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Distinct immunologic features of finnish Sjgren's syndrome patients with HLA alleles DRB1.17803910301 DQA1.pdf0501 and DQB10201. Alterations in circulating T cell receptor ╨Ю╤Ц╨Ю╥С subsets

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ARTHRITIS & RHEUMATISM
Val. 39, No. 10, October 1996, pp 1733-1739
8 1996, American College of Rheumatology
1733
DISTINCT IMMUNOLOGIC FEATURES OF
FINNISH SJOGREN’S SYNDROME PATIENTS WITH
HLA ALLELES DRB1*0301, DQA1*0501, ANR DQB1*0201
Alterations in Circulating T Cell Receptor $6 Subsets
TUIJA 0. KERITULA, PEKKA COLLIN, ANNE POLVI, MARKKU KORPELA,
JUKKA PARTANEN, and MARKKU MAKI
Objective. To determine whether there were differences in the circulating T lymphocyte subsets or
clinical features of patients with primary Sjogren’s
syndrome (SS) who were positive for different HLA
alleles.
Methods. Two- and three-color flow cytometry
analyses were performed, using a whole blood lysing
method.
Results. Patients with SS who had the HLA alleles
DRB1*0301, DQA1*0501, and DQB1*0201 had lower
levels of circulating VS1-positive T cell receptor y/S
(TCRy/G) cells and higher levels of circulating
CD45RO-positive TCRyIG cells compared with patients
with SS who did not have these alleles. The patient
subgroup with these alleles also had higher levels of
anti-SS-A/Ro and anti-SS-B/La.
Conclusion. These results indicate that patients
with primary SS may be immunologically divided into
subgroups according to their HLA status. These
immunologic changes in SS may also be typical of other
The Celiac Disease Study Pioject is supported by the Medical
Research Council, the Academy of Finland, the Sigrid Juselius Foundation, the Foundation for Paediatric Research, the Paivikki and
Sakari Sohlberg Foundation, the Medical Research Fund of Tampere
University Hospital, and the Emil Aaltonen Foundation.
Tuija 0. Kerttula, MD: Tampere University Hospital, Tampere, Finland; Pekka Collin, MD, PhD, Mar& Korpela, MD, PhD:
Tampere University Hospital, and Medical School, University of
Tampere, Tampere, Finland; Markku Maki, MD, PhD: Tampere
University Hospital, and Institute of Medical Technology, University
of Tampere, Tampere, Finland; Jukka Partanen, PhD, Anne Polvi.
MSc: Finnish Red Cross Blood Transfusion Service, Tissue Typing
Laboratory, Helsinki, Finland.
Address reprint requats to Tuija 0. Kerttula, MD, Department of Clinical Microbiology, Tampere University Hospital, PO Box
2000, FIN-33521 Tampere, Finland.
Submitted for publication Octoher 4, 1995; accepted in revised form April 16, 1996.
autoimmune disorders in patients with the HLA-DR3
haplotype.
Sjogren’s syndrome (SS) is an autoimmune disease that is characterized by chronic inflammation of the
lacrimal and salivary glands, resulting in keratoconjunctivitis sicca and xerostomia. Many immunologic abnormalities have been identified in patients with SS. These
abnormalities include increased humoral immunoresponses, such as hypergammaglobulinemia, production
of rheumatoid factor and other autoantibodies (1,2), and
elevated levels of antibodies against gliadin, gluten, and
reticulin glycoprotein (3), as well as decreased cellular
immune responses and lymphocyte proliferative responses to various antigens and mitogens (45).
In most previous studies of peripheral blood
lymphocyte subsets in SS, patients with primary SS have
been compared with healthy controls. In those earlier
studies, decreased levels of circulating T lymphocytes (6)
and increased levels of circulating T cell receptor y/S
(TCRyIG) cells (7) were demonstrated in the peripheral
blood of patients with primary SS. Moreover, patients
with primary SS had increased proportions of activated,
HLA-DR+ T lymphocytes, both TCRa/P+ and
TCRy/S+ , which correlated positively with the duration
of disease (8). HLA status most probably played a role in
the immunologic abnormalities seen in those patients.
