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,
Departments of
*
Anesthesiology,
Surgery,
Medicine, and
Pathology, Washington University School of Medicine, St. Louis, MO 63110
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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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The purpose of the present study was to determine the effects of sepsis on dendritic cells (DCs)4 and macrophages, critical components of the immune system. Both DCs and macrophages are essential in coordinating the host response to microorganisms. For example, follicular dendritic cells (FDCs) are essential in sustaining the viability, growth, and differentiation of activated B cells (12). Therefore, it is possible that the loss in B cells and lymphoid follicles documented in spleens of septic patients may be due in part to the loss of FDCs.
Also, studies show that both DCs and macrophages have the capacity to undergo rapid apoptotic death (13, 14, 15, 16). In the case of mature DCs, it is hypothesized that apoptosis helps to ensure that the inflammatory response does not become excessive and result in damage to the host (13). Apoptosis in macrophages is a result of the attempt of the invading pathogens to evade host defenses by eliminating these phagocytic cells (16). For example, Legionella pneumophila and Yersinia enterocolitica can induce macrophages to undergo programmed cell death (16). Thus, both DCs and macrophages have been demonstrated to be capable of rapid deletion during infection and this process could be accelerated in sepsis.
A final aim of the study was to examine the effect of sepsis on MHC II
expression. MHC II is normally expressed on DCs, macrophages, and B
cells and is essential in displaying peptides derived from
extracellular microbes. The MHC II peptide complex is recognized by CD4
T cells which respond by activating macrophages (to eliminate
extracellular microbes that have been phagocytosed) and B cells (to
make Abs against the extracellular pathogen). Macrophages from patients
with sepsis have been reported to have decreased expression of the MHC
II molecule HLA-DR and treatment with IFN-
restores HLA-DR
expression and improves survival (7).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Three patients
with sepsis had spleen samples obtained intraoperatively during a
procedure to remove spleens with abscess formation. In the spleen
samples obtained postmortem, a protocol for immediate tissue sampling
allowed for tissue harvesting in the intensive care unit as soon as
informed consent could be obtained from next of kin. The spleen sample
was placed in 10% buffered formalin for 24 h before paraffin
embedding and sectioning. The length of time between onset of death and
tissue sampling ranged from 15 min to 6 h with the vast majority
obtained between 30 and 90 min (17). In the three patients
with sepsis whose spleens were removed intraoperatively, the sample was
obtained from a section of the spleen which was not directly contiguous
with the site of infection and which appeared grossly normal. The
protocol for tissue sampling was approved by the Human Studies
Committee at Washington University School of Medicine (St. Louis,
MO).
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Patients were classified as septic based on one of the three
following criteria: 1) positive blood, abdominal fluid, or tissue
cultures for bacteria or fungi (see Table I
), 2) intraoperative
evidence of infection, e.g., perforated large bowel with peritoneal
contamination, ischemic bowel with purulent peritoneal fluid, or 3) a
histopathologic diagnosis of infection at postmortem examination (e.g.
bronchopneumonia, intra-abdominal abscess). All patients also had
premortem clinical evidence of sepsis with signs and symptoms of sepsis
consisting of hypo- or hyperthermia, altered mental status, and
hemodynamic instability usually requiring vasopressors (see Table I).
Trauma patients as a control population
Due to the inability of obtaining a normal human spleen,
patients with blunt or penetrating abdominal trauma necessitating a
splenectomy were used as a control population for comparison with the
patients with sepsis (Table II). Of note,
none of the trauma patients had significant comorbidities or were
taking immunosuppressive medication and, presumably, findings from this
group are representative of those of a normal population. Spleens were
removed rapidly after injury (usually within 3–8 h) and therefore,
values for DCs and macrophages should reflect those of a normal spleen.
Fourteen of the trauma patients were included in a previous study
(11), while six trauma patients were new. Nine of the 20
trauma patients were in shock (systolic blood pressure <90 mm Hg).
These patients received fluid boluses and vasopressors to maintain
normal arterial blood pressure.
