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Expression of histocompatibility antigen HLA В ЭDR by salivary gland epithelial cells in Sjgren's syndrome.

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1105
EXPRESSION OF HISTOCOMPATIBILITY ANTIGEN
HLA-DR BY SALIVARY GLAND EPITHELIAL CELLS
IN SJOGREN’S SYNDROME
ROBERT I. FOX, THOMAS BUMOL, KICHARD FANTOZZI,
ROBERT BONE, and ROBERT SCHREIBER
Recent studies have suggested that the induction
of HLA-DR antigens on epithelial cells plays an important role in the pathogenesis of autoimmune endocrine
exocrine disorders. We found that salivary gland
epithelial cells (i.e., acinar and ductal cells) in salivary
gland biopsy specimens from patients with primary
Sjogren’s syndrome (keratoconjunctivitis sicca) expressed high levels of HLA-DR antigen, which were
detected by staining frozen tissue sections with monoclonai antibodies and immunoperoxidase technique. In
contrast, Salivary gland epithelial cells from normal
subjects did not express this antigen. Lymphocytes
eluted from the salivary gland biopsy specimens of
patients who had Sjogren’s syndrome produced a soluble factor that stimulated HLA-DR synthesis by a
salivary gland-derived cell line (Sal-1). These tissue
culture supernatants contained y-interferon, and their
ability to induce HLA-DR synthesis was blocked by
monoclonal anti-y-interferon antibody. These results
Publication number 4078BCR from the Scripps Clinic and
Research Foundation, La Jolla, California.
From the Departments of Rheumatology, Basic and Clinical
Research, Head and Neck Surgery, and Immunology, Scripps Clinic
and Research Foundation, La Jolla, California, and the Eli Lilly
Research Laboratory, Indianapolis, Indiana.
Supported in part by grants Ah4-33294, AM-33983, and
CA-34120 from the National Institutes of Health, a grant from the
Eli Lilly Research Laboratories, and a grant from the Kieckhefer
Foundation.
Robert I. Fox, MD, PhD: Departments of Rheumatology
and Basic and Clinical Research; Thomas Bumol, PhD: Eli Lilly
Research Laboratory; Richard Fantozzi, MD: Department of Head
and Neck Surgery; Robert Bone, MD: Department of Head and
Neck Surgery; Robert Schreiber, PhD: Department of Immunology.
Address reprint requests to Robert I. Fox, MD, PhD,
Scripps Clinic and Research Foundation, 10666 North Torrey Pines
Road, La Jolla, CA 92037.
Submitted for publication October 2, 1985; accepted in
revised form March 17, 1986.
Arthritis and Rheumatism, Vol. 29, No. 9 (September 1986)
demonstrate the presence of HLA-DR antigen on salivary gland epithelial cells and suggest that local production of y-interferon plays a role in this induction.
During the past several years, the importance of
histocompatibility antigens encoded by the HLA region of chromosome 6 in immune responsiveness and
disease susceptibility has been established (1,2). The
HLA--DR region encodes 2 polypeptides (molecular
weights 34,000 and 28,000) that were initially recognized on macrophages and B cells. These molecules
probably provide a structure that helps orient T
helpedinducer cells during recognition of antigens
(2-4). The HLA-DR molecules are highly polymorphic, and the HLA-DR3 allele has been associated
with autoimmune endocrine-exocrine diseases such
as Sjiigren’s syndrome (SS), Hashimoto’s thyroiditis,
insulin-dependent diabetes, Addison’s disease, and
primary biliary cirrhosis (5,6). However, the structural
basis for the association of autoimmune diseases with
HLA-DR alleles remains unknown. Investigators
have recently demonstrated the presence of HLA-DR
antigens on thyroid epithelial cells in patients with
autoimmune thyroid disease, but not on normal thyroid tissues (6,7). It also has been proposed that
autoantigens at the thyroid cell membrane might associate with the newly induced HLA-DR molecules and
thus be recognized by immune T cells to initiate or
perpetuate immune responses (6-8).
