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,§,§,§,§
Departments of
*
Pathology and
Medicine, Harvard Medical School, Boston, MA 02115; and
Department of Pathology and
§
Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and TNF-
play central roles in the mastocytosis
(9, 12, 13, 16, 18). Other T cell-derived factors such as
IL-9 (19, 20, 21) are needed to instruct the expanded
population of MCs in the jejunal epithelium to produce mouse MC
protease-1 (mMCP-1), mMCP-2 (14, 22, 23, 24), and other
mediators. During the recovery phase of a Trichinella spiralis infection that occurs at weeks 2–5, the excess eosinophils and MCs slowly disappear from the jejunum. The MCs initially disappear from the upper villi, and at least some of these cells migrate laterally and downward toward the submucosa (14). Apoptotic MCs are rare but have been found in the jejunum of helminth-infected rats (25), and glucocorticoid treatment of helminth-infected mice results in the rapid engulfment of at least a portion of these jejunal MCs by resident macrophages (26, 27). Because MCs developed in vitro with IL-3 spontaneously undergo apoptosis when their viability-enhancing factors are removed from the culture medium (28), it has been assumed that most jejunal MCs undergo apoptosis locally once the pathogen-specific T cells cease to be prominent in the intestine after the adult T. spiralis helminths are expelled.
Mouse MCs store in their granules various combinations of a carboxypeptidase (29) and at least 13 serine proteases (designated granzyme B, cathepsin G, mMCP-1 to mMCP-10, and transmembrane tryptase) (22, 23, 30, 31, 32, 33, 34, 35, 36, 37, 38). MCs take a number of days to turn over their granule constituents (39). Thus, the particular panel of neutral proteases that a MC expresses in the BALB/c mouse at any time in this cell’s life span appears to be dictated by the combination of regulatory factors the MC encounters in both its current and previous microenvironments (14, 15, 39, 40, 41, 42, 43). For example, the v-abl-immortalized V3 MC line expresses mMCP-1 and mMCP-2 when this mMCP-1-/mMCP-2- cell line is adoptively transferred into the jejunum of normal BALB/c mice (43). We previously reported that the MCs in the jejunum of T. spiralis-infected BALB/c mice undergo time- and strata-dependent changes in their expression of mMCP-1, mMCP-2, mMCP-5, mMCP-6, mMCP-7, and mMCP-9 (14, 15). Using a variety of approaches, we now report that during the recovery phase of T. spiralis infection, many of the expanded jejunal MCs and eosinophils exit the intestine and preferentially translocate to spleen and draining lymph nodes, respectively.
Metachromatic cells that express the high-affinity IgE receptor have been found in the blood of humans with various allergic disorders that have some features of MCs (e.g., surface expression of CD117 (c-kit) and granule expression of chymase, carboxypeptidase A, and multiple tryptases) and some features of basophils (e.g., blood location, segmented nuclei, and surface expression of Bsp-1) (44). Although most mouse MCs possess a large, centrally positioned, nonsegmented nucleus, some occasionally possess segmented nuclei (45). We now report that many of the senescent MCs in the intestine of T. spiralis-infected mice undergo sequential changes in their nuclear profiles as they make their way to the spleen. Thus, in this model system, nuclear segmentation of the T cell-dependent population of MCs that expands in the jejunum during a helminth infection is an early indicator of senescence.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were infected orally with 400 freshly isolated stage-3 T. spiralis larvae, as described (14, 15, 41). Mice were killed at various times after helminth infection. The jejunum, large intestine (i.e., cecum; ascending, transverse, and descending colon), spleen, liver, draining mesenteric lymph nodes, and ear were removed and fixed for analysis. All mouse MCs that have been examined to date in fixed, dehydrated, and embedded tissues contain abundant levels of chloroacetate esterase activity (14). Thus, with a modification (46) of the enzyme cytochemistry procedure of Leder (47), fixed tissue sections were incubated at 30°C for 1 h with a solution containing naphthol AS-D chloroacetate. The tissue preparations were rinsed and counterstained with hematoxylin. For histochemical identification of eosinophils, appropriate sections were stained with hematoxylin/eosin/azure II, which stains eosinophils pink (46), or with Congo red, which stains eosinophils orange (48). Wright Giemsa stain was also used in some tissue sections to identify all granulocytes.