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FDCs. An Ab to CD21 (clone 1F8; DAKO, Carpinteria, CA) was used. The CD21 Ag is present at high density on FDCs. As stated by DAKO (package insert) and validated by our laboratory, the staining of B cells is "reduced or abolished in paraffin embedded sections" while the staining of FDCs is "unaffected by paraffin embedding." The cells that were positively stained by CD21 in paraffin sections were also examined histologically to confirm that they were spindled/stellate in shape and had the characteristic dendritic cytoplasmic processes.
Macrophages. Three different Abs were used to identify splenic macrophages: CD14 (clone 7; NovoCastra, Newcastle, U.K.), CD68 (clone PG-M1; DAKO) and the anti-macrophage mAb 3A5 (NovoCastra). The CD14 Ag is expressed on cells of the myelomonocytic lineage including monocytes and macrophages. Although a low level of expression can be observed on neutrophils and B cells, these cells did not stain for CD14 in the present study of paraffin-embedded spleens. CD68 is expressed on macrophages and blood monocytes. 3A5 is selective for macrophages in routinely processed, formalin-fixed tissues (18). The results of the different immunohistochemical stains were compared.
MHC II. The anti-MHC II Ab (clone TU39; BD PharMingen, San Diego, CA) was used. MHC II is expressed on dendritic cells, macrophages, and B cells with the level of expression dependent upon the activation state of the cell. Lower levels of expression of MHC II may, in some instances, be seen in T cells and vascular endothelial cells. The concentrations of the primary anti-MHC Ab and secondary Ab were 11.25 and 8.75 µg/ml, respectively.
Staining protocol. After heating, slides were rinsed in CitraSolv (Fisher Scientific, St. Louis, MO) and rehydrated in decreasing concentrations of alcohol. Endogenous peroxidase was blocked and Ag retrieval performed according to the manufacturer’s recommendations. Slides were blocked with horse serum and incubated with primary Ab at room temperature for one hour. CD68 was prediluted by the manufacturer but CD14 and CD21 were used at concentrations of 1/75 and 1/150, respectively. Specimens stained for CD14 and MHC II were incubated with a biotinylated horse anti-mouse secondary Ab for 30 min followed by incubation with an avidin-biotin complex (VectaStain ABC standard kit; Vector Laboratories, Burlingame, CA). Slides were developed with 3,3'-diaminobenzidine tetrahydrochloride, counterstained with hematoxylin, dehydrated, and mounted.
The CD21 staining method deviated from the above protocol in that the secondary Ab was an HRP polymer from the DAKO En Vision staining system.
Evaluation and image analysis
For evaluation of CD21, CD14, and CD68 staining, slides were examined in a blinded fashion at a magnification of x100 as described previously (11). Three images of each specimen were obtained in random fashion using a Nikon COOLPIX 900 digital camera (Melville, NY) and the values were averaged. The percentage area of the visible field that was positively stained for the respective cell marker (CD21, CD14, CD68) was calculated using Metamorph (Universal Imaging, West Chester, PA). Using Metamorph, the region of the tissue section that was positively stained by immunohistochemistry was thresholded and pseudocolored. Next, the percentage area of the tissue section that was pseudocolored was automatically calculated by the analysis program.
For evaluation of MHC II staining, slides were graded by an
experienced clinical pathologist (P. E. Swanson) who
was blinded to sample identity. The grading scale (see Table II) was
established before evaluating the slides.
Statistical analysis
Data were analyzed with a statistical software program, Prism (GraphPad, San Diego, CA). CD14, CD21, and CD68 were analyzed using a Student’s t test. A Mann-Whitney nonparametric test was used for analysis of MHC II. The data are presented as the mean ± SEM. Significance was accepted at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cells that stained positively for CD21 demonstrated the
characteristic appearance and location of FDCs (Fig. 1). Specifically,
positively stained spindled and stellate
cells with long cytoplasmic processes were located in lymphoid
follicles. Small round lymphocytes were not positive for CD21 in any of
the B cell rich splenic areas, i.e., germinal center, mantle, or
marginal zones (Fig. 1). There was a marked decrease in the percentage
area of the spleen occupied by FDCs in septic vs trauma patients, 0.70
± 0.17% (n = 23) vs 2.88 ± 0.44%
(n = 19) for septic and trauma patients, respectively
(p < 0.0001; Fig. 2).
