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Tubuloreticular structures within labial salivary glands in sjgren's syndrome.

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Tubuloreticular Structures within Labial Salivary Glands
in Sjijgren’s Syndrome
Troy E. Daniels, Robert A. Sylvester, Sol Silverman, Jr., Vibeke Polando,
and Norman Tala1
Tubuloreticular structures were found in endothelial cells of biopsies
from labial salivary glands of 6 of 20 patients with Sjiigren’s syndrome,
and were absent in 11 control patients. Patients with these structures
had evidence of severe disease as manifested by xerostomia, lymphoid
infiltrates in the salivary glands, hypergammaglobulinemia, and autoantibodies. The nature of these inclusions remains controversial.
Discrete cytoplasmic inclusions have been
observed within endothelial cells, lymphocytes, and tumor cells from a variety of hu-
man and animal conditions including multisystem autoimmune diseases, neoplasia.
and virus infections (1-3). These inclusions
have been called by a number of d e s a i p
From the Division of Oral Biology, School of
tive terms, including “virus-like’’structures,
Dentistry, and the Department of Medicine, School
of Medicine, University of California, San Francisco: “tubular arrays” (3), and “tubuloreticular
and the Section of Clinical Immunology and Arthri- structures” (TRS) (4). They occur with
tis, Veterans Administration Hospital, San Franhighest frequency in the renal endothelium
cisco, California.
This research was supported in part by the US of patients with systemic lupus erythemaPublic Health Service (General Research Support tows (SLE), but are observed consistently
Grant 5 501 RR-05305) and and the Veterans Adin patients with other connective tissue disministration; it was presented in part at the annual
meeting of the International Association for Dental ease as well (2). Tubuloreticular structures
Research, Washington, DC, April 1973 (Abstract 428). were present in 89% of renal biopsy speciTROY E DANIELS,
DDS: Assistant Professor, Division mens in a series of 36 patients with SLE
of Oral Biology, School of Dentistry, University of
( 5 ) , and were seen in all of another series of
California, San Francisco; ROBERT A SYLVESTER,
Research Associate, Veterans Administration Hospi- 52 patients (2). These structures have been
tal, San Francisco (present address, Maine Medical found in the renal endothelium of patients
Center, Portland, Maine); SOL SILVERMAN,
Professor and Chairman, Division of Oral Biology, with Sjijgren’s syndrome (2,6,7), and there
School ot Dentistry, University of California, San is a report of TRS in the parotid gland of
Francisco; VIBEKE POLANW: Staff Research Associate, one patient with Sjogren’s syndrome (7).
Division of Oral Biology, School of Dentistry, UniSjogren’s syndrome is a multisystem conversity of California, San Francisco: NORMAN TALAL,
MD: Professor of Medicine, School of Medicine, nective tissue disease with diverse clinical
University of California, San Francisco, and Chief, and pathologic features (8,9). The distinSection of Clinical Immunology and Arthritis, Vetguishing clinical features of diminished lacerans Administration Hospital, San Francisco.
Address reprint requests to: Dr Troy E Daniels, rimal or salivary gland function, producing
Division of Oral Biology, School of Dentistry, Uni- keratoconjunctivitis sicca (KCS) or xerostoversity of California, San Francisco, California 94143.
mia, can occur singly or together, and in
Submitted for publication December 31, 1973;
approximately 50% of patients a second
accepted March 27,1974.
Arthritis and Rheumatism, Vol. 17, No. 5 (September-October 1974)
connective tissue disease is present, usually
rheumatoid arthritis. Sjogren’s syndrome
can remain as a slowly progressive disease
with localized glandular dysfunction, or can
progress into virtually any organ system
with a potentially life-threatening prognosis (8,9).
Because both Sjogren’s syndrome and
SLE are autoimmune diseases with multisystem involvement, and because T R S have
been observed in both conditions, we decided to examine tissues systematically for
the presence of TRS in 20 patients with
Sjogren’s syndrome. Labial salivary gland
specimens were chosen because they are
readily available and are often heavily infiltrated by lymphocytes in this disease (10).
for routine histopathologic study and for electron
Electron Microscopy
Specimens were fixed in 1.5% Karnovsky glutaraltlehyde for 2 hours or more at 4°C and postfixed in
1% Millonig buffered osmium tetraoxide for 1 hour
at 4°C. After dehydration, tissue samples were embedded in Epon 812. Ultra thin sections were cut
on a Porter Blum MT-2 ultramicrotome, stained
with saturated uranyl acetate and lead citrate, and
examined on a Siemens-Elmiskop 1A electron microscope.