To determine if similar mechanisms might be
present in another autoimmune disease associated
with HLA-DR3, we examined salivary gland specimens from patients who had SS, which is characterized by lymphocytic infiltration of the minor salivary
glands (9). This disorder is particularly well-suited to
1106
FOX ET AL
serve as a model for autoimmune endocrine-exocrine
disease, since it is relatively common and the target
organs (i.e., salivary glands) are safely accessible to
biopsy (9,lO). Studies using monoclonal antibodies
and in vitro functional studies have shown that the
saliv,arygland is infiltrated predominantly by T cells of
the Leu-3a-positive (OKT4+) subset that have T
helperhnducer cell function (10-12). The salivary
glands of these patients are active sites of autoantibody and interleukin-2 (IL-2) production (13,14).
We have extended those studies by demonstrating,
with the use of monoclonal antibodies and immunohistologic techniques, the presence of HLA-DR
antigen on salivary gland epithelial cells in biopsy
specimens from SS patients. To understand the mechanisrri(s) responsible for antigen induction, we investigated the role of recombinant y-interferon (y-IFN) on
salivary gland cells cultured in vitro, since recent
reports have indicated the ability of this lymphokine to
stimulate HLA-DR expression by epithelial cells (8).
Also, we wished to determine whether lymphocytes
eluted from salivary gland biopsy specimens of SS
patients could be stimulated to secrete -/-IFN in vitro
and tlius provide a signal for HLA-DR induction.
PATIENTS AND METHODS
Patients. Twelve patients with primary SS had
keratoconjunctivitis sicca, xerostomia, and a minor salivary
gland specimen classified as grade IV on the ChisholmMason1 scale (from I-IV) (9,10,15). These patients did not
have associated rheumatoid arthritis and had not received
corticosteroids or immunosuppressive drugs for at least 3
months before the biopsy was performed (10). Normal
salivary gland tissue was obtained from autopsy samples and
from the histologically normal margins of glands removed
because of benign tumors. Three parotid tumors (Warthin's
tumor or papillary cystadenoma lymphomatosum [PCL])
were studied (16). This type of parotid tumor is particularly
interesting since it consists of columnar epithelial cells
overlying a dense lymphoid infiltrate (16-18).
Immunohistologicstudies. All specimens were placed
in sterile saline until they were embedded in OCT medium
(Miles, Napersville, IL), frozen in liquid nitrogen, and stored
at -70°C. Frozen tissue sections (5p) were acetone-fixed
and stained with monoclonal antibodies (MoAb) using immunoperoxidase methods previously described (19,20).
Briefly, the tissue sections were incubated with specific
MoAb or a control antibody of the same isotype and concentration. After rinsing, the sections were reacted with
peroxiclase-conjugated goat anti-mouse IgG and substrate
3',3'-diaminobenzidine, resulting in an insoluble brown reaction product at sites where the original specific MoAb
was bound.
Monoclonal antibodies. Monoclonal antibody SC2, a
murine IgG2 antibody produced in our laboratory, detects a
nonpolymorphic determinant on HLA-DR molecules (2 1).
MoAb Q513, produced by Dr. V. Quaranta, detects an
antigenic epitope on HLA-DR molecules distinct from that
recognized by MoAb SC2 (22). MoAb B539 recognizes the
invariant ( y )chain that associates with the cytoplasmic form
of HLA-DR (23,24). Antibody Leu-I0 (reactive with
HLA-DQ), anti-Leu-MS (reactive with monocytes and tissue dendritic cells), and anti-cytokeratin (antibodies) were
obtained from Becton-Dickinson (Mountain View, CA).
Mature T cells were enumerated with anti-Leu-4 (BectonDickinson) and mature B cells with MoAbs B-1 (Coulter,
Hialeah, FL) and Leu-I4 (Becton-Dickinson). A monoclonal
antibody against y I F N (MoAb M125) was recently produced in one of our laboratories (25) and has been shown to
block the effects of y I F N on monocytes (26).
Preparation of salivary gland lymphocytes and detection of y-IFN production. Salivary gland lymphocytes (SGL)
were obtained from the parotid glands of 4 SS patients who
had undergone surgery to rule out lymphoma and/or infection (12). The SGL were eluted by cutting the tissues into 0.5
x 0.5-cm squares and gently pressing them through stainless
steel mesh to obtain a suspension containing 107-109 SGL.