In addition to SS, several diseases with autoimmune features, including celiac disease and type I
diabetes mellitus, have been associated with the antigens
HLA-B8 and DR3 (9-11). There is evidence that even
in healthy individuals who are positive for HLA-B8 and
DR3, immune regulation and T cell activation are
defective (12-15).
1734
KERTTULA ET AL
T he haplotype HLA-DRB1*0301; DRB3*0101;
DQA1*0501; DQB1*0201 (HLA-DR3; DQ2) has been
associated with SS, particularly in white patients (16);
these same alleles have been shown to be prevalent in
celiac disease (17). Patients with celiac disease have
increased percentages of CD45RO + lymphocytes in
their peripheral blood; these lymphocytes comprise a
primed population of T cells (including memory cells).
This phenomenon is most prominent within the circulating TCRy/G+ population (18). Yet, many immunologic features are now found in latent forms of celiac
disease as well (9,19).
Previous studies have shown an association between SS and celiac disease (20). Patients with SS who
have the the HLA-DR3 haplotype are especially prone
to developing celiac disease, albeit in a clinically silent
form (10). Since many patients with SS have the same
autoimmune-type HLA haplotype as patients with celiac
disease, we hypothesized that in SS in the absence of
celiac disease, increased memory-marker positivity
among TCRyl8-t lymphocytes may be seen, and these
alterations in peripheral blood lymphocyte subpopulations may correlate with certain HLA-DQ alleles. In the
present study, we also examined the clinical features of
patients with SS. In particular, we investigated whether
these patients may be immunologically and clinically
divided into subgroups according to their HLA status.
PATIENTS AND METHODS
Patients and controls. Peripheral blood samples were
collected from 20 patients with primary SS (16 female and 4
male). The diagnosis of primary SS was made according to the
Fox criteria (21). The mean age of the patients was 54 years
(range 27-67). DNA was available for 18 of these patients.
Clinical examination of all patients included the evaluation of
extraglandular manifestations. The presence of celiac disease
was excluded by small bowel biopsy. In addition, all patients
tested negative for serum autoantibodies (9).
Nine healthy adult volunteers from the medical staff (6
female and 3 male) served as controls. Their mean age was 43
years (range 29-60). The control subjects were not HLA typed
because the present study focused specifically on different
subgroups of patients with SS who had different HLA types.
The study protocol was approved by the Ethical Committee of Tampere University Hospital.
Basic laboratory tests. Laboratory measurements included a complete blood cell count, as well as tests for
antinuclear antibodies, rheumatoid factor by immunoturbidimetric method, serum immunoglobulins IgA, IgG, and IgM by
laser nephelometry, anti-SS-A/Ro and SS-B/La antibodies by
enzyme-linked immunosorbent assay (QUANTA Lite;
INOVA Diagnostics, San Diego, CA), and serum Pzmicroglobulin by radioimmunoassay.
HLA typing. The DRBl alleles were typed using a
2-step polymerase chain reaction (PCR) method in whch
group-specific PCR products were digested with a set of
restriction enzymes in order to be able to identify different
alleles in each group. This method can identify up to 24 alleles.
The PCR protocol was identical to that described by Westman
et a1 (22). The DQAl alleles were typed by using the PCR/
restriction fragment length polymorphism method of Ota et a1
(23), which identifies the following alleles: 0101 + 0102, 0103,
0201, 03, 0401, 0501, and 0601. PCR amplification was performed according to the method described by Kimura and
Sasazuki (24). The DQBl alleles were determined by using the
oligotyping method of the Eleventh International Histocompatibility Workshop (24). A total of 17 hybridization probes
were used and they identified all alleles frequently observed in
the Finnish population. The accuracy of our typing methods is
constantly monitored by participation in the DNA exchange
organized by the UCLA Tissue Typing Laboratory.
Lymphocyte counts and phenotype analysis by flow
cytometry. Lymphocyte counts were derived from an automated cell counter (Technicon H1; Tarrytown, NY) on
EDTA-treated blood. Lymphocyte subsets were analyzed by 2or 3-color direct immunofluorescence and flow cytometry with
a FACScan (Becton Dickinson, Oxford, UK) using a lysed
whole blood method. All blood samples were examined within
24 hours after collection.