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Cells that stained for CD14 demonstrated the characteristic
appearance of macrophages. These cells were generally larger than
lymphocytes and tended to have an irregular cell outline compared with
lymphocytes; nuclei were larger than those of adjacent lymphocytes,
irregular in contour with an open chromatin pattern and usually
indistinct nucleoli (Fig. 3). Notably,
there was no staining of neutrophils or lymphocytes. A small subgroup
of both septic and nonseptic spleens contained CD14-reactive FDCs. For
this reason, analysis of the percent area of spleens positive for CD14
did not include active germinal centers. Note that macrophages are not
thought to be components of the B cell follicle and, therefore,
excluding follicles from analysis because of the FDC staining should
not significantly affect the results. There was no difference in the
percentage area of spleen that stained positive for macrophages, i.e.,
0.77 ± 0.14% and 0.65 ± 0.13% sepsis and trauma,
respectively (Fig. 2).
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MHC II grading scale
Spleens that were stained for MHC II were divided by the
pathologist (P. E. S.) into four arbitrary categories based
upon preliminary review of cytoarchitecture (the distribution of and
relationship between cell populations in the lymphoid spleen), the
numbers of cells in B and T cell zones, and a comparison to matched
CD21 stains. (Table III). Spleens in
categories one and two had normal splenic architecture and normal
numbers of lymphocytes in lymphoid zones (i.e., the red to white pulp
ratio and number of lymphoid follicles were normal). Category one
differed from category two in the degree of MHC II expression detected
by immunohistochemistry. In category three (Fig. 4-1), staining was weak
(though generally present, and accentuated focally in macrophages and
FDCs), whereas moderate to strong reactivity characterized category two
(Fig. 4-2, A and B). The latter, but
not the former, group also contained MHC II-reactive
interdigitating dendritic cells in the T cell rich periarteriolar
lymphoid sheath (PALS). Category two was further divided by the
presence of well-formed germinal centers: Fig. 4-2A contained
well-formed germinal centers with strong MHC II staining (Fig. 4-2A), whereas Fig. 4-2B was largely devoid of
active germinal centers (Fig. 4-2B). Spleens in category
three (Fig. 4-3) had an overall decrease in B cells,
follicular and interdigitating DCs, and in the number of lymphoid
follicles, but MHC II staining persisted in the remaining DCs and B
cells. Macrophages were normally distributed and uniformly expressed
MHC II. Spleens in category four (Fig. 4-4) had severe
depletion of most nonendothelial mononuclear cell elements and MHC II
staining was of low intensity in B cells, positive in the few DCs that
were present (almost none of which were located in PALS), and
moderately to strongly positive in macrophages.
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The pattern of MHC II staining of spleens from septic patients
differed from trauma patients (Table III, p = 0.0012).
In general, macrophages were positively stained in spleens from both
septic and trauma patients while T cells did not appreciably stain in
either group (Fig. 4). B cells were positively stained for MHC II with
the greatest expression of MHC II in B cells in germinal
centers,followed by B cells in the mantle zone, and the least
expression in B cells in marginal zone (Fig. 4-2,
A and B). Although not as quantitative as the
CD14 macrophage staining, the MHC II results supported the CD14
findings because they demonstrated comparable numbers of cells with the
morphologic features of macrophages in spleens from septic and trauma
patients. Importantly, MHC II staining confirmed the CD21 results by
demonstrating a decrease in FDCs in spleens from septic patients
compared with trauma patients (Fig. 4). Similarly, MHC II stains
suggested that the number of interdigitating DCs in PALS was decreased
in spleens from septic vs trauma patients although this was not
quantitatively determined. Interestingly, DCs did not stain for MHC II
when located in the marginal zone even though their presence in the
marginal zone was documented by DC staining using CD21 (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2). In
addition to the loss of FDCs, MHC II results demonstrate that
interdigitating DCs were decreased in sepsis as well. The development
of new methods to study DCs has resulted in an appreciation for the
critical role that DCs play in orchestrating the immune response
(12, 13, 14, 19). There are major differences in the origin
and type of Ag presented by FDCs and interdigitating DCs (13, 19). Although FDCs are highly efficient stimulators of B cells,
interdigitating DCs activate T cells. In addition to Ag presentation,
DCs produce an array of cytokines (IFN-
, IL-12, IL-15, etc.) that
can direct the immune response (12, 19). FDCs are
essential in sustaining the viability, growth, and differentiation of B
cells. In this regard, the loss in FDCs documented in the present study
may be contributing to the profound loss in B cells and lymphoid
follicles known to occur in patients with sepsis (11).