For MC immunohistochemistry, tissue sections from noninfected and T. spiralis-infected mice were stained with immunoalkaline phosphatase, as described (14, 15, 49). Collected tissues were fixed for 4 h at room temperature in 4% paraformaldehyde in 0.1 M sodium phosphate (pH 7.6), were washed twice with PBS containing 2% DMSO, and were suspended in 50 mM NH4Cl overnight at 4°C. The specimens were dehydrated and embedded in accordance with the JB-4 kit from Polysciences (Warrington, PA). Sections were cut on a Reichert-Jung Supracut microtome (Leica, Deerfield, IL) with glass knives and were picked up on glass slides. The slides were incubated sequentially for 15 min at 37°C in 2 mM CaCl2 containing 0.025% trypsin, for 15 min at room temperature in PBS containing 0.05% Tween 20 and 0.1% BSA, for 30 min at 37°C in PBS containing 0.05% Tween 20 and 4% normal goat serum, and then overnight at 4°C in 4% normal goat serum containing purified rabbit anti-mMCP-2 Ig (39) or rabbit anti-mMCP-9 Ig (36). The Abs specific for mMCP-2 and mMCP-9 were obtained previously against synthetic peptides that correspond to residues 56–71 and 144–152 in the respective serine protease. Samples were washed, incubated for 40 min at room temperature in buffer containing biotin-labeled goat anti-rabbit IgG, washed twice in 0.1% BSA and 0.05% Tween 20 in PBS, incubated for 40 min at room temperature in Vectastain ABC-AP reagent (Vector Laboratories, Burlingame, CA), and then incubated for 15 min in the dark at room temperature in an alkaline phosphatase substrate solution. After the tissue sections were counterstained with Gill’s hematoxylin in 20% ethylene glycol, coverslips with Immu-Mount (Shandon, Pittsburgh, PA) were applied.
The v-abl-immortalized V3 cell line (43) was used to confirm that viable MCs could leave a tissue site and translocate to the spleen. In these experiments, one to four million V3 MCs were injected into either the tail vein or the peritoneal cavity of a BALB/c mouse. Two weeks after the adoptive transfer of this immortalized cell line, the chloroacetate enzyme cytochemistry procedure was used to evaluate the movement of the foreign V3 MCs into the spleen and liver of the recipient mice.
Apoptosis and proliferation assays
Three procedures were used to identify MCs and eosinophils in different stages of apoptosis. MCs in their very late stages of apoptosis were identified by the immunoalkaline phosphatase/Gill’s hematoxylin procedure, which stains mMCP-2+/mMCP-9+ granules red and the condensed and/or fragmented nucleus dark blue. MCs in their late stages of apoptosis also were identified by the Masson’s trichrome staining procedure (50), which stains the granules and apoptotic nuclear bodies of intraepithelial MCs bright orange and jet-black, respectively. Serial sections were used to identify MCs in their earlier stages of apoptosis. In this assay, one tissue section is stained with hematoxylin/eosin/azure II, Congo red, anti-mMCP-2 Ig, or anti-mMCP-9 Ig. The adjacent tissue section is then subjected to the TUNEL biochemical assay (51) with a kit from Boehringer Mannheim (Indianapolis, IN). The TUNEL assay preferentially labels genomic DNA that has been cleaved in a caspase-dependent pathway. The Congo red and TUNEL assays also were used to identify apoptotic eosinophils.