Tubuloreticular structures were observed
in labial salivary glands from 6 of 20 patients with Sjogren’s syndrome and were
absent from all of 11 control patients (Table 1). I n the six positive specimens the
structures were seen in endothelial cells of
small vessels (Figure 1). I n the specimen
All patients were examined in the Oral Medicine
Clinic of the University of California, San Francisco. from the patient with SLE, TRS were also
Both diagnostic and experimental procedures were seen in lymphocytes that had infiltrated the
explained to the patients and informed consent was glandular stroma and the acini between secobtained. The diagnosis of Sjogren’s syndrome re- retory cells. One of the 5 positive patients
quires the presence of two of three major components of the disease (xerostomia. KCS, connective
tissue disease) (8s). Objective parameters for the
diagnosis of xerostomia were: decreased rate of
stimulated parotid flow bilaterally, abnormal sequential salivary scintigraphy (1l), and lymphoid
infiltration in the labial salivary gland (10). Parameters for KCS included abnormal Schirmer test,
corneal staining by rose bengal solution, and diminished or absent tear lysozyme (8). T h e diagnosis
of rheumatoid arthritis or SLE was based on American Rheumatism Association criteria.
Control patients had connective tissue diseases,
without evidence of KCS or xerostomia, or other
systemic diseases.
Biopsy Specimens
After local anesthetic infiltration deep to the
glandular layer, labial salivary glands were obtained
through a 1.5-cm linear incision in the inferior
labial mucosa, lateral to the midline. The salivary
glands were removed after submucosal blunt dissection of the margins; they were fixed immediately
Table 1. Tubuloreticular Structures in Labial
Salivary Glands of Patients with Various Diseases
Sjogren’s syndrome
Sicca complex without connective
tissue disease
Sicca complex and rheumatoid
Sicca complex and systemic lupus
Sicca complex and polymyositis
or scleroderma
Control patients.
Patients with
5 0 f 11
Oof 4
lof 2
Oof 3
‘Three patients had rheumatoid arthritis, three
had amyloidosis, and one each had systemic
lupus erythematosus, polymyositis, sarcoidosis,
and hemochromatosis without sicca complex.
One patient was undiagnosed.
Arthritis and Rheumatism, Vol. 17, No. 5 (September-October 1974)
Fig 1. Capillary endothelial cell of a labial salivary gland from a patient with Sjogren’s syndrome.
Tubuloreticular structures are present within dilated rough-surfaced endoplasmic reticulum (arrows). (Original magnification X126,OOO.)
Arthritis and Rheumatism, Vol. 17, No. 5 (September-October 1974)
with sicca complex had pseudolymphoma
(9) with lymphoid infiltration in major salivary glands, liver, and gall bladder and also
had a n enlarged supraclavicular lymph
node. T R S were abundant in lymphocytes
from this lymph node.
T h e TRS appeared as randomly arranged
aggregates of microtubules, usually occurring within dilated rough-surfaced endoplasmic reticulum or perinuclear cisternae.
T h e diameter of the individual tubules was
approximately 20 nm. T h e structures were
never observed in regular crystalline array
or as linear rods.
T h e 6 patients whose labial salivary
glands contained T R S were women ranging
in age from 29 to 74 years who had been ill
for 1 to 10 years. They all had KCS, an
increased erythrocyte sedimentation rate,
hypergammaglobulinemia, positive serum
antinuclear factor, and negative LE cell
preparations. In addition, 2 of 6 had rheumatoid factor and 2 of 5 had antisalivary
duct antibody. Their labial biopsies all
showed severe lymphoid infiltration (grade
four by the criteria of Chisholm and Mason) (10). Xerostomia was severe with stimulated rates of parotid flow less than 0.8 ml
per gland in 10 minutes. However, none of
these characteristics or any combination of
them were unique to the patients who had
TRS, being present as well in many of the
other patients.
T h e nature and significance of the tubuloreticular structures are unknown. A viral
origin has been suggested (2) on the basis of
certain morphologic similarities between
TRS and unenveloped nucleocapsids of
known paramyxoviruses (1,2,6), and on the
basis of the elevation of serum antibodies
to several viruses that occurs in patients
with SLE (12-14). However, TRS, which
are usually 20 to 25 nm in diameter, are
larger than most paramyxovirus nudeocap
sids, which are approximately 18 nm in diameter (15). Furthermore, paramyxoviruses
are usually located in the cytoplasm but
outside endoplasmic or perinuclear cisternae, whereas T R S are almost always located
within those membrane-bound spaces (1).
Gyorkey and coworkers (2) suggested that
the structures are not mature infectious virions but rather subviral structures, and that
these structures may represent defective viruses that are etiologically important in
connective tissue diseases. Pincus and associates (15) suggested that the T R S are a
modification of endoplasmic reticulum that
may develop in response to various insults.
SchaE and associates (4) concluded that the
T R S are proteinaceous, that the presence
of nucleic acids seemed unlikely, and that
their data supported the hypothesis that
T R S represent a cellular reaction to unknown factors. Grimley and associates (16)
reported that T R S could be induced after
treatment of a suspension culture of lymphoid cells with 5-bromodeoxyuridine. They
suggested that the structures in lymphoid
cells could represent a host reaction to partially expressed Epstein-Barr virus, or, possibly, a n incomplete form of virus infection.
