Immunohistochemical Assessment of Fractalkine, Inflammatory Cells, and Human Herpesvirus 7 in Human Salivary Glands
Center for Oral Biology (LRL,MAF,DJC), Center for Aging and Developmental Biology (HAG), Center for Vaccine Biology and Immunology (SD), and the Departments of Pharmacology and Physiology (DJC), Neurology (HAG), and Microbiology and Immunology (SD), University of Rochester Medical Center, Rochester, New York
Correspondence to: Dr. David J. Culp, Center for Oral Biology, 601 Elmwood Avenue, Box 611, Rochester, NY 14642-8611. E-mail: david_culp{at}urmc.rochester.edu
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Summary |
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Key Words: chemokine infection parotid submandibular labial
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Introduction |
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As in other tissues, salivary glands are afflicted by chronic inflammatory and autoimmune disorders and are also targets for viral infection (Rice 1999). Salivary glands are a collection of distinct glandular structures, each of which contributes its own exocrine and fluid secretory constituents into the oral cavity. Three "major" pairs of salivary glands (parotid, submandibular, and sublingual) are linked to the oral cavity through relatively long excretory ducts. In addition, localized just under the oral epithelium are many smaller "minor" glands, named according to their anatomic locations (i.e., labial, lingual, palatal, buccal, and minor sublingual). Salivary glands differ not only in their anatomic location but also in their constituent acinar cell types. The acinar cells of parotid glands are of the serous phenotype (Pinkstaff 1980
). Submandibular glands also contain serous acini but in addition have secretory endpieces composed of short tubules of columnar mucous cells capped by serous-like cells referred to as serous demilune cells (Pinkstaff 1980
). Labial glands, on the other hand, contain predominantly mucous tubules capped with serous demilune cells (Hand et al. 1999
). Surrounding the secretory endpieces of salivary glands are myoepithelial cells, which have branching processes containing actin filaments (Hand et al. 1999
). This cell type is present in various amounts among the different salivary glands but tends to be more prevalent in glands that contain a higher proportion of mucous cells (Hand et al. 1999
).
Salivary glands are a major site for a persistent and productive infection by human herpesvirus (HHV)-7 (Sada et al. 1996). HHV-7 infection occurs primarily in early childhood (Wyatt et al. 1991
; Clark et al. 1993
), and infectious virus is readily isolated from saliva (Hidaka et al. 1993
). Nevertheless, the pattern and cellular localization of HHV-7-infected cells in the two largest major salivary glands, the parotid and submandibular glands, has yet to be elucidated. Moreover, mechanisms by which HHV-7 gains entry to salivary gland cells and evades host immune responses are largely unknown. However, HHV-7 encodes two proteins, U12 and U51, with homology to a seven-transmembrane protein encoded by the US28 gene of human cytomegalovirus (HCMV) (Rosenkilde et al. 2001
). The US28 gene product appears to mimic CX3CR1 in its binding to fractalkine and enhances virioncell fusion in a cell type-specific fashion (Pleskoff et al. 1998
; FraileRamos et al. 2001
). In a similar manner, HHV-7 U12 and/or U51 may interact with salivary fractalkine to enhance viral entry or spread (FraileRamos et al. 2001
). One or both of these proteins may also modulate chemokine signaling pathways and subsequent immune responses by sequestering soluble tissue fractalkine (FraileRamos et al. 2001
).
It is unknown whether fractalkine is expressed in human salivary glands. Therefore, the first aim of this study was to evaluate fractalkine protein expression and its cellular localization by immunocytochemistry (ICC) in three different human salivary glands: parotid, submandibular, and labial. All tissue specimens were normal in appearance when initially excised. Nevertheless, fractalkine expression was found to be highly variable, with some specimens expressing undetectable or very low levels of fractalkine. Given such variable expression levels of fractalkine, we further explored whether inflammatory cell infiltration or HHV-7 infection of salivary cells was related to the expression of fractalkine. We reasoned that if fractalkine is required for either process, then inflammatory cells and/or HHV-7-infected cells will be associated only with epithelial cells that express fractalkine. Our results are consistent with a role for fractalkine in the infiltration of inflammatory cells, whereas regions in which cells are infected by HHV-7 vary in fractalkine expression.
