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Normal Structure, Function, and Histology of Mucosa-Associated Lymphoid Tissue

Mark F. Cesta
Toxicol Pathol 2006 34: 599
DOI: 10.1080/01926230600865531

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Toxicologic Pathology, 34:599–608, 2006
Copyright

C by the Society of Toxicologic Pathology

ISSN: 0192-6233 print / 1533-1601 online

DOI: 10.1080/01926230600865531

Normal Structure, Function, and Histology of Mucosa-Associated

Lymphoid Tissue
MARK F. CESTA

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

ABSTRACT
The mucosa-associated lymphoid tissue (MALT) initiates immune responses to specific antigens encountered along all mucosal surfaces. MALT
inductive sites are secondary immune tissues where antigen sampling occurs and immune responses are initiated. Effector sites, present as diffuse
lymphoid tissue along all mucosal surfaces are the sites of IgA transport across the mucosal epithelium. Though there are many differences between
inductive sites in various organs, they all contain the same basic compartments—follicles, interfollicular regions, subepithelial dome regions, and
follicle-associated epithelium. The morphologic differences between MALT and other secondary lymphoid tissues, between the MALT sites of differing
anatomic locations, and species differences among laboratory animals are described. The morphologic changes in MALT associated with aging, route
of nutrition, and genetic mutation (i.e., the nude and SCID mutations) are also discussed. MALT tissues comprise the mucosal immune system which
can function independently of the systemic immune system and are, therefore, an important and often overlooked aspect of immunopathology.
Keywords. BALT, GALT, immunopathology, lab animal, MALT, morphology, mucosal immune system, NALT.

INTRODUCTION disseminated lymphoid tissue diffusely distributed through-

About half the lymphocytes of the immune system are in
the Mucosa-associated lymphoid tissue (MALT) (Croitoru
and Bienenstock, 1994). MALT is situated along the surfaces
of all mucosal tissues. Its most well-known representatives
are gut-associated lymphoid tissue (GALT), nasopharynx-
associated lymphoid tissue (NALT), and bronchus-associated
lymphoid tissue (BALT); however, conjunctiva-associated
lymphoid tissue (CALT), lacrimal duct-associated (LDALT),
larynx-associated (LALT) and salivary duct-associated lym-
phoid tissue (DALT) have also been described. The main
function of MALT is to produce and secrete IgA across mu-
cosal surfaces in antigen specific, Th 2-dependent reactions,
though Th 1 and cytotoxic T-cell mediated reactions can also
occur, the later resulting in immunotolerance (Gormley et al.,
1998; Kiyono and Fukuyama, 2004).
MALT can be functionally divided into effector sites and
inductive sites. GALT, BALT and NALT, CALT in mice, dogs,
(Giuliano et al., 2002) and baboons (Astley et al., 2003), and
DALT in cynomolgus macaques (Nair and Schroeder, 1986;
Sakimoto et al., 2002) are inductive sites. Inductive sites con-
tain secondary lymphoid tissues in which IgA class switching
and clonal expansion of B-cells occurs in response to anti-
gen specific T-cell activation. After activation and IgA class
switching, T- and B-cells migrate from inductive sites to ef-
fector sites. Effector sites are present in all mucosal tissues as
Address correspondence to: Mark F. Cesta, Integrated Laboratory Sys-
tems, Inc., 601 Keystone Park Drive, Suite 100, Durham, North Carolina
27713, USA; e-mail: mcesta@ils-inc.com
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 Laborato-
ries Inc., and the National Institute of Environmental Health Sciences with
preparation of photographs included in this paper.
This research was supported in part by the Intramural Research Program
of the NIH, National Institute of Environmental Health Sciences.
599
out the lamina or substantia propria (Yan et al., 2003). In ef-
fector sites, secretory IgA, or S-IgA (2 IgA molecules joined
by a J-chain and bound to secretory component, an epithelial
cell membrane receptor) is secreted across the mucosal ep-
ithelium (Pabst, 1987). In rodents, hepatocytes also produce
secretory component, so S-IgA also enters the gut lumen via
the bile duct (Pabst, 1987). The cellular composition of effec-
tor sites includes T-cells, the majority of which are CD4+ , IgA
plasma cells with fewer IgG and IgM plasma cells, and few B-
cells, dendritic cells, and macrophages (Pabst, 1987; Kelsall
and Strober, 1999; MacDonald, 2003). Though MALT sites
are anatomically separated, they are functionally connected
in what has been termed the “common mucosal immune sys-
tem,” so that antigen presentation and B-cell activation at one
mucosal site can result in IgA secretion at mucosal sites of
different organs (Bienenstock et al., 1999; Hiroi et al., 1998;
Kiyono and Fukuyama, 2004; Kuper et al., 2002). Further-
more, the mucosal immune system can act independently of
the systemic immune system making evaluation of MALT an
important aspect of immunopathology (Kuper et al., 2002).
Intraepithelial lymphocytes, T-lymphocytes found amid
epithelial cells of all mucosal tissues, are another component
of MALT. They are predominantly CD8+ and are relatively
abundant, typically with 1 lymphocyte per 4-6 epithelial cells
(Kelsall and Strober, 1999; Kuper et al., 2002; MacDonald,
2003; Pabst et al., 2005). They are somewhat unique, par-
ticularly in rodents, in that a large proportion of them ex-
press the γ δ TCR and many express the CD8αα homod-
imeric form of the CD8 receptor rather than the αβ TCR and
CD8αβ heterodimer found in most other CD8+ T-cell popu-
lations (Eberl and Littman, 2004; Kelsall and Strober, 1999;
Pabst et al., 2005; Saito et al., 1998). They also uniquely ex-
press the αE β7 integrin, which is thought to be important
for sequestering these lymphocytes in the epithelium (Kel-
sall and Strober, 1999; MacDonald, 2003). Evidence suggests
that these cells are generated in extrathymic locations in the