Proliferating cells in the spleen of helminth-infected BALB/c mice were identified immunohistochemically with a mouse anti-bromodeoxyuridine (BrdU) monoclonal Ab (52) from Boehringer Mannheim. Two weeks after mice were infected with T. spiralis, 1 ml of a 5-mg/ml solution of BrdU in a pH 7.0 buffer was injected i.p. 6 h and then again 2 h before the animals (n = 2) were killed and their spleens analyzed. After standard fixation, embedding, and serial sectioning of the tissue, those cells in the spleen that had incorporated BrdU into their genomic DNA were identified immunohistochemically using the mouse anti-BrdU and goat anti-mouse Abs (Vector Laboratories). MCs were identified in the subsequent serial section with the chloroacetate esterase cytochemistry procedure.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although most of the chloroacetate
esterase+/mMCP-2+ MCs in
the mouse intestine at the height of the T. spiralis
infection at week 2 resided in the jejunum, increased numbers of these
cells were also found in epithelium of the large intestine (Fig. 1
). The MCs in the large intestine at
this time point were generally large in size. Although most of these
cells possessed a centrally positioned, large-sized, nonsegmented
nucleus, a few possessed crescent-shaped, eccentric nuclei. MCs in
various stages of apoptosis at this time point in the infection were
rarely detected. However, during the recovery phase of the infection at
weeks 3–5, nearly all of the chloroacetate
esterase+/mMCP-2+ MCs in
the large intestine exhibited noticeable morphologic changes. Many were
substantially smaller in size. Although a few of these cells possessed
the crescent-shaped, eccentric nuclei seen at the height of the
infection, most contained either a segmented/bilobed nucleus or a
condensed nucleus typical of a cell undergoing the late stages of
apoptosis. This continuum of morphologic changes suggests not only that
most of the expanded MCs residing in the large intestine undergo
apoptosis locally but also that nuclear segmentation is an early
indicator of MC senescence.
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). MCs were occasionally detected
in the lumen during the recovery phase of the infection (Fig. 3). Some mMCP-2+
MCs with condensed nuclei typical of cells undergoing apoptosis were
found in the epithelium at this time point. Moreover, MCs in their
earlier stages of apoptosis also were occasionally seen at this
location with the TUNEL assay. Nevertheless, unlike the proportion in
the large intestine during the recovery phase of the helminth infection
(Fig. 1
), <5% of the >1000 MCs examined in the jejunum in these
varied assays were in their early or late stages of apoptosis. In
addition, nearly all of these apoptotic MCs resided in the epithelium
rather than in the lamina propria or submucosa (Fig. 3, b
and e). Macrophages that had engulfed apoptotic MCs were not
detected in the jejunum. The discovery that more MCs were detected in
the lamina propria during the recovery phase of the infection (Figs. 2c and 3f) than at the height of the infection
(Fig. 2b) is consistent with the previous granule
morphologic data (14) that had indicated that at least
some of the intraepithelial MCs migrated into the lamina propria. The
pronounced motility of these MCs raised the possibility that they had
the ability to exit the jejunum.
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, d–f). However, in contrast to where the MCs localized, the
eosinophils resided in either the submucosa or lamina propria of the
lower villus. None appeared in the epithelium. With the TUNEL assay,
apoptotic eosinophils were rarely found in the jejunum at any time
point during the infection. Moreover, only rarely could a macrophage be
detected in the jejunum that had engulfed an apoptotic eosinophil (data
not shown). These findings also raised the possibility that many of the
excess jejunal eosinophils were translocating to a different
tissue site. Translocation of jejunal eosinophils to the draining lymph nodes and jejunal MCs and V3 MCs to the spleen
During the recovery phase of the helminth infection, the
mesenteric draining lymph nodes contained large numbers of eosinophils
but very few MCs (Fig. 4). When a MC was
detected, it generally was small in size and possessed a segmented
nucleus. As assessed histochemically, many of the eosinophils in the
lymph nodes had apoptotic nuclei. Moreover, many macrophages in the
lymph nodes had phagocytosed apoptotic cells, including
eosinophils.
