follicles. The marginal zone metallophilic macrophages are a unique subset of macrophages at the inner margin of the marginal zone adjacent to the PALS and follicles (Dijkstra and Veerman, 1990; Matsuno et al., 1989; Mebius and Kraal, 2005). They can be visualized by silver staining and with the monoclonal antibody MOMA-1 (Mebius and Kraal, 2005). Adjacent and peripheral to the marginal zone metallophilic macrophages is the marginal sinus. It is continuous with vessels that feed the capillary beds of the PALS and follicles and is lined by MADCAM1+, sinus-lining endothelial cells (Mebius and Kraal, 2005). Peripheral to the marginal sinus, is the thick outer ring of the marginal zone, composed of reticular fibroblasts, marginal zone macrophages, dendritic cells, and medium sized marginal zone B-cells (Dijkstra and Veerman, 1990; Mebius and Kraal, 2005). The marginal zone blends into the red pulp. The marginal zone macrophages are another population of splenic macrophages that stain with the monoclonal antibody ERTR-9 (Van Rees et al., 1996). While all the potential functions of the marginal zone metallophilic macrophages are not known, the marginal zone macrophages are important in clearance of microorganisms and viruses. They express a number of pattern recognition receptors such as toll-like receptors (TLRs) and the macrophage receptor with collagenous structure (MARCO), which are important in the uptake of various bacteria (Mebius and Kraal, 2005). The marginal zone B-cells are a unique subset of noncirculating B-cells that have an IgM+/IgD– phenotype as opposed to follicular B-cells which are IgM+/IgD+ (Van Rees et al., 1996).

View larger version (584K): [in this window] [in a new window]   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.

Vascular arrangements are perhaps the greatest source of species variation in splenic architecture. Species variation in the structure and morphology of the venous sinuses forms the basis for the classification of spleens into two groups, sinusal spleens and nonsinusal spleens (Schmidt et al., 1985a). Sinusal spleens are found in rats and dogs and nonsinusal spleens are found in mice (Schmidt et al., 1985a). The venous sinuses of sinusal spleens are larger, more abundant, make numerous anastamoses, and have a characteristic wall structure relative to the venous sinuses of nonsinusal spleens (for an in depth description of these differences, see Snook (1950) and for more detail on the wall structure of each vessel type, see Blue and Weiss (1981) (Schmidt et al., 1985a). The venous sinuses of nonsinusal spleens are so different, in fact, that some investigators use the term pulp venules rather than venus sinuses (Schmidt et al., 1985a). The larger venous sinuses of the rat spleen are far more conspicuous than those of the mouse spleen.

There are also species differences in the arterial vasculature. Schmidt et al. have reported that, in dogs, the arterial capillaries both terminate in the reticular meshwork (open circulation) and empty directly into the venous sinuses with no interruption of the endothelial lining (closed circulation) (Schmidt et al., 1982, 1983, 1993). In dogs, but not rats, the arterial capillaries are surrounded by dense, circumferential clusters of macrophages known as ellipsoids or periarterial macrophage sheaths (PAMS) (Blue and Weiss, 1981; Satodate et al., 1986). In dogs, there are very few capillaries within the PALS, as opposed to rats and mice where the PALS have abundant capillaries (Schmidt et al., 1983, 1985a, 1985b, 1993).

Extra medullary hematopoiesis is more prevalent in spleens of mice than rats. In dogs, hematopoietic tissue is present in the spleen in pathologic conditions such as neoplasia and anemia, but may be present in the absence of underlying disease (HoganEsch and Hahn, 2001). When the hematopoietic tissue is predominantly myeloid, the term myeloid hyperplasia may be applied. The incidence of splenic myeloid hyperplasia in the absence of underlying disease was 4% in beagle dogs in one study (HoganEsch and Hahn, 2001).