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600 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 1.—Peyer’s Patch, small intestine; Sprague–Dawley rat, male, 31 days old. General structure of a Peyer’s patch with a centrally located follicle (F)
containing a germinal center (GC) flanked by parafollicular or interfollicular regions (IFR). The germinal center is composed of a basal dark zone and an apical
light zone with the mantle zone or corona (C) of the follicle superficial to the light zone. The follicle-associated epithelium (FAE) is separated from the follicle by
the subepithelial dome region (SED). 2.—Peyer’s Patch, small intestine; Sprague–Dawley rat, male, 31 days old. The follicle-associated epithelium (FAE) contains
clusters of lymphocytes which may be associated with an M-cell. It is also slightly attenuated and has fewer goblet cells relative to the villous epithelium (VE).
The subepithelial dome region (SED) contains lymphocytes, macrophages, and dendritic cells. C = corona or mantle zone. 3.—Peyer’s patch, small intestine;

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Vol. 34, No. 5, 2006 MUCOSA-ASSOCIATED LYMPHOID TISSUE 601

intestinal mucosa, but this remains controversial (Saito et al., (Haley, 2003). B-cell areas are larger than T-cell areas, which
1998). is reflected in the T cell:B cell ratio of 0.2 (Sminia and Kraal,
This paper focuses on the normal morphology of the induc- 1999). The size, number, distribution, and composition of
tive sites of BALT, GALT, and NALT, and these terms will Peyer’s patches may vary depending on species or strain. For
be used to refer to these secondary lymphoid tissues. The example, Peyer’s patches are generally smaller in Fischer
functional compartments of these tissues are the lymphoid 344 rats than in Wistar rats (Bruder et al., 1999). The ratio of
follicles, the interfollicular region, the subepithelial dome re- CD4+ to CD8+ T-cells of 5.0 is approximately 2-fold higher
gion, and the overlying follicle-associated epithelium, or lym- in Peyer’s patches than in NALT or BALT (2.4 and 2.6, re-
phoepithelium, which contains M-cells (Figure 1). M-cells spectively) (Sminia and Kraal, 1999). In Lewis rats, however,
are specialized epithelial cells within the follicle-associated the ratios are nearly equal (Kuper et al., 1992).
epithelium that transport microorganisms, and macro- and Isolated lymphoid follicles, also located on the antimesen-
soluble molecules from the intestinal lumen to the subepithe- teric border of the small intestine, have been identified in
lial dome region giving the lymphoid tissues access to lumi- the rat, mouse, rabbit, and guinea pig (Hamada et al., 2002;
nal antigens (Gebert and Pabst, 1999; Kelsall and Strober, Lorenz and Newberry, 2004; Pabst et al., 2005). They are
1999). They are difficult to distinguish light microscopically smaller than Peyer’s patches with an average diameter of 150
but have a distinct ultrastructural appearance. The apical sur- microns and appear as barrel-shaped lymphoid aggregates
face of M cells is characterized by small, irregular, disor- in shortened intestinal villi and are typically associated with
ganized microvilli with a poorly developed brush border or a single dome (Pabst et al., 2005). They are very similar to
microfolds rather than the dense brush border of absorptive Peyer’s patches having 1-2 B-cell follicles that may contain
enterocytes (Gebert and Pabst, 1999; Kelsall and Strober, germinal centers and a small population of CD4+ T-cells,
1999). The basal membrane of M cells is invaginated, form- an overlying follicle-associated epithelium with M-cells, and
ing a pocket that typically contains one or more lymphocytes scattered dendritic cells with few macrophages, (Lorenz and
(T-cells or B-cells) and occasionally macrophages (Gebert Newberry, 2004; Pabst et al., 2005). Up to 200 isolated lym-
and Pabst, 1999; Pabst, 1987). Since there are no specific phoid follicles per mouse have been identified, though this
histochemical or immunohistochemical markers for M cells, number may vary depending on mouse strain. Hamada et al.