Monoclonal antibodies (MAb). The following commercial MAb were used: anti-Leu-4 (anti-CD3), anti-Leu-3a
(anti-CD4), anti-leu-2b (anti-CD8), pan-TCRalP (antiTCRaIP), TCRG1 (anti-TCRy/S), GVl(a) (anti-VGl), antiLeu-45RO (anti-CD45RO), anti-HLA-DR (anti-DR), and
anti-interleukin-2 receptor (anti-IL-2R; anti-CD25). PanTCRaIP, TCRGl, and 6Vl(a) were purchased from T Cell
Diagnostics (Cambridge, MA), and all other MAb were from
Becton Dickinson (San Jose, CA). MAb were either fluorescein isothiocyanate conjugated (FITC), phycoerythrin conjugated (PE), or peridin chlorophyll protein conjugated (PerCP).
The following combinations were used: CD4/CD8,
CY/P/CD~~RO/C
CY/P/IL-~R,
D~,
oJP/HLA-DR, y/6/CD45RO/
CD3, y/6/IL-2R, y/G/HLA-DR, or V61/CD45RO/CD3.
Labeling procedure. EDTA-treated blood (100 ~ 1 was
)
incubated with a mixture of direct-labeled MAb. After 15
minutes of incubation at room temperature in the dark,
erythrocytes were lysed by addition of 2 ml of lysis solution
(FACSlyse; Becton Dickinson) and incubated for a further 10
minutes. Following centrifugation at 300g, the cells were
washed once in phosphate buffered saline, resuspended in 500
~1 of sheath fluid (FACSFlow; Becton Dickinson) with 1%
paraformaldehyde, and kept at 4°C until analysis.
Flow cytometry. The lymphocyte population was identified by a combination of light scattering and immunofluorescence, as described by Loken et al (25), using Simultest
LeucoGATE (CD45/CD14) from Becton Dickinson. Calibrate
beads (Becton Dickinson) were used for the instrument setup,
and the fluorescent compensations were adjusted using a
mixture of FITC-conjugated anti-CD4, PE-conjugated antiCD8, and PerCPconjugated anti-CD3. Background fluorescence was determined with FITC-conjugated IgG1, PEconjugated IgG2a, and PerCP-conjugated IgGl control MAb,
and with an unlabeled sample, and subtracted from the results.
Data for 5,000-10,000 lymphocytes were analyzed by FACScan
1735
CIRCULATING TCRyIG CELLS IN PATIENTS WITH SS
Table 1. Percentages of different T lymphocyte subsets in the peripheral blood of patients with Sjogren’s syndrome versus controls*
~~
Cell subset
Lymphocytes
CD3 +
CD4 +
CD8+
alp +
Y/6+
vs1+
Sjogren’s syndrome
(n = 20)
Controls
(n = 9)
P
66.8 i- 10.2
35.8 i- 8.3
31.4 2 10.7
63.6 i- 10.5
3.1 t 3.0
1.2 t 1.6
66.0 f 7.1
41.8 ? 3.9
30.3 ? 6.8
63.4 2 6.9
2.2 ? 1.1
0.95 t- 0.57
NS
NS
NS
NS
NS
NS
30.8 ? 16.0
20.2 ? 9.8
64.4 -C 12.5
17.5 -t 6.5
22.6 t 6.2
57.7 ? 9.1
<0.05
NS
NS
47.1 2 23.6
2.4 2 2.1
45.5 i 26.6
50.8 ? 31.6
40.9 i 14.0
4.5 t 1.6
62.4 f 15.0
42.5 ? 18.3
NS
<0.05
NS
NS
a/p+ cells
HLA-DR +
IL-2R+
CD45RO+
y/6+ cells
HLA-DR+
IL-2R +
CD45RO +
V61+
* Values are the mean t SD percentage of cells. NS
IL-2R = interleukin-2 receptor.
=
not significant;
software (LYSYS 11; Becton Dickinson). To allow better
analysis of CD45RO profiles of the small TCRy/S+ lymphocyte subsets, the live gate was extended with FLl (TCRS1 or
SVl) and FL3 (anti-Leu-4) in such a way that only cells
positive for both MAb were included in the gate. Thereafter,
500-1,000 gated cells, or as many cells as were available, were
collected. The percentage of V61+ TCRyIS cells was calculated on the presumption that all circulating V61 cells were
TCRyIS cells.