Alternatively, B cells have been shown to be critical for FDC survival
as well (20). Therefore, it is possible that the loss in B
cells that occurs in sepsis is the driving force behind the loss in
FDCs. A similar symbiotic relationship may exist between
interdigitating DCs and CD4 T cells (21).
DCs are essential for an effective immune response to infection. They
are highly efficient at displaying Ag to T cells; the concentration of
MHC peptide complexes is 10–100 times higher on DCs than on other APCs
like B cells and monocytes (Ref. 12 ; note the increase in
intensity of MHC II staining in DCs relative to other cell types
in Fig. 4-2B). Also, DCs express many accessory molecules
that interact with receptors on T cells to enhance T cell adhesion and
signaling (19). DCs are also capable of directing T
cells toward a Th1 or Th2 pathway (22). For example, DCs
make IL-12 that can direct T cells to differentiate into the Th1
response (22). In addition to the well-known effects on T
cells, DCs are now recognized to have major effects on B cell growth
and immunoglobulin synthesis (12). Thus, the loss in DCs
documented in spleens from patients with sepsis in the present study
has profound implications regarding the ability of the host to
eradicate the microorganisms.
In contrast to the loss in DCs in sepsis, no loss in macrophages was detected in spleens from patients with sepsis vs trauma. One possible explanation for the difference in the response to sepsis of these two cell types may be their propensity to undergo apoptosis. Kinetic studies in mice demonstrate that DCs undergo rapid turnover after presentation of Ag to T cells (14). Interdigitating DCs that have been activated by Ag capture and processing are programmed to die unless they receive a survival signal from T cells. However, the T cell survival signal only temporarily postpones the apoptotic cell death program of DCs. Hence, active DCs are rapidly eliminated after a brief time interval. It is speculated that the reason for the short life span of activated DCs is to keep the inflammatory response from becoming too robust (13). Although macrophages are reported to undergo apoptosis in response to certain types of pathogens, it is not clear that they undergo apoptosis to the extent that routinely occurs in DCs. For example, treatment with rapamycin, an immunosuppressive agent, induces DC, but not macrophage, apoptotic cell death (23).
MHC II immunostaining, interestingly, highlights the marked loss of
splenic B cells and lymphoid follicles that we demonstrated in earlier
clinical studies (11, 17). The majority of spleens from
patients with sepsis, but not spleens from trauma patients,
demonstrated unequivocal depletion of mononuclear cellular elements of
the white pulp (Table III). Despite an overall loss of cells, the B
cells and DCs that persisted nonetheless expressed MHC II. Thus, the
present findings do not support the concept that sepsis causes loss of
the MHC II receptor.
Limitations
The major focus of the present investigation was to determine the effect of sepsis on DCs, macrophages, and MHC II class expression. The results convincingly demonstrate that patients with sepsis have a dramatic decrease in follicular and interdigitating DCs while macrophages were not lost. It is possible that these histopathologic changes are not exclusive to sepsis but also may occur in patients who are critically ill from other diseases, e.g., renal failure, congestive heart failure, and liver failure. Previous work from our laboratory showed that the loss in B and CD4 T cells that occurred in septic patients did occur in isolated critically ill nonseptic patients but was not statistically significant in the group when considered as a whole. Thus, future studies including larger numbers of critically ill patients will be necessary to address this difficult question.