clusters of lymphocytes in the follicle-associated epithelium (2002) identified 150–200 per mouse in BALB/cA/Jcl and
may be the only light microscopic clue to the presence of an M 100–150 per mouse in C57BL/6J/Jcl. Isolated lymphoid fol-
cell. Other common features of MALT include the lack of af- licles are not present in neonatal mice, becoming consis-
ferent lymphatics and medullary regions and the presence of tently detectable in the duodenum and proximal jejunum
high endothelial venules (Figure 5) within the interfollicular by light microscopy at 7 days of age in BALB/cA/Jcl and
regions. The cellular components of MALT include B-cells, at 25 days of age in C57BL/6J/Jcl (Hamada et al., 2002).
CD4+ and CD8+ T-cells, antigen-presenting dendritic cells, According to Lorenz and Newberry, C57BL/6 mice have
macrophages, and, occasionally, mast cells and eosinophils fewer and smaller isolated lymphoid follicles that are located
in the interfollicular region. Thus, they contain all the cell predominantly in the distal small intestine and are not con-
types necessary to initiate an immune response. fined to the antimesenteric border (Lorenz and Newberry,
2004).
Cryptopatches, lymphoid aggregates found in the inter-
GUT-ASSOCIATED LYMPHOID TISSUE cryptal lamina propria of the small intestine, are small ag-
Several types of lymphoid nodules have been described gregates of T-cells and dendritic cells with an average diam-
in the intestine, including Peyer’s patches, isolated lymphoid eter of 80 µm (Eberl and Littman, 2004; Mowat and Viney,
follicles, cryptopatches, and, in the large intestine, lymphog- 1997; Pabst et al., 2005). They form after weaning and are far
landular complexes. Peyer’s patches and lymphoglandular more numerous than isolated lymphoid follicles and Peyer’s
complexes are the primary inductive sites in the gut, but the patches with up to 1700 per adult mouse (Eberl and Littman,
functions of the isolated lymphoid follicles and cryptopatches 2004). Studies suggest that cryptopatches are primary lym-
are unclear. phoid tissue in which extrathymic generation of intraepithe-
Peyer’s patches (Figures 1–5) are randomly distributed lial lymphocytes occurs, though this remains controversial
throughout the mucosa and submucosa of the gastrointesti- (Eberl and Littman, 2004; Saito et al., 1998).
nal tract but are of greatest density in the jejunum and are Lymphoglandular complexes (Figures 6 and 7) in the
oriented along the anti-mesenteric border (Schuurman et al., colon resemble Peyer’s patches, however, they are smaller
1994). The Peyer’s patch follicles in rodents typically con- and have fewer follicles with smaller germinal centers
tain 6-12 basally located germinal centers, which are more (Owen et al., 1991). Also, crypts extending into the colonic
numerous in Peyer’s patches than in either NALT or BALT submucosa that are lined by follicle-associated epithelium
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Sprague–Dawley rat, male, 31 days old. Germinal center of a Peyer’s patch follicle with apoptotic lymphocytes and tingible body macrophages. Germinal centers
also contain follicular dendritic cells, B-cell centrocytes and centroblasts, and few CD4+ T-cells. 4.—Peyer’s patch, interfollicular region; Sprague–Dawley rat,
male, 31 days old. The interfollicular region of a Peyer’s patch contains CD4+ T-cells, macrophages, interdigitating dendritic cells, few B-cells and plasma cells,
and high endothelial venules (H). 5.—Peyer’s patch, high endothelial venule; Sprague–Dawley rat, male, 31 days old. High magnification view of a high endothelial
venule, important in lymphocyte trafficking—note the lymphocytes attached to the endothelial cell surface. 6.—Lymphoglandular Complex. The general structure
is similar to a Peyer’s patch in the small intestine, but there is an invaginated crypt (IC) lined by goblet cell-poor follicle-associated epithelium in the interfollicular
region (IFR). FAE = follicle-associated epithelium, SED = subepithelial dome region, F = follicle.