After Ficoll-Hypaque centrifugation, the SGL were cultured
in vitro at 37°C in RPMI 1640 (Flow Laboratories,
Inglewood, CA) containing 5% fetal calf serum (FCS; Gibco,
Grand Island, NY) that previously had been screened for the
absence of endotoxin. Flat-bottom microtiter plates (Falcon
Plastics, Oxnard, CA) containing 2 x lo5 lymphocytes
received either media alone or mitogen stimulation with
pretitered phytohemagglutinin (PHA; 0.1 pglml) plus 1%
phorbol myristate acetate (PMA; Sigma, St. Louis, MO), as
previously described (27). After 72 hours, the tissue culture
supernatants were harvested and stored at -70°C until
analyzed by solid-phase enzyme-linked immunosorbent assay (ELISA; Centocor, Malverne, PA) for ./-IFN. Tonsillar
lymph node lymphocytes from immunologically normal
adults were prepared and cultured in a manner similar to that
used for the SGL.
Tissue culture of Sal-1 cells and induction of HLA-DR
antigens by y-IFN. A continuous cell line (Sal-I) was established by collagenase digestion of a PCL parotid tumor,
followed by culture of adherent cells in RPMI 1640 (Gibco)
plus 10% FCS. This cell line has been maintained in culture
for over 16 months and continues to have epithelial cell
morphology, extracellular matrix proteins (defined by
monoclonal antibodies), and electron microscopic features
suggestive of an epithelial cell (Bumol T, Fox RI: manuscript
in preparation).
In certain experiments, the Sal-1 cells were grown on
sterile multichamber wells (Labtek, Napersville, IL) in the
presence of either: (a) 50 international reference units
(IRU)/ml recombinant ./-IFN (Cetus, San Francisco, CA) in
RPMI 1640 plus 5% FCS; (b) 1,000 IU/ml of recombinant
a-IFN (Hoffman-La Roche, Nutley, NJ) in RPMI 1640 plus
5% FCS; (c) cell supernatants (previously stimulated in vitro
as described above) from SGL of SS patients; or (d) cell
supernatants derived from stimulated SGL that contained a
pretitered anti-y-IFN monoclonal antibody. After 5 days of
incubation at 37"C, the slide chambers were fixed in cold
HLA-DR ON SALIVARY GLAND CELLS
1107
Figure 1. Immunohistologic evaluation of salivary gland specimens. A, Minor salivary gland
biopsy specimen from a Sjogren’s syndrome (SS) patient, stained with monoclonal antibody
(MoAb) anti-HLA-DR, demonstrating reactivity of the acinar and ductal cells (arrows). B,
Serial section of the salivary gland biopsy specimen from an S S patient, which was reacted
with a control murine myeloma antibody. C, Normal minor salivary gland biopsy specimen,
which was tested with MoAb anti-HLA-DR. D, Serial section of a normal salivary gland
(shown at lower magnification) reacted with MoAb Leu-MS, which detects monocytes and
dendritic cells. E, Frozen tissue section of parotid tumor stained with MoAb anti-HLA-DR,
which reacts with cells in the lymphoid region (brown stain); the epithelial cells were unreactive (only methylene blue counterstain). F, Serial section of parotid tumor stained with
anti-cytokeratin MoAb, showing staining of the epithelial cells (arrow); the lymphoid cells were
unreactive. (A, B, C, E, and F, original magnification x 400;D, original magnification x 100.)
acetone, and stained with monoclonal antibodies using immunoperoxidase techniques.
Microscopy. Photographs of immunoperoxidasestained slides were taken with a Nikon Optiplot microscope.
For scanning electron microscopy, Sal-1 cells were plated on
circular (12-mm) glass coverslips in Linbro 24-well culture
vessels. Established cultures were rinsed in phosphate buffered saline (PBS), pH 7.4, and subsequently fixed in 1%
glutaraldehyde in PBS, pH 7.4, for 15 minutes at room
temperature. After fixation, the samples were subjected to a
graded series of ethanol dehydration, followed by critical
point drying from Freon 13 and carbon shadowing. These
samples were then evaluated by a Hitachi scanning electron
microscope.