Another potential limitation to the present study regards the
possibility that the observed findings were secondary to a delay in
tissue fixation. The majority of spleens from septic patients were
removed within 30–90 min after death and, thus, we believe that it is
unlikely that this short delay affected the present findings. Studies
from our laboratory in which spleens were removed, left at room
temperature for six hours, and sampled at different time points did not
demonstrate histologic evidence of splenocyte apoptosis or loss of cell
phenotypes (11, 17). Also, no change in the percentage of
cells positive for active caspase 3 or active caspase 9 in these
delayed fixation studies occurred (11, 17). Furthermore,
unlike the intestine and the kidney, the spleen does not undergo rapid
autolytic changes. Finally, spleen samples from septic patients 16 and
17 (see Table I) were obtained in the operating room (immediate
fixation), and had very low percentage areas for CD21, i.e., 1.0 and
0.1% respectively, thereby establishing that the findings were not a
fixation artifact.
A final limitation of the study regards the use of CD markers to identify specific cell phenotypes. As demonstrated with CD68 and 3A5, great care must be used in ascribing the results to a particular cell type. In the present study, FDCs were defined not only by CD21 reactivity but also by characteristic morphologic features and location within the spleen. In addition, MHC II immunohistochemical staining demonstrated loss of cells with dendritic morphology but no decrease in macrophages and thereby served as another confirmatory method.
In conclusion, patients dying of sepsis and multiple organ failure exhibit a profound loss of splenic follicular and interdigitating DCs but experience no appreciable decrease in splenic macrophages. Immunohistochemical staining for MHC II demonstrated marked sepsis-induced loss of splenocytes in white pulp, but the remaining lymphoid cells continued to express MHC II. The sepsis-induced loss in DCs and the resultant impact on the adaptive immune system may be important factors in the immunodepression that occurs in this highly lethal disorder.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Richard Hotchkiss, Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: hotch{at}morpheus.wustl.edu
3 Current address: Department of Pathology, University of Washington School of Medicine, Seattle, WA 98110.
4 Abbreviations used in this paper: DC, dendritic cell; FDC, follicular dendritic cell; PALS, periarteriolar lymphoid sheath.
Received for publication October 2, 2001. Accepted for publication December 19, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P. A. Efron, A. Martins, D. Minnich, K. Tinsley, R. Ungaro, F. R. Bahjat, R. Hotchkiss, M. Clare-Salzler, and L. L. Moldawer Characterization of the Systemic Loss of Dendritic Cells in Murine Lymph Nodes During Polymicrobial Sepsis J. Immunol., September 1, 2004; 173(5): 3035 - 3043. [Abstract] [Full Text] [PDF]
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J. G. R. WEAVER, M. S. ROUSE, J. M. STECKELBERG, and A. D. BADLEY Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis FASEB J, August 1, 2004; 18(11): 1185 - 1191. [Abstract] [Full Text] [PDF]
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C. F. Benjamim, C. M. Hogaboam, N. W. Lukacs, and S. L. Kunkel Septic Mice Are Susceptible to Pulmonary Aspergillosis Am. J. Pathol., December 1, 2003; 163(6): 2605 - 2617. [Abstract] [Full Text]
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K. W. Tinsley, M. H. Grayson, P. E. Swanson, A. M. Drewry, K. C. Chang, I. E. Karl, and R. S. Hotchkiss Sepsis Induces Apoptosis and Profound Depletion of Splenic Interdigitating and Follicular Dendritic Cells J. Immunol., July 15, 2003; 171(2): 909 - 914. [Abstract] [Full Text] [PDF]
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A. K. De, K. Laudanski, and C. L. Miller-Graziano Failure of Monocytes of Trauma Patients to Convert to Immature Dendritic Cells is Related to Preferential Macrophage-Colony-Stimulating Factor-Driven Macrophage Differentiation J. Immunol., June 15, 2003; 170(12): 6355 - 6362. [Abstract] [Full Text] [PDF]
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, macrophages; ART, arteriole.