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602 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 7.—Lymphoglandular complex, colon; Sprague–Dawley rat, male, 31 days old. The follicle-associated epithelium (FAE) of the colon contains even more
lymphocytes than that of the small intestine (Figure 2). Note the decreased numbers of goblet cells relative to the crypt epithelium (CE). Here, the subepithelial
dome region (SED) is difficult to distinguish from the corona (C). 8.—NALT; Sprague–Dawley rat, male, 31 days old. Location of NALT on the lateroventral floor
of the proximal nasopharyngeal duct (ND). NS = nasal septum, P = hard palate, ET = ethmoid turbinates. 9.—NALT; Sprague–Dawley rat, male, 31 days old. A
well-defined NALT follicle (F). The overlying follicle-associated epithelium (FAE) is attenuated and contains no goblet cells and fewer cilia relative to the respiratory
epithelium (RE). Several high endothelial venules (H) are present in the interfollicular region (IFR) at the edge of the follicle. A nerve (N) is present within the IFR.
ND = nasopharyngeal duct, P = hard palate. 10.—NALT; Sprague–Dawley rat, male, 31 days old. Germinal center (GC) within a NALT follicle. The subepithelial

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Vol. 34, No. 5, 2006 MUCOSA-ASSOCIATED LYMPHOID TISSUE
and surrounded by lymphoid tissue may occasionally be
evident (Figure 6) (Owen et al., 1991). In the mouse distal
colon, lymphoglandular complexes are randomly distributed
with an average of 1.4 patches per centimeter of colon
(Owen et al., 1991). Lymphoglandular complexes in the
proximal colon of the mouse and throughout the colon in
the rat are oriented toward the antimesenteric border (Deasy
et al., 1983; Morfitt and Pohlenz, 1989; Perry and Sharp,
1988). In mice, at least one lymphoglandular complex, the
rectal patch, can consistently be found within 10 mm of the
anus (Owen et al., 1991). The cecal patches, large aggregates
of lymphoid follicles in the proximal cecum opposite the
ileocecal valve, also have a consistent location (Owen et al.,
1991). In Fisher rats, the “proximal colonic lymphoid tissue”
is a lymphoid nodule that is consistently present in the
submucosa of the proximal colon roughly at the distal end
of the first fifth of the colon (Crouse et al., 1989).
Dogs have a total of 26–29 Peyer’s patches (HogenEsch
and Hahn, 2001). They have two types of Peyer’s patches, as
opposed to rats and mice that have uniform Peyer’s patches
(Haley, 2003). In the jejunum and upper ileum, the Peyer’s
patches of dogs are smaller and more discrete (similar to those
of mice and rats), while in the terminal ileum, there is a 26–30
cm long Peyer’s patch that completely encircles the distal
6–10 cm of the ileum and narrows proximally to a 1-cm-wide
band on the antimesenteric border (Haley, 2003; HogenEsch
and Hahn, 2001). The ileal Peyer’s patch has small domes and
interfollicular regions and an inconspicuous corona relative
to those of the duodenum and jejunum (HogenEsch and Fels-
burg, 1992). The duodenal Peyer’s patches differ in that they
have intrafollicular invaginations of the dome epithelium
(HogenEsch and Felsburg, 1992). The dome regions in dogs
contain more plasma cells than the dome regions in rats or
mice (Haley, 2003). Dogs have pinpoint to >2 mm diameter
lymphoid nodules throughout the gastric lamina propria,
most numerous in the fundic region, but these are not asso-
ciated with a follicle-associated epithelium (HogenEsch and
Hahn, 2001; Kolbjornsen et al., 1994). In rhesus macaques,
ileal Peyer’s patches are larger than those in the jejunum, duo-
denum, or colon (Veazey et al., 1997). In comparison to rat
Peyer’s patches, those of Baboons are smaller and they lack
the IgA+ centroblasts associated with the high endothelial
venules as described by Spencer et al. (Spencer et al., 1986).
Rabbits are unique in that they have an appendix, represented
as a large collection of lymphoid nodules at the ileocecal
valve, as well as a sacculus rotundus, which is a large,
circumferential Peyer’s patch in the terminal ileum (Haley,
2003).
Nasopharynx-Associated Lymphoid Tissue
NALT (Figures 8–12), found in rats, mice, hamsters, and
non-human primates, is composed of paired lymphoid aggre-
gates in the caudoventral portion of the left and right nasal
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
dome region (SED) is often inapparent and, as shown here, may contain numerous lymphocytes extending from the corona (C). ND = nasopharyngeal duct, RE =
respiratory epithelium, IFR = interfollicular dome region, H = high endothelial venule, F = follicle. 11.—NALT; Sprague–Dawley rat, male, 31 days old. High