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Materials and Methods |
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For dual detection of fractalkine and either CD3 or CD68, sections were again blocked (30 min in 10% NHS in PBS) followed by 1-hr incubation at room temperature with rabbit anti-human CD3 or mouse monoclonal anti-human CD68 (both from DAKO; Carpinteria, CA). Anti-human CD3 and its negative control were applied as received from DAKO without dilution. Anti-human CD68 and normal mouse IgG (negative control) were diluted to 3.8 µg/ml in 10% NHS in PBS. Sections were treated with secondary antibody (biotinylated horse anti-mouse/rabbit) as described above and immunodetection performed using the avidinbiotinalkaline phosphatase complex method (Vectastain ABC-AP kit and Vector Red substrate; Vector) according to the manufacturer's directions. As positive controls in dual staining, we used sections of human tonsil (DAKO) or lymphoid tissue juxtaposed to portions of a human parotid gland obtained locally during surgery. Because antibody titers were not sufficient to allow dual staining for fractalkine and HHV-7, serial sections were examined.
After antibody detection, sections were washed, dehydrated, cleared in xylene, and mounted in Refrax (Anatech; Battle Creek, MI). Sections were examined with a Nikon Eclipse E800 microscope (Nikon; Melville, NY) under DIC (differential interference contrast) optics. Digital images were captured with a Spot 2 digital camera and software (Diagnostic Instruments; Sterling Heights, MI) and prepared for figures using Adobe Photoshop software (Adobe Systems; San Jose, CA).
Sections from each tissue sample were processed simultaneously with primary antibody and appropriate negative control as one of two groups: (a) sections from all labial gland samples, or (b) sections from all samples of parotid and submandibular glands. Stained sections were examined under low-power (x100) light microscopy and scored qualitatively by a single observer (DJC) using a four-plus system. After examination of all samples and negative controls for a given antigen, the sample with the most abundant cellular staining throughout the tissue, regardless of cell type, was considered to represent 100% maximal staining. This specimen and all others judged to have total staining >75% to 100% of maximal were given a score of four-plus. Specimens judged to have total staining >50% to 75% of maximal were given a score of three-plus. Similarly, specimens with total staining of >25% to 50% and >0% to 25% of maximal were given scores of two-plus and one-plus, respectively. No obvious differences in the distribution of cell types were noted among the specimens. Scoring is therefore with respect to all glandular samples for each antigen and is not a comparison among antigens.
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Results |
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Large clusters of CD3-positive cells were detected only in specimens #8 and #9. These clusters were localized in regions of loose connective tissue that contained vascular structures and large duct structures (Figure 3A) . Adjacent duct structures and nearby acini were consistently positive for fractalkine. In some sections there was an obvious gradient in the intensity of epithelial cell fractalkine staining; with less intense staining the further removed epithelial cells were from a locus of CD3-positive cells (Figure 3A). Some CD3-positive cells were also positive for fractalkine (Figure 3C). In sections from specimen #2, we found only a single small cluster of about five cells that were CD3-positive (not shown). All other specimens displayed negative staining, even in the presence of high levels of fractalkine expression (e.g., specimens #7, #12, and #13; see Table 1). Cells positive for CD68 were present primarily as only one (specimen #9) or two (specimen #8) small groups of about a dozen cells within the loose connective tissue near large duct structures (Figure 3D; Table 1). A subset of CD68-positive cells was also positive for fractalkine. Based on alternate staining of serial sections, these groups of CD68-positive cells were mostly localized to regions independently of CD3-positive cells (not shown). On the other hand, approximately one-quarter of the clusters of CD3-positive cells in specimen #8 contained one or two cells positive for CD68.