Statistical analysis. Data on the lymphocyte subsets
were analyzed by Student’s t-test or Mann-Whitney U test
when appropriate. Student’s t-test, chi-square test with Yates’
correction, and Mann-Whitney U test were used to compare
the clinical parameters and results of basic laboratory tests for
the patients with SS.
RESULTS
Lymphocyte subsets in all patients with SS versus controls. Lymphocyte counts were not significantly
different between patients with SS and controls (mean ?
SD 1.95 +- 1.17 X 109/liter versus 1.94 5 0.37 X
10g/liter).Furthermore, there were no significant differences in the percentages of CD3+, CD4+, CD8+,
TCRaIP+, TCRy/G+, or V61+ lymphocytes (Table 1).
The antigens HLA-DR, IL-2R, and CD45R0,
which indicate activation of a cell, were measured separately in TCRaIP+ and TCRyI8-t cells. The percentage of HLA-DR+ TCRa/P+ cells was markedly increased in the patient group compared with controls
(mean 2 SD 30.8 2 16.0% versus 17.5 -+ 6.5%; P <
0.024), but in TCRyl8-t cells, there were no statistically
significant differences between the groups (Table 1).
The proportions of IL-2R-t TCRa/P+ cells were similar
between the 2 groups, but there was some decrease in
IL-2R+ TCRy/G+ cells in the patients with SS (mean 2
SD 2.4 2 2.1% versus 4.5 5 1.6% in controls; P <
0.014). Lymphocytes expressing CD45RO showed no
statistically significant differences between the 2 groups
(Table 1). The percentage of Val+ cells expressing
CD45RO was also measured and no significant differences were observed (mean -+ SD 20.0 t 13.5% in
patients with SS versus 25.6 2 11.5% in controls).
Lymphocyte subsets in different groups of patients with SS. HLA-DRB1 and DQ alleles were determined in 18 of the patients with SS from whom DNA
was available. According to the results, the patients were
divided into 2 subgroups: patients with the alleles HLADQA1*0501 and DQB1*0201 formed subgroup DQ2+
(9 patients) and those without these alleles comprised
subgroup DQ2- (9 patients). The distribution of the
DRBl and DQ alleles within the 2 subgroups is shown in
Table 2.
There were no statistically significant differences
in the lymphocyte counts between the 2 subgroups of
patients with SS (mean ? SD 1.7 +- 0.9 X 109/liter in
DQ2+ versus 2.3 -+ 1.5 X 109/liter in DQ2-). Moreover, the percentages of CD3+, CD4+, CD8+,
TCRa/p+, and TCRyl8-t cells were comparable between subgroups (Table 3). HLA-DR+ cells showed
Table 2. HLA-DRB1, DQA, and DQB alleles in patients with
Sjogren’s syndrome”
Subgroup,
patient
DQ2+
1
2
3
4
5
6
7
8
9
DQ2 10
11
12
13
14
15
16
17
18
HLA alleles
DRBl
DQA
DQB
0301
15, 0301
0301, 13
0301, 0801/3
01, 0301
0301, 15
01, 0301
0301, 0801/3
0301, 04
0501
010112, 0501
0501, 0101/2
0501, 0401
0101/2, 0501
0501, 0101/2
0101/2, 0501
0501, 0401
0501, 03
0201
0602,0201
0201, 0604
0201, 04
0501, 0201
0201, 0602
0501, 0201
0201, 04
0201, 0302
12, 080113
01, 04
01, 16
01
1.5
15
15, 080113
04, 0801/3
01, 04
0501, 0401
0101/2, 03
0101/2
0101/2
0101/2
010112
0101/2 0401
03, 0401
0101/2, 03
0301, 04
0501, 0302
0501, 0502
0501
0602
0602
0602,04
0302, 04
0501, 0302
* Patients were grouped according to whether they had (DQ2+) or did
not have (DQ2-) both HLA-DQA1*0501 and DQB1*0201.