endothelial venules (H) in the interfollicular region (IFR) of NALT at the margin of a follicle (F). NALT high endothelial venules more frequently extend to the
margin of the follicle than those of Peyer’s patches or BALT. N = nerve, P = hard palate. 12.—Comparison of follicle-associated epithelium of NALT (top) with
adjacent respiratory epithelium of the nasopharyngeal duct (bottom); Sprague–Dawley rat, male, 31 days old. The follicle-associated epithelium is attenuated, lacks
goblet cells, and has fewer cilia.
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603
passages at the entrance to the nasopharyngeal duct (Figure 8)
(Spit et al., 1989). It is visible in the caudal portions of level
II and throughout level III of the nasal cavity as sectioned for
toxicological studies performed by the National Toxicology
Program (Herbert and Leininger, 1999). NALT is consid-
ered the rodent equivalent to Waldeyer’s ring, the oro- and
nasopharyngeal lymphoid tissues (tonsils) found in humans
and some other species (Heritage et al., 1997). Though simi-
lar in appearance, there are a number of differences between
NALT and Peyer’s patches. There are fewer intraepithelial
lymphocytes In NALT (Sminia and Kraal, 1999). The rela-
tive sizes of the B- and T-cell areas are roughly equal to each
other in NALT, which is reflected in the higher T:B cell ratio
of 0.9 (Sminia and Kraal, 1999). Plasma cells are present pre-
dominantly in the connective tissues deep to the NALT (i.e.,
away from the nasal passage) (Sminia and Kraal, 1999). The
efferent lymphatic vessels and high endothelial venules ex-
tend deep into the interfollicular region to the follicular mar-
gins, the former confined to the basilar portion (Bienenstock
and McDermott, 2005; Kuper et al., 2002; Sminia and Kraal,
1999). Though macrophages and dendritic cells are scattered
throughout, dendritic cells in the subepithelial dome region
are less numerous than in Peyer’s patches (Sminia and Kraal,
1999). There are no significant species differences in NALT,
except that NALT in nonhuman primates is more extensive
than in rodents, extending to the lateral surface of the nasal
cavity (Haley, 2003).
Bronchus-Associated Lymphoid Tissue
There is a great deal of species variability in BALT. For
example, BALT is normally absent in dogs, cats, and Syrian
hamsters (Brownstein et al., 1980; Pabst and Gehrke, 1990).
Rabbits typically have the most BALT in regard to the num-
ber of BALT sites, followed by rats, guinea pigs, and mice
(Pabst and Gehrke, 1990). BALT is absent in germ-free pigs,
while germ-free rats have BALT, though much less than in
their conventionally reared counterparts (Bienenstock et al.,
1973; Pabst and Gehrke, 1990). The situation in mice (and
humans) is somewhat more controversial. There are conflict-
ing reports on the presence of BALT in germ-free mice (i.e.,
in the absence of antigenic stimulation). Bienenstock and
McDermott have reported the presence of BALT in germ-
free mice (Bienenstock and McDermott, 2005; Bienenstock
et al., 1999), but others report that BALT is not present in
germ-free in mice (Moyron-Quiroz et al., 2004; Seymour
et al., 2006). Furthermore, Pabst and Gehrke reported the
presence of BALT in only 43% of 4-month-old SPF mice
(Pabst and Gehrke, 1990), so the presence of BALT in mice
in general appears to be rather variable. Regardless of this is-
sue, BALT can be induced in mice by exposure to pathogens,
and this BALT, referred to as inducible BALT, or iBALT, by
some, has characteristics similar to BALT in other animals
(Moyron-Quiroz et al., 2004).
604 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 13.—BALT nodules along a primary bronchiole; Sprague–Dawley rat, male, 31 days old. The nodules are randomly distributed along the airways, but
there is a predilection for branching points. The nodules are typically located between the airway and an artery. 14.—BALT nodule; Sprague–Dawley rat, male, 31
days old. Submucosal lymphoid nodule with patchy overlying follicle-associated epithelium (FAE) lacking goblet cells and cilia. The interfollicular region (IFR) is
identified by the presence of high endothelial venules (H) but is otherwise difficult to distinguish from the follicle. A nerve (N) runs through each BALT nodule,
though it may not be present in all sections. SED = subepithelial dome region, A = alveolus, L = bronchiolar lumen, RE = respiratory epithelium, SM = smooth
muscle. 15.—BALT nodule; Sprague–Dawley rat, male, 31 days old. Higher magnification view of high endothelial venules (H) in the interfollicular region (IFR).