RESULTS
Immunohistologic characterization of HLA-DR
expression in salivary gland biopsy specimens. Salivary
gland epithelial cells in specimens from all 12 S S
patients showed staining with anti-HLA-DR antibody
1 1013
FOX ET AL
Figure 2. Induction of HLA-DR antigen on salivary gland-derived cell line. A, Scanning electron microscopic view of the salivary
gland-derived cell line (Sal-l), showing its dendritic morphology (original magnification x 1,000). B, Sal-1 cells cultured for 5 days at 37°C in
the preisence of recombinant yinterferon (y-IFN) (50 international reference unitsiml). The cells were fixed with acetone and stained with
monocllonal antibody (MoAb) anti-HLA-DR using irnmunoperoxidase methods (arrows). C, Sal-1 cells cultured in the absence of yIFN, which
fail to show staining with MoAb anti-HLA-DR (arrows). D, Sal-1 cells cultured in the presence of tissue culture supernatant derived from
mitogem-stimulated salivary gland lymphocytes (SGL) and then stained with MoAb anti-HLA-DR (arrows). E, Sal-1 cells cultured in the
presence of monoclonal anti-yIFN antibody plus cell supernatant from stimulated SGL and then stained with MoAb anti-HLA-DR antibody
(arrows). F, Sal-1 cells cultured as in E, but stained with control murine myeloma protein (arrow). (B, C, and D, original magnification X 100;
E and F, original magnification X 400.)
(Figure 1A). The staining was most marked in areas of
lymphoid infiltration and was barely detectable in
adjacent areas. No staining was noted when a control
myeloima antibody was used in place of the specific
MoAb (Figure IB). A similar pattern of staining also
was noted when MoAb Q513 (which detects distinct
epitopes on HLA-DR) and MoAb B539 (which detects
the invariant y chain associated with the cytoplasmic
HLA-DR ON SALIVARY GLAND CELLS
1109
form of HLA-DR) were used (Fox RI et al: unpublished observation).
In contrast, no detectable staining of the
epithelial cells was noted in normal salivary glands
(Figure lC), although some reactive cells were present
between the epithelial cells. Examination of serial
tissue sections of normal salivary glands revealed that
these HLA-DR positive cells also were stained by
anti-Leu-MS, but were not stained with antibodies
against B cells or against complement receptors CR1
or CR2. These cells are distributed throughout the
normal salivary gland (Figure 1D).
In comparison, we found that the epithelial cells
in a PCL parotid tumor were not stained by antiHLA-DR antibodies (Figure lE), in contrast to the
underlying lymphoid regions. We have recently shown
that the intense staining of the lymphoid component of
this parotid tumor results from a high content of
dendritic-type cells which are reactive with MoAb
Leu-MS and from a few B cells which are reactive with
MoAb B-1 or Leu-12 (16). The epithelial cells in the
parotid tumor could be stained with anti-cytokeratin
antibody (Figure 1F). The underlying lymphoid cells
were not reactive with this MoAb. A similar pattern of
epithelial cell staining (i.e., absence of HLA-DR and
presence of anti-cytokeratin) was noted in 3 of 3 PCL
biopsies.
Induction of HLA-DR on salivary gland epithelial cells by y-IFN. In order to investigate the role of
soluble factors in HLA-DR induction by salivary
gland epithelial cells, a cell line (Sal-1) was established
from a PCL salivary gland tumor. These cells have
been maintained in continuous culture for over 12
months. They exhibit a dendritic morphology under
scanning electron microscopy (Figure 2A) and contain
features at the biochemical and ultrastructural level
which indicate that they are epithelial in origin (Bumol
T, Fox RI: manuscript in preparation). The Sal-1 cell
line can be induced to express HLA-DR by culturing
in the presence of y I F N (50 IRU/ml for 5 days), as
indicated by cytoplasmic staining with MoAb SC-2
(Figure 2B). No cytoplasmic staining was noted when
Sal-1 cells were cultured in the absence of yIFN or
with other lymphokines (a-IFN, P IF N , or IL-2) (Figure 2C). Cell supernatants obtained from stimulated
SGL were able to stimulate synthesis of this class I1
histocompatibility antigen (Figure 2D). When the Sal-1
cells were cultured with monoclonal anti-yIFN antibody plus the SGL supernatant, the induction of
HLA-DR was abolished since no cytoplasmic staining
was detected (Figure 2E). These results suggest that
y IFN is sufficient and necessary for the induction of
this histocompatibility antigen by Sal- 1 cells.