KERTTULA ET AL
1736
Table 3. Percentages of different T lymphocyte subsets in the peripheral blood of patients with Sjogren’s syndrome who either had
(DQ2+) OT did not have (DQ2-) HLA alleles DQAlr0501 and
DQB1*0201*
0
I+
m
;
v)
Cell subset
Lymphocytes
CD3 +
CD4 +
CD8+
(YIP+
$6 +
V61+
alp+ cells
HLA-DR+
IL-2R+
CD45RO +
y/6+ cells
HLA-DR +
IL-2R+
CD45RO+
V61+
DQ2+
subgroup
(n = 9)
DQ2 subgroup
(n = 9)
P
65.9 2 12.1
37.1 t 7.9
28.2 2 7.5
62.0 2 11.3
3.8 2 3.5
0.96 2 1.2
66.2 ? 8.2
35.8 t 8.7
31.4 t 9.1
63.4 i 9.5
2.7 t 2.9
1.5 t 2.1
NS
NS
NS
NS
NS
NS
25.9 2 9.1
22.1 2 10.3
59.8 2 15.4
38.4 2
2.6 2
58.5 2
33.9 2
21.1
2.8
21.8
26.1
34.0 t 18.7
19.2 f 8.7
69.8 f 8.8
53.4 f 26.0
2.1 f 1.5
34.3 ? 26.2
65.1 t 32.7
* Values are the mean t SD percentage of cells. NS
IL2R = interleukin-2 receptor.
=
Q)
0
NS
NS
NS
NS
NS
<0.05
<0.05
not significant;
some increase in both TCRa/P+ and TCR-yl8-t cells in
subgroup DQ2-, although neither change was statistically significant (Table 3).
Patients with SS who had the DQA1*0501 and
DQB1*0201 alleles (subgroup DQ2-t) had significantly
higher percentages of CD45RO+ TCR-y/G+ cells in
their peripheral blood as compared with patients without these alleles (mean ? SD 58.5 ? 21.8% in DQ2-t
versus 34.3 t 26.2% in DQ2-; P < 0.049) (Figure 1).
The proportion of Val+ TCR7IG-t cells was
calculated and there appeared to be a markedly lower
percentage of these cells in patients with SS who had the
alleles DQA1*0501 and DQB1*0201 compared with
those patients without these alleles (mean t SD 33.9 ?
26.1% in DQ2+ versus 65.1 ? 32.7% in DQ2-; P <
0.040) (Table 3 and Figure 2). Val cells expressing
CD45RO showed no statistically significant differences
between the 2 subgroups of patients with SS (24.6 -+
14.5% in DQ2+ versus 16.7 -+ 12.0% in DQ2-).
Clinical and basic laboratory parameters. The 2
subgroups of patients with SS had no statistically significant differences in clinical parameters. However, according to basic laboratory results, patients with the
DQA1*0501 and DQB1*0201 alleles seemed to be more
immunologically active than patients without these alleles (Table 4). Compared with the DQ2- subgroup,
there were more patients in the DQ2+ subgroup who
were positive for SS-A/Ro antibodies (7 of 9 versus 4 of
-
60
P
+
0
\
40
U
m
n
20
n
-
P
0
8
0
0
0
0
7
0
p<0.05
v
Group DQ2+
Group DQ2-
Figure 1. Frequency of CD45RO expression on T cell receptor y/6+
cells in the peripheral blood of patients with Sjogren’s syndrome who
either had (DQ2+) or did not have (DQ2-) HLA alleles DQA1*0501
and DQB1*0201. Bars show the mean percentage of cells and 95%
confidence intervals.
8) and SS-B/La antibodies (5 of 9 versus 1of 8), although
the differences were not statistically significant. However, the differences were significant when antibody
levels were compared. The level of SS-A antibodies was
61 -+ 60 arbitrary units (mean ? SD) in subgroup DQ2+
100
00
0
-8-
0
0
-0-
0
-
0
0
0
0
0
0
0
Group DQ2+
0
p<o.o5
Group DQ2-
Figure 2. Frequency of Val+ T cell receptor yl6 cells in the peripheral
blood of patients with Sjogren’s syndrome who either had (DQ2+) or
did not have (DQ2-) HLA alleles DQAlr0501 and DQB1*0201. Bars
show the mean percentage of cells and 95% confidence intervals.