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Vol. 34, No. 5, 2006 MUCOSA-ASSOCIATED LYMPHOID TISSUE 605

BALT (Figures 13–16) is randomly distributed along the
airways but is most consistently located at sites of bronchial
tree bifurcation and is usually located between a bronchus
and an artery (Figure 13). Of the 3 main MALT sites,
BALT is the most divergent. The follicle-associated epithe-
lium of BALT contains the fewest intraepithelial lymphocytes
(Sminia and Kraal, 1999). Germinal centers and tingible body
macrophages are less common in BALT than either NALT or
Peyer’s patches (Sminia and Kraal, 1999). Follicular dendritic
cells, identified by ED5 staining, have been detected in GALT
and NALT, but not BALT (Kuper et al., 1992). The divisions
between the B- and T-cell areas are less conspicuous than
in Peyer’s patches and NALT and, in the rat, there does not
appear to be any consistent spatial relationship between the
two regions nor to surrounding structures (e.g., bronchus or
artery) (Breel et al., 1988; Sminia and Kraal, 1999). Similari-
ties do exist, however. For example, the relative sizes of the B-
and T-cell areas in BALT are roughly equal, and the T:B cell
ratio of 0.7 is comparable to that of NALT (Sminia and Kraal,
1999). The general structure and cellular composition of
BALT is also similar to NALT (Bienenstock and McDermott,
2005).
Tonsils
Tonsils are secondary lymphoid organs located in the oro-
and nasopharynx of most species except rodents. Dogs have 4
sets of tonsils, the lingual (diffuse lymphoid tissue at the cau-
dodorsal base of the tongue), palatine (on the lateral wall of
the pharynx just caudal to the palatoglossal arch), pharyngeal
(on the roof of the nasopharynx), and tubal (at the openings
of the auditory tubes) tonsils. Primates have at least 3 sets of
tonsils (in addition to NALT as described above), the lingual,
palatine, and pharyngeal, and may have tubal tonsils (as do
humans and all other domestic animals except rodents), but
descriptions of tubal tonsils in these species are lacking. Two
types of tonsils have been described, those with crypts (fol-
licular tonsils) and those without. Tonsilar crypts are blind,
often branched invaginations of the surface epithelium into
the submucosal lymphoid tissue. Tonsils without crypts typ-
ically have a slightly folded surface epithelium and bulge
into the oro-or nasopharynx (Banks, 1993). They are struc-
turally similar to Peyer’s patches but differ in the overlying
epithelium.
There are two types of epithelium overlying the tonsils:
reticular and non-reticular (Belz and Heath, 1995). Reticu-
lar epithelium is spongy in appearance and is located over
the apices of lymphoid follicles (Belz and Heath, 1995). It
contains M-cells, numerous lymphocytes, macrophages and
dendritic cells, and may contain a few granulocytes (Belz
and Heath, 1995; Bernstein et al., 1999). The non-reticular
epithelium, which separates islands of reticular epithelium,
is stratified squamous in the oropharynx (palatine and lin-
gual tonsils) and respiratory in the dorsal and some lateral
surfaces of the nasopharynx (pharyngeal and tubal tonsils).
The palatine tonsil is located in the palatine fossa, partially
covered by the semilunar fold.
NONPATHOLOGIC FACTORS AFFECTING
MALT MORPHOLOGY
Age
In general, MALT is relatively undeveloped at birth with
low cellularity. Upon stimulation after birth by exposure to
environmental antigens, especially the developing gut mi-
croflora, T-cell areas expand and become fully populated and
follicular germinal centers develop (as previously stated, ger-
minal centers are frequent in GALT, but relatively infrequent
in NALT and BALT). There are several differences in the
ontogeny of the MALT sites. In fetal animals, BALT is gen-
erally absent, but is present by 4 days of age, initially as a
few lymphocytes within a reticular stroma (Hameleers et al.,
1989; Pabst and Gehrke, 1990; Sminia and Kraal, 1999). In
contrast, Peyer’s patches are present before birth and NALT
is present at birth (Sminia and Kraal, 1999). T- and B-cell
regions do not develop in BALT until 3-4 weeks of age,
whereas distinct B- and T-cell areas are discernible at 10
days of age in both NALT and GALT (Hameleers et al.,
1989; Sminia and Kraal, 1999). Last, Peyer’s patches and
NALT are initially composed of T-cells, whereas B-cells are
the first lymphocytes to populate BALT (Sminia and Kraal,
1999).
Though much of the work on the effects of aging on
the mucosal immune system has focused on changes in
antibody production, evidence suggests that aging also al-
ters lymphocyte proliferative capacity (Taylor et al., 1992;
Schmucker et al., 2001; Schmucker, 2002). With age, the
number of Peyer’s patches does not change significantly,
however, in aged mice, but not rats, the Peyer’s patches do
have fewer T-cells in the interfollicular and parafollicular
regions relative to younger animals (Kawanishi and Kiely,
1989; Schmucker, 2002; Schmucker et al., 2001). The num-
ber of antibody-containing plasma cells in the Peyer’s patches
of mice and lamina propria of rats intraduodenally immunized
with cholera toxin decreases with age (Haaijman et al., 1977;
Taylor et al., 1992). There may also be decreased numbers of
B-cells and changes in the distribution of lymphocyte sub-
sets in the intestine, but evidence regarding changes in the
number of dendritic cells is conflicting (Schmucker, 2002;
Schmucker et al., 2001). None of these studies, however, re-
ported detectable, light microscopic changes, so even though