Though there is a lot of individual variation, mice tend to have a greater proportion of white pulp than rats, but the follicles and marginal zone of mice are less distinct than those of rats (Figures 1, 2, and 7) (Ward et al., 1999). In rats, the marginal zone comprises up to 28% of the splenic volume and is the largest B-cell region in the spleen (Dijkstra and Veerman, 1990; Schmidt et al., 1993). Approximately one-third of the B-cells in the rat spleen have the marginal zone B-cell phenotype, whereas in the mouse, only 15% of the splenic B-cells have this phenotype (Van Rees et al., 1996). Though the region where the marginal sinus is located is more consistently discernible in rats, electron microscopic studies show that the marginal sinus is up to 6 times larger in mice (Schmidt et al., 1993).

View larger version (583K): [in this window] [in a new window]   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.

Numerous references discuss the effects of aging on lymphocyte function and changes in the distribution of lymphocyte subsets. Lymphocyte numbers, however, may also decrease with age. One study showed a greater than 80% decrease in lymphocyte numbers in the white pulp of Fisher rats between 4 and 30 months of age (Cheung and Nadakavukaren, 1983). This change corresponded, light and electron microscopically, to a decrease in lymphocyte density in the white pulp (Cheung and Nadakavukaren, 1983). There was also an increase in the number of reticular cells and macrophages in the same regions (Cheung and Nadakavukaren, 1983). Some degree of white pulp atrophy is also a common aging change in Sprague–Dawley rats (Losco, 1992). The spleens of older dogs and rodents typically have fewer germinal centers (HoganEsch and Hahn, 2001; Losco, 1992).

Extra medullary hematopoiesis tends to be decreased in adult animals, but can increase in any animal when there is increased demand for these cells as in cases of anemia, inflammation, decreased production by the bone marrow, or in cases of neoplasia (Losco, 1992). The amount of hemosiderin present in the spleen tends to increase with age in both rodents and dogs (HoganEsch and Hahn, 2001; Losco, 1992; Van Rees et al., 1996) and, in mice, is more prevalent in females than males (Ward et al., 1999).

Genetics
Genetic mutations in rats and mice, either spontaneous or engineered, resulting in immunodeficiency markedly affect the morphology of the spleen. Among the immunodeficient strains, nude rats and SCID (severe combined immunodeficiency disease) mice are perhaps the best known and most commonly used in scientific studies. Nude rats are congenitally athymic and so are deficient in T-lymphocytes. The spleens of nude rats (and mice) are smaller than those of their wild-type counterparts. They have sparsely populated PALS regions and, since T-cell activity is required for the formation of germinal centers, lack secondary follicles (Figures 11 and 12) (Bell et al., 1987; Hanes, 2005). SCID mice are homozygous for the Prkdc^scid mutation, a mutation in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) (Perryman, 2004; Seymour et al., 2006). This results in a defect in V(D)J recombination of T-cell receptors and B-cell immunoglobulin receptors and a lack mature B- and T-cells (Perryman, 2004). The spleens of SCID mice are smaller than those of wild-type mice and all three regions of the white pulp contain few lymphocytes but do contain macrophages (Custer et al., 1985). The follicles are variable in size and contain occasional plasma cells, however, follicular dendritic cells are absent since B and T cells are required for the development of these cells (Custer et al., 1985; Seymour et al., 2006). The marginal zone is markedly decreased in size and is poorly demarcated from the PALS and follicles (Figure 13). In both the SCID and nude mutants, the reticular framework of the sparsely populated white pulp is intact (Custer et al., 1985; Hanes, 2005).

View larger version (1024K): [in this window] [in a new window]   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.

	Acknowledgments

 
This work was supported by NIEHS contracts N01ES35513 and N01ES95435. The author wishes to acknowledge the assistance of the staffs of Integrated Laboratory Systems Inc., Experimental Pathology Laboratories Inc., and the National Institute of Environmental Health Sciences with preparation of photographs included in this paper and the helpful comments from Dr Jerrold Ward.

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Toxicologic Pathology, Vol. 34, No. 5, 455-465 (2006)
DOI: 10.1080/01926230600867743


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