Production of y-IFN by salivary gland lymphocytes. The content of yinterferon in each of the
supernatants from salivary gland lymphocytes was
measured by solid-phase ELISA (Table 1). The
mean k SD a-IFN content was 67 5 11 IRU/ml. The
production of y I F N by normal tonsillar lymphocytes
(64 5 18 IRU/ml) was not significantly different from
that of stimulated salivary gland lymphocytes. In the
absence of mitogen stimulation, neither SGL nor tonsillar lymphocytes produced detectable y I F N (<1
IRU/ml) (Table 1).
DISCUSSION
Epithelial cells lining the ducts and acini of
salivary gland biopsy specimens from SS patients
show intense staining with monoclonal antibodies
against HLA-DR. This reactivity was confirmed using
several different anti-HLA-DR monoclonal antibodies
and using an antibody against the invariant ( y ) chain
associated with HLA-DR molecules. In contrast, no
significant staining of epithelial cells from normal
salivary glands or from parotid PCL tumors was
noted. The presence of HLA-DR antigens in salivary
gland epithelial cells in SS biopsy specimens could be
due either to synthesis by these cells or to passive
acquisition from other cells. The induction of
HLA-DR on a salivary gland cell line by y I F N
suggests that the presence of this antigen is due, at
least in part, to synthesis. The induction of HLA-DR
Table 1. Comparison of production of ?interferon (yIFN) by
salivary gland and lymph node lymphocytes
yIFN, international reference
unitshl
Stimulated
~
Salivary gland lymphocytes
from Sjogren’s syndrome
patients*
Patient 1
Patient 2
Patient 3
Patient 4
Mean ? SD
Tonsillar lymph node
lymphocytes from
normal subjects
(n =: 3), mean SD
*
~~~
Unstimulated
~
71.3
76
48.3
74
67 k l l t
<1
<1
Cl
<1
645 18
<I
<It
* In the absence of mitogen, or after incubation for 72 hours at 37°C
with phytohemagglutinin plus phorbol myristate acetate.
t P < 0.001.
11 1 0
antigens may be important in pathogenesis, since
epithelial cells bearing these molecules may be able to
“present” antigens to T lymphocytes in order to
generate immune responses (2,3).
Our findings on SS specimens are similar to
those observed in biopsies from patients with
Hashimoto’s thyroiditis, where epithelial cells were
found to express HLA-DR antigens (6,7). It is intriguing tbat patients with these autoimmune diseases have
an increased prevalence of HLA-DR3 histocompatibility antigen. Perhaps extrinsic antigens (such as a
virus) or an intrinsic autoantigen(s) may associate with
the HLA-DR present on salivary gland epithelial cells
to initiate or perpetuate immune reactions.
The induction of HLA-DR-like molecules on
non-hematopoietic cells was first demonstrated with
conditioned media from activated T cells, and the
enhancing substance was shown to be y I F N (27-29).
Therefore, we examined supernatants from stimulated
SGL from S S patients and found that these fluids could
stimulate HLA-DR synthesis of a salivary glandderived cell line. The active substance again appears
to be yIFN, since the enhancing activity was abolished by monoclonal anti-yIFN antibody. Furthermore, the induction of HLA-DR could be reproduced
by recombinant yIFN. Thus, this lymphokine appears
to be necessary and sufficient for HLA-DR induction
by salivary gland cells. Other substances, including
mitogens (PHA, PMA) , recombinant a-IFN , recombinant ki-IFN, and recombinant IL-2 were examined, but
no stiinulatory activity was noted.
In summary, the present study demonstrates
the presence of HLA-DR antigens on salivary gland
epithelial cells and shows that this induction may be
caused by yIFN. The HLA-DR molecules on the
epithelial cells may allow these cells to present antigens to immune T cells, and thus hitiatelperpetuate
immune responses. These results extend previous
observations on induction of HLA-DR in human
autoimmune disease (Hashimoto’s thyroiditis) (649,
by demonstrating similar induction in a different disease state, thereby suggesting that this may be a
common feature shared by autoimmune endocrineexocrine disorders. Further, we have demonstrated
the production of y I F N by lymphocytes at the disease
site, iridicating the potential of these cells to mediate
the induction of HLA-DR antigens.
Addendum. After this manuscript was submitted, we
became aware of a report by Lindahl G, Hedfors E,
Klareskog L, Forsum U: Epithelial HLA-DR expression in
FOX ET AL
T lymphocyte subsets in salivary glands in Sjogren’s syndrome. Clin Exp Immunol 61:475482, 1985
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