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). This new finding raised the
possibility that the spleen was a major repository for the disappearing
jejunal MCs. The number of MCs in the spleen at week 4 was >10-fold
higher than the number in the spleen of noninfected mice or mice that
had been exposed to the helminth for just 1 wk (Fig. 6). Kinetic experiments revealed that the
rise in MC numbers in the spleen occurred when MCs began to disappear
in the jejunum. At no time were MCs detected in the liver of a
helminth-infected animal. At week 2 of the infection, when MCs began to
increase in number in the spleen, analysis of serial-sectioned tissue
revealed a notable absence of MCs that incorporated BrdU into their
genomic DNA (Fig. 7). The fact that the
MCs were evenly dispersed throughout the sinusoids (Fig. 8) rather than in clusters of two or more
also implied that the increased number of MCs in this organ at 4 wk was
not the result of local proliferation of a MC-committed progenitor in
the spleen.
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). MCs that expressed mMCP-2 and mMCP-9 (Fig. 9) also were occasionally found in the
lumen of the blood vessels in contiguity with splenic sinusoids.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. spiralis infects the small intestine of the mouse to
elicit a T cell-dependent (8) eosinophilia and
mastocytosis in the jejunum (Figs. 2 and 6). A less pronounced
mastocytosis occurs in the large intestine (Fig. 1). Although larvae
become encysted in skeletal muscle, mice are able to expel the adult
nematode from the intestine if the load of experimentally introduced
T. spiralis is not excessive. During the recovery phase of
the infection at weeks 2–5, the number of MCs in the jejunum slowly
and progressively decreases to baseline (Fig. 6). The secondary
eosinophilia in the jejunum around day 28 is more systemic and
coincides with the peak of T. spiralis larvae encystment in
skeletal muscle. Despite the dramatic fall in the number of eosinophils
during weeks 2–3, we were unable to detect many apoptotic eosinophils
in the jejunum. Large numbers of apoptotic intraepithelial MCs were
found in the large intestine (Fig. 1), but only a few apoptotic MCs
were found in the jejunal epithelium (Fig. 3). Even at that latter
site, <5% of the intraepithelial MCs at any time during the infection
were in their early or late stages of apoptosis. Dying MCs also were
rarely seen in the jejunal lamina propria or submucosa, even though
most jejunal MCs resided in these sites at weeks 2–4. In rats infected
with the tapeworm Hymenolepis diminuta, the number of
apoptotic MCs in the jejunum never exceeds 3% (25). Thus,
our failure to see large numbers of apoptotic MCs in the jejunum of the
T. spiralis-infected BALB/c mouse does not appear to be a
consequence of the animal or parasite used in these studies.
The fact that most MCs and eosinophils in the small intestine were not
apoptotic or necrotic could be a consequence of their rapid engulfment
and destruction by jejunal macrophages. Macrophages that had engulfed
an eosinophil and/or lymphocyte were occasionally found in the jejunum.
However, our failure to detect large numbers of macrophages in the
lamina propria or submucosa of the jejunum with remnants of eosinophil
or MC granule constituents suggested that during the recovery phase of
the helminth infection most senescent jejunal eosinophils and MCs are
able to escape engulfment by jejunal macrophages. The phagocytosis of
apoptotic neutrophils and eosinophils by macrophages is mediated by
CD36, thrombospondin, and the
Vß3 integrin
(53, 54). The
Vß3 integrin
recognizes vitronectin and fibrinogen. Inasmuch as both vitronectin and
fibrinogen inhibit the macrophage-mediated apoptosis of senescent
neutrophils in vitro, it is possible that senescent MCs and eosinophils
escape apoptosis in the jejunum because of increased deposition of
vitronectin and/or fibrinogen at this site. Alternately, the jejunal
MCs and eosinophils might not express one of the ligands for the
apoptotic regulatory proteins.