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Discussion |
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Fractalkine is considered to function as an integral type I plasma membrane protein, either as the intact molecule or as the soluble extracellular fragment after proteolytic cleavage (Chapman et al. 2000; Lucas et al. 2001
). In the present study, fractalkine was indeed localized to plasma membranes of salivary epithelial cells. Because of the antigen retrieval step and the extensive washings used in the processing of tissue sections, it is unlikely that soluble fractalkine remained for subsequent detection in our specimens. On the other hand, we found predominant fractalkine staining within the nuclear region of cells. This staining pattern is not an artifact contributed by the antigen retrieval method or by the secondary staining protocols, as evidenced by the fact that the same procedures and reagents were used for determining HHV-7 immunolocalization in adjacent sections. Furthermore, staining in the nuclear region was observed in the absence of the antigen retrieval step and/or when alternate secondary antibody and detection systems were used, although staining intensities were markedly reduced (not shown). To date, the immunoreactivity of fractalkine in other cell types has not been localized exclusively to plasma membranes. Immunostaining has been reported in the cytoplasm of keratinocytes (Sugaya et al. 2003
) and in punctate vesicle-like structures adjacent to nuclei of neuron cell bodies (Tong et al. 2000
). The staining observed in the nuclear region of salivary cells may represent newly-synthesized fractalkine in the rough endoplasmic reticulum. Subsequent steps in the transport and/or glycosylation of fractalkine may mask the chemokine antigenic site. The relatively lower levels of membrane staining might be explained by the rapid proteolytic cleavage of fractalkine after insertion in the plasma membrane. Alternatively, the observed immunoreactivity in the nuclear region may represent, in part, fractalkine chemokine domains in the nuclei of salivary cells or in specialized endocytic vesicles. Elucidation of the life cycle of fractalkine (i.e., synthesis, intracellular processing and transport, membrane insertion, proteolytic cleavage, or possible endocytosis) is beyond the scope of the present study and requires the use of model systems other than paraffin sections of pathological specimens.
A number of studies have demonstrated a role for fractalkine in tissue responses to injury and subsequent inflammation. For example, soluble fractalkine released from the cell surface is a chemotactic factor for monocytes, NK-cells, and T-cells expressing CX3CR1 (Bazan et al. 1997; Chapman et al. 2000
). Furthermore, membrane-bound fractalkine may assist in adhesion of CX3CR1-expressing leukocytes to epithelial cells and in retention of leukocytes in the surrounding connective tissue (Imai et al. 1997
; Haskell et al. 1999
; Chakravorty et al. 2002
). As a case in point, during renal inflammation subsets of leukocytes (CD68-positive macrophages and CD3-positive T-cells) were found adjacent to fractalkine-expressing tubule epithelial cells (Cockwell et al. 2002
). In the present study we found large clusters of CD3-positive cells as well as cells positive for CD68 only in tissue sections from two submandibular glands (specimens #8 and #9). Both glands were removed because of chronic sialoadenitis, whereas all other submandibular and parotid specimens were from tissue samples removed due to either intra- or extraglandular carcinomas. Therefore, the presence of inflammatory cells in specimens #8 and #9 is not surprising, although the presence of a subset of leukocytes expressing fractalkine should be noted. The expression of fractalkine by tissue macrophages has been reported previously (Fraticelli et al. 2001
; Greaves et al. 2001
). Furthermore, primary macrophages upregulate fractalkine in response to interleukin-4, suggesting that fractalkine expression may serve as a marker for T-helper type 2 immune responses (Greaves et al. 2001
). These results are consistent with the presence of infiltrating lymphocytes expressing type 2 cytokines in labial glands of patients with Sjögren's syndrome (Mitsias et al. 2002
).
Leukocytes identified in specimens #8 and #9 were consistently found adjacent to epithelial cells that were intensely positive for fractalkine. In some cases fractalkine staining was gradually less intense in epithelial cells that were further removed from a cluster of CD3-positive cells. These results are consistent with a function of fractalkine in the recruitment and/or retention of inflammatory cells in salivary glands. On the other hand, the absence of detectable inflammatory cells in other specimens in which high levels of fractalkine was expressed indicates that other factors are required for the recruitment of leukocytes into salivary glands. One such factor may be the release from epithelial membranes of soluble fractalkine, the more chemoattractant form of the chemokine. As mentioned above, it is likely that soluble fractalkine was washed out of our specimens during processing.