I n a later paper (1) Schaff and coworkers cytochemically compared T R S from patients
with SLE to chicken cells infected with Newcastle disease virus. They concluded that
although the tubules of T R S are of “viruslike” proportions, there was no evidence
for a relationship to a known paramyxovirus, and that T R S consist principally of
phospholipid and acidic glycoprotein, perhaps representing a host reaction in virustransformed cells. From a study of transplanted human lymphoid tumors, Pothier
and associates (3) suggested that T R S relate
generally to immunoglobulin synthesis and
Arthritis and Rheumatism, Vol. 17, No. 5 (September-October 1974)
that they are more closely associated with
gamma heavy-chain synthesis than with mu
heavy-chain synthesis.
T h e irregular occurrence of T R S in the
labial salivary glands of patients with Sjogren’s syndrome contrasts sharply with their
consistent observation in renal endothelium
of patients with SLE (2). This difference in
the frequency of observation may relate to
the scarcity of T R S within a given specimen, possibly due to a lower proportion of
endothelium in salivary glands compared
to renal cortex. Alternatively, one may
speculate that the T R S represent a cyclic
or transient tissue manifestation corresponding to a stage in the clinical course of the
I t is a pleasure to thank Miss Shirley Carthon
for her valuable clinical assistance, and Drs. Williani
Codfrey, Bruce Ostler, and Khalid Tabbara for performing the ophthalomologic examinations.
I . Schaff Z, Barry DW, Grimley PM: Cytochemistry of tubuloreticular structures in lymphocytes from patients with systemic lupus erythematosus and in cultured human lymphoid
cells: Comparison to a paramyxovirus. Lab
Invest 29:577-586, 1973
2. Gyorkey F, Sinkovics JG, Min KW, et al: A
morphologic study o n the occurrence and
distribution of structures resembling viral
nucleocapsids i n collagen disease. Am J
Med 53: 148-158, 1972
3. Pothier L, Uzman BG, Kasac H, et al: Immunoglobulin synthesis and tubular arrays
in the endoplasmic reticulum in transplanted human tumors of lymphoid origin.
Lab Invest 29:607-613, 1973
4. Schaff Z, Heine U, Dalton AJ: Ultramorphological and ultracytochemical studies on tubuloreticular structures in lymphoid cells.
Cancer Res 322696-2706, 1972
5. Bariety J, Richer D, Appay MD, et al: Frequency of intraendothelial ‘virus-like’ parti-
cles: An electron microscopy study of 376
human renal biopsies. J Clin Pathol 26:2124, 1973
6. Shearn MA* Tu WH,
BG* et al:
Virus-like structures in Sjogren’s syndrome.
Lancet 1:568-569, 1970
7. Albegger KW, Aubock L: Elektronenmikroskopischer Nachweis “virusahnlicher” Einschluszkiirper bei myoepithelialer Sialadenitis im Rahmen des “Sjogrens”-Syndroms.
Arch Klin Exp Ohren Nasen Kehlkopfheilkd
203:153-165, 1972
8. Shearn MA: Sjogren’s Syndrome: Major
Problems in Internal Medicine. Vol 2. Philadelphia, W B Saunders Co, 1971, p 9
9. Tala1 N: Sjiigren’s syndrome and connective
tissue disease with other immunologic disorders, Arthritis and Allied Conditions: A
Textbook of Rheumatology. Eighth edition.
Edited by J L Hollander, DJ McCarty, Jr.
Philadelphia, Lea and Febiger, 1972, p p
10. Chisholm DM, Mason DK: Labial salivary
gland biopsy in Sjogren’s disease. J Clin
Pathol 21:656-660, 1968
1I . Schall GL, Anderson LG, Wolf RO, et al:
Xerostomia in SjBgren’s syndrome: Evaluation b y sequential salivary scintigraphy.
JAMA 216:2109-2116, 1971
12. Hurd ER, Dowdle W, Casey H, et al: Virus
antibody studies in systemic lupus erythematosus. Arthritis Rheum 15:267-274, 1972
13. Evans AS, Rothfield NF, Niederman JC:
Raised antibody titres to E. B. virus in systemic lupus erythematosus. Lancet 1: 167168, 1971
14. Phillips PE, Christian CL: Myxovirus antibody increases in human connective tissue
disease. Science 168:982-984, 1970
15. l’incus T, Blacklow NK, Grimley PM, et al:
Glomerular microtubules of systemic lupus
erythematosus. Lancet 2: 1058-1061, 1970
16. Grimley PM, Barry DW, Schaff Z: Induction of ”virus-like” tubular structures in the
endoplasmic reticulum of human lymphoid
cells treated with 5-bromodeoxyuridine
(BrdU) [Abstract 41873. Fed Proc 32964
abs, 1973
Arthritis and Rheumatism, Vol. 17, No. 5 (September-October 1974)
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