The failure to detect appreciable numbers of apoptotic jejunal MCs and
eosinophils at wk 4, coupled with the previous observation that MCs
migrate in the various strata of the intestine during the infection
(14), raised the possibility that most senescent MCs and
eosinophils translocate from the jejunum to another tissue site. During
the recovery phase of helminth infection, the draining lymph nodes
contained large numbers of eosinophils but, surprisingly, very few MCs
(Fig. 4). At day 11 in the infection, the spleen and lymph nodes
contained 
3- and >100-fold more eosinophils, respectively, than the
corresponding tissue in a noninfected mouse (Fig. 6). The additional
finding that many of the eosinophils in the lymph nodes were undergoing
apoptosis and were being engulfed by macrophages (Fig. 4) now indicates
that draining lymph nodes are graveyards for most of the senescent
eosinophils that leave the jejunum.
The failure to see comparable numbers of MCs in the draining lymph
nodes and the failure to see macrophages that had engulfed apoptotic
MCs (Fig. 4) suggest that the MCs that leave the jejunum lack the
necessary complement of adhesion receptors to be physically retained in
the draining lymph nodes. Alternately, they must depart by a different
route. Large numbers of V3 MCs (43) and bone
marrow-derived MCs (55) are found in the sinusoids of the
spleen after their i.v. administration into BALB/c and
C57BL/6-KitW-v mice, respectively. Although these
findings indicate that certain populations of MCs prefer to translocate
to the spleen and/or liver from the peripheral blood, we sought
evidence that viable MCs could emigrate from a tissue, enter the blood
stream, and eventually translocate to the spleen. To address this
issue, v-abl-immortalized V3 MCs were adoptively transferred
i.p. into normal, noninfected BALB/c mice. Some of these transformed
MCs were able to leave the peritoneal cavity and make their way to the
spleen (Fig. 5). The inability of V3 MCs to translocate to the liver
when injected i.p. suggests that these MCs probably alter their surface
homing receptors as they move from the peritoneal cavity to the
peripheral blood.
Based on the V3 MC data and the reports of others (56, 57, 58)
that the spleen is the major filtration organ for circulating
erythrocytes and other hematopoietic cells, the MCs in the spleen were
quantitated (Fig. 6) and phenotyped (Figs. 7 and 8) during the
different phases of helminth-induced mastocytosis. MCs were sparse in
number in the spleen of noninfected BALB/c mice. Although the MCs in
the spleen of noninfected BALB/c mice express many mMCPs
(43), these cells do not express mMCP-9 (36).
As assessed by the chloroacetate esterase cytochemistry procedure, the
number of MCs in the spleen of T. spiralis-infected mice at
wk 4 were >10-fold higher than the number in the spleen of noninfected
animals (Fig. 6). More importantly, essentially all of these splenic
MCs expressed mMCP-2 and mMCP-9 (Fig. 8).
Based on the observations that only a few MCs in the jejunum of
helminth-infected mice were extruded into the lumen (Fig. 3), that only
a few MCs in the jejunum were undergoing apoptosis (Fig. 3), that
mMCP-9+ MCs increased in number in the spleen of
helminth-infected mice when their numbers decreased in the jejunum
(Fig. 6), and that the splenic MCs were not proliferating (Figs. 7 and 8), we conclude that most of the MCs found in the spleen during the
recovery phase of the infection probably originated in the small
intestine. The occasional finding of a
mMCP-2+/mMCP-9+ MC in the
lumen of the blood vessels in contiguity with splenic sinusoids (Fig. 9) is compatible with this conclusion. Although apoptosis of
lymphocytes occurs primarily in the central and mantle zones of the
lymphoid follicles in the medulla, senescent erythrocytes undergo
destruction in the cortex. This site is lined by cells of the
mononuclear phagocytic system. Inasmuch as the
mMCP-9+ MCs in the spleen 4 wk after helminth
infection preferentially reside in the sinusoids of the cortex,
senescent MCs and erythrocytes probably use comparable mechanisms to
localize to this organ. It is possible that excess jejunal MCs are
preferentially targeted to the spleen simply because the normal
clearance mechanism is overwhelmed in this region of the intestine.
However, targeting of the jejunal MCs to the spleen would ensure that
any mMCP that is nonspecifically released from the dying cell is
rapidly trapped and destroyed by this macrophage-rich organ.