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
L = bronchiolar lumen, SM = smooth muscle, SED = subepithelial dome region. 16.—Comparison of the follicle-associated epithelium of BALT (top) with the
bronchial respiratory epithelium (bottom); Sprague–Dawley rat, male, 31 days old. The attenuated follicle-associated epithelium (FAE) is patchy and contains no
goblet or ciliated cells but does contain M cells, though they are not readily apparent with light microscopy. RE = respiratory epithelium, SED = subepithelial dome
region, SM = smooth muscle. 17.—Peyer’s patch, small intestine; BALB/cA nude mouse, 8 weeks old. The follicle (F) is well developed and contains numerous
B-cells, but high endothelial venules are not apparent in the interfollicular region (IFR) and lymphocytes numbers are decreased in the IFR, the subepithelial dome
region (SED), and the follicle associated epithelium (FAE). 18.—NALT; BALB/cA nude mouse, 8 weeks old. As with the PP in Figure 17, the follicular region (F)
is well developed, but the interfollicular region (IFR) is largely devoid of lymphocytes and high endothelial venules. FAE = follicle associated epithelium, RE =
respiratory epithelium, ND = nasopharyngeal duct, P = hard palate.

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606 CESTA TOXICOLOGIC PATHOLOGY

FIGURE 19.—NALT; NIH nude rat, 8 weeks old. NALT in nude rats is very similar to NALT in nude mice (Figure 18), but there are slightly more lymphocytes
in the interfollicular region (IFR). As in nude mice, the follicular region (F) and the follicle associated epithelium (FAE) are well developed. RE = respiratory
epithelium, ND = nasopharyngeal duct, P = hard palate. 20.—BALT; NIH nude rat, 8 weeks old. Similar to other MALT structures in nude mice and rats with
a well developed follicle (F) and follicle associated epithelium (FAE) and an interfollicular region (IFR) depleted of lymphocytes and high endothelial venules.
RE = respiratory epithelium. 21.—Peyer’s Patch, small intestine; CB-17 SCID mouse, 8 weeks old. Both the follicular region and interfollicular region are poorly
developed, difficult to distinguish from each other, and contain relatively few lymphocytes. The follicle associated epithelium (FAE) is proportionately decreased
in size. SED = subepithelial dome region. 22.—NALT; CB-17 SCID mouse, 8 weeks old. The follicular region and the interfollicular region are largely devoid of
lymphocytes and are poorly delineated. The follicle associated epithelium (FAE) is decreased in size. RE = respiratory epithelium, ND = nasopharyngeal duct.

cell numbers may be decreased, whether or not this is de-
tectable morphologically is unknown.
In dogs, Peyer’s patch precursors can be seen as small
aggregates of lymphocytes in intestinal villi in 45 day old
fetuses, but lymphoglandular complexes first appear in the
cecum 1 week after birth (HogenEsch and Hahn, 2001). In
50-day-old fetuses, the Peyer’s patches are much more well
developed with domes and submucosal follicles, however,
germinal centers do not form until 1 week of age (HogenEsch
and Hahn, 2001). The ileal Peyer’s patch expands rapidly after
birth, reaching maximal size by 6 months of age (HogenEsch