Although HHV-7 is a persistent and productive infectious agent in human salivary glands, the cellular distribution of virions has been described only for labial minor glands (Yadav et al. 1997). Duct cells were consistently labeled in all 20 specimens examined, whereas staining in serous demilune cells and mucous cells was limited to scattered foci of cells (Yadav et al. 1997
). In the present study we did not observe HHV-7 immunoreactivity in all labial specimens, nor were duct cells consistently stained in infected glands. These differences may be related to the antibody probes used. In the previous study, monoclonal antibody KR4 was used to detect viral antigen (Yadav et al. 1997
). To our knowledge, neither the specificity of this antibody nor its target epitope has been described. We used monoclonal antibody 5E1, which is directed against tegument protein pp85 of HHV-7 (Stefan et al. 1997
; Kempf et al. 1998
). This antibody was previously listed as detecting virus in six of ten salivary glands of unspecified type (Kempf et al. 1998
). In a separate study, positive staining of parotid acinar cells served only as a positive control experiment (Kempf et al. 1997
). Nevertheless, neither study provided a complete account of the cellular localization of 5E1 immunoreactivity in parotid glands or other salivary glands. In general, we found that 5E1 immunoreactivity in all three types of salivary glands was limited to foci of cells, and that serous and serous demilune cells were more intensely stained than duct or mucous cells. The higher intensity of staining in serous and demilune cells may represent either a greater production of virions by these two cell types and/or the cytoplasmic accumulation of tegument-containing material at a biosynthetic site or depot (Stefan et al. 1997
). Alternatively, virus may be produced no more efficiently but is released at a slower rate and therefore stored in these two cell types. All epithelial cell types in salivary glands are therefore targets for HHV-7 infection, but the ability of each cell type to support the synthesis, assembly, and release of viral particles may be strikingly different. In addition, unlike labial and parotid glands, all of our submandibular specimens were positive for 5E1 immunoreactivity and with scores of at least two-plus. Although our sampling of glandular tissues is not statistically relevant, it is worth noting that these results are consistent with those of Sada et al. (1996)
, in which HHV-7 DNA was detected by PCR in all 59 specimens of submandibular glands tested, compared with 85% and 59% for parotid and labial glands, respectively. Submandibular glands may therefore be more susceptible to infection by HHV-7 compared with other salivary glands.
Despite the presence of foci of cells infected with HHV-7 in the majority of specimens examined, inflammatory cells were detected in only three cases. These results are consistent with the evolution by HHV-7 of mechanisms to target salivary epithelial cells for reproduction and to evade host defenses, leading to the persistent release of infectious virus into saliva (Wyatt and Frenkel 1992; Clark et al. 1993
). We speculated that the putative fractalkine-binding proteins encoded by HHV-7 genes U12 and U51 may assist in viral entry by binding to cell surface fractalkine of epithelial cells. Alternatively, if fractalkine is induced by viral infection, then one or both these proteins could conceivably aid in evasion of host defenses by sequestering extracellular fractalkine, thus attenuating the recruitment of CX3CR1-expressing cells to the site of infection (Tortorella et al. 2000
). Another scenario is for HHV-7 entry to promote the downregulation of constitutive fractalkine expression (Tortorella et al. 2000
). Our results are inconsistent with all of these putative relationships between HHV-7 infection and fractalkine expression. For example, we observed cases in which cells infected with HHV-7 were either positive or negative for fractalkine, suggesting that infection does not necessarily lead to up- or downregulation of fractalkine expression. Furthermore, because fractalkine expression is not constitutive and its expression by infected cells is variable, fractalkine is probably not an absolute requirement for viral entry. We recognize that a functional interrelationship between cellular fractalkine and HHV-7 may still exist in salivary gland infection and/or immune evasion, but in a more complex manner. Given the absence of an in vitro model system in which to study the interactions between salivary epithelial cells and HHV-7, our results nevertheless provide initial insights into the cellular distribution of a viral parasite in salivary glands. In addition, we describe for the first time the expression in salivary glands of a unique protein with chemokine activity that is likely to participate in other cellular functions that have yet to be elucidated.
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Acknowledgments |
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We wish to thank Ashley John Grillo and Sally Chuang for excellent technical assistance, and Dr Seth Perry for valuable discussions. We also thank Dr Gene Watson for assistance in procuring tissue samples.
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Footnotes |
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