At no time during the helminth infection do the MCs in the large
intestine express mMCP-9. Because essentially all of the MCs in the
spleen during the recovery phase of the infection express mMCP-9 (Fig. 8b), it is unlikely that a high proportion of the apoptotic
MCs in the large intestine eventually translocate to the spleen.
Although the ultimate fate of this MC population remains to be
determined, MCs occasionally can be seen in the lumen during the
recovery phase of the infection (Fig. 3a). Thus, it is
possible that this population tends to directly exfoliate into the
lumen. The reason why most of the amplified MCs residing in the large
intestine do not translocate to the spleen is unknown, but it might be
an indirect consequence of the regulatory factors released from the
functionally distinct intraepithelial T cells that reside in the large
and small intestines (59).
Metachromatic/high-affinity IgE receptor+ cells, which have been classified as basophils primarily because of their segmented nuclei, have been found in the peripheral blood (60) and spleen (61) of helminth-infected mice, as well as in the spleen of mice receiving goat anti-mouse IgD (62). Although MCs generally have nonsegmented nuclei, in vivo- and in vitro-differentiated MCs with segmented nuclei have been found occasionally in the mouse (45). The discovery of mMCP-2+/mMCP-9+ MCs with segmented nuclei in the large intestine, jejunum, blood, and spleen of the BALB/c mouse during the recovery phase of a T. spiralis infection now suggests that the cells that have been classified as basophils in some of the above studies are actually senescent, T cell-dependent MCs in transit.
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Acknowledgments |
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Footnotes |
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2 D.S.F. and M.F.G. contributed equally to this study.
3 Current address: School of Pathology, University of New South Wales, New South Wales 2052, Sydney, Australia.
4 Address correspondence and reprint requests to Dr. Richard L. Stevens, Department of Medicine, Brigham and Women’s Hospital, Smith Building, Room 616B, 1 Jimmy Fund Way, Boston, MA 02115.
5 Abbreviations used in this paper: MC, mast cell; BrdU, bromodeoxyuridine; mMCP, mouse MC protease.
Received for publication January 3, 2000. Accepted for publication April 13, 2000.
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J. R. MacKenzie, J. Mattes, L. A. Dent, and P. S. Foster Eosinophils Promote Allergic Disease of the Lung by Regulating CD4+ Th2 Lymphocyte Function J. Immunol., September 15, 2001; 167(6): 3146 - 3155. [Abstract] [Full Text] [PDF]
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Y. Li, L. Li, R. Wadley, S. W. Reddel, J. C. Qi, C. Archis, A. Collins, E. Clark, M. Cooley, S. Kouts, et al. Mast cells/basophils in the peripheral blood of allergic individuals who are HIV-1 susceptible due to their surface expression of CD4 and the chemokine receptors CCR3, CCR5, and CXCR4 Blood, June 1, 2001; 97(11): 3484 - 3490. [Abstract] [Full Text] [PDF]
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P. A. Knight, S. H. Wright, C. E. Lawrence, Y. Y.W. Paterson, and H. R.P. Miller Delayed Expulsion of the Nematode Trichinella spiralis in Mice Lacking the Mucosal Mast Cell-specific Granule Chymase, Mouse Mast Cell Protease-1 J. Exp. Med., December 18, 2000; 192(12): 1849 - 1856. [Abstract] [Full Text] [PDF]
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 G. W. Wong, L. Li, M. S. Madhusudhan, S. A. Krilis, M. F. Gurish, M. E. Rothenberg, A. Sali, and R. L. Stevens Tryptase 4, a New Member of the Chromosome 17 Family of Mouse Serine Proteases J. Biol. Chem., June 1, 2001; 276(23): 20648 - 20658. [Abstract] [Full Text] [PDF]
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) and
eosinophils (
). At each time point, two to three high power fields
(HPF) were examined in a tissue section. Results are the mean ±
SEM of cell counts from three animals analyzed at each time
point.