and Hahn, 2001). Upon reaching sexual maturity, the follicles
of the canine ileal Peyer’s patch become markedly reduced
in size (HogenEsch and Hahn, 2001).
Route of Nutrition
Administration of total parenteral nutrition (TPN) has been
shown to affect GALT, decreasing lymphocyte numbers in
both rats and mice (Tanaka et al., 1991; King et al., 1997).
In mice, both B and T cells in Peyer’s patches and lamina
propria and the intraepithelial lymphocytes decreased sig-
nificantly after 2 days of receiving TPN with the maximal
decrease in the lamina propria occurring after 2 days and in
the Peyer’s patches after 3 days (King et al., 1997). These
Peyer’s patches and lamina propria changes were shown to
be reversible in mice after returning to enteral nutrition and
returned to control levels after 2 days (King et al., 1997). The
intraepithelial lymphocytes responded much more slowly and
by day 5, had not yet returned to normal levels (King et al.,

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Vol. 34, No. 5, 2006 MUCOSA-ASSOCIATED LYMPHOID TISSUE
1997). Histologic evaluation of rats receiving TPN revealed
markedly atrophied Peyer’s patches and restriction of intraep-
ithelial lymphocytes to the basal third of the intestinal villi
(some intraepithelial lymphocytes were noted in the distal
two-thirds of the villi in control rats) (Tanaka et al., 1991).
MALT in Immunodeficient Mutant Mice and Rats
There are a number of immunodeficient mutant mice and
rats, both naturally occurring and genetically engineered, in
which the morphology of MALT is altered. In SCID mice
(Figures 21 and 22), which are deficient in both B- and T-
cells, the lymphoid structures of the gut and lung are very
small (almost nonexistent) and disorganized with sparsely
scattered lymphoid cells of variable size, often appearing im-
mature (Custer et al., 1985). Effector sites are similarly af-
fected, as exemplified by the relative lack of immune cells in
the lamina propria of the intestine. This phenotype, however,
may vary with background strain and age, as the SCID mu-
tation is “leaky” and these mice may develop more B- and
T-cells later in life. Athymic nude rats and mice (Figures 17–
20), being T-cell deficient, have decreased numbers of in-
traepithelial lymphocytes and depleted T-cell regions (inter-
follicular/parafollicular regions) (Hanes, 2005; Rocha et al.,
1994) which, in nude rats at least, have increased numbers of
macrophages. Also, since the formation of germinal centers
requires T-cell activity, nude rats and mice are typically de-
void of germinal centers (Hanes, 2005). Other components of
the lymphoid structures in these animals are variably present.
For example, in both SCID and nude animals, the stromal
cells of the lymphoid structures are comparable in number
and appearance to those of immunocompetent strains (Custer
et al., 1985; Hanes, 2005). RAG1−/− mice, a genetically en-
gineered mutant deficient in B- and T-cells similar to SCID
mice, have limited follicle associated epithelium and fewer M
cells, but both are present and associated with small Peyer’s
patch anlagen (MacDonald, 2003).
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