1737
CIRCULATING TCRyIG CELLS IN PATIENTS WITH SS
Table 4. Characteristics of patients with primary Sjogren’s syndrome who have the alleles HLADQA1*0501 and DQB1*0201 (DQ2+) compared with those without these alleles (DQ2-)*
Characteristic
Age (years)
Duration of sicca symptoms (years)
Parotid swelling (no. of patients)
Extraglandular manifestations (no. of patients)
Rheumatoid factor positive (no. of patients)
ANA positive (no. of patients)
SS-A/Ro antibodies (no. of patients)
SS-B/La antibodies (no. of patients)
SS-A and/or SS-B antibodies (no. of patients)
SS-A antibodies (arbitrary units)
SS-B antibodies (arbitrary units)
Serum IgG (gmkter)
Serum &-microglobulin (mdliter)
Immunosuppressive treatment
Corticosteroids (no. of patients)
Cytotoxic drugs (no. of patients)
Subgroup DQ2+
(n = 9 )
Subgroup DQ2(n = 9 )
P
49 2 14
13 -t 9
5
4
7
7
7
5
8
61 i- 60
67 t 83
23.9 t 7.2
3.0 2 1.2
57 2 7
11t5
4
4
5
5
4t
It
4t
17 2 26
11 -t 32
20.1 2 6.8
2.6 -t 0.3
NS
NS
NS
NS
NS
NS
NS
NS
NS
<0.05
<0.05
NS
NS
7
2
4
0
NS
NS
* Except where otherwise indicated, values are the mean t SD. ANA
tn=8.
versus 17 -t 26 units in subgroup DQ2- ( P < 0.02), and
the level of SS-B antibodies was 67 ? 83 arbitrary units
in subgroup DQ2-t versus 11 -+ 32 units in subgroup
DQ2- (P< 0.02). There were no statistically significant
differences in any of the other basic laboratory parameters.
DISCUSSION
In the present study, the proportion of HLADR+ TCRa/P cells was increased in patients with
primary SS compared with healthy controls, as has been
reported previously (8). However, the slight increase in
the percentages of all TCRyIS cells and HLA-DR+
TCRyIS cells did not reach statistical significance.
Patients with SS and HLA alleles DRB1*0301,
DQA1*0501, and DQB1*0201 (subgroup DQ2+) had
significantly higher levels of CD45RO-t TCRyIS cells
and lower levels of Val+ TCRyIS cells compared with
patients without these alleles (subgroup DQ2-).
CD45RO is commonly a marker of memory cells, although it may correlate more closely with cell activation
or division than with memory (26). These cells presumably need continuous stimulation by antigen in order to
retain their state of activation (27). However, in the
present study, the antigen was unknown.
The differences in CD45RO expression in
TCRyIG cells between the 2 subgroups of patients with
SS in our study seemed to be mostly due to alterations in
the Val+ subset of TCRyIG cells. In peripheral blood,
most TCRy/G+ lymphocytes express the Vy9-VS2- en-
=
antinuclear antibodies.
coded TCR, whereas a minor subset of lympocytes
express a 8 chain encoded by the VS1 gene segment
(28,29). Yet, these TCRyISS cells display differential
expression of CD45RO. The vast majority of V62+ cells
express CD45R0, while only a minority of V61+ cells
are CD45RO positive (30,31). In other words, a decrease in the proportion of circulating Val+ TCRyIS
cells leads to an increase in the proportion of
CD45RO-t TCRyIS cells.
Patients with SS and HLA alleles DRB1*0301,
DQA1*0501, and DQB1*0201 (subgroup DQ2-t) had
hgher SS-A/Ro and SS-B/La antibody levels than did
patients without these alleles (subgroup DQ2-). Earlier
reports have shown that in SS, autoimmune reactions to
La or Ro antigen are associated with the HLA-DR3
antigen in North European whites (32,33). Furthermore,
patients with primary SS who have high antibody titers
to Ro and/or La antigen also tend to have leukopenia
and hypergammaglobulinemia and are positive for rheumatoid factor more often than other patients with
primary SS (2,32,33). In our study, there were no
statistically significant differences in the latter clinical
parameters, but this may be due partly to the small size
of the subgroups.
According to our results, there appeared to be 2
subgroups of patients with primary SS, those with the
DQAl*0501 and DQB1*0201 alleles and those without
these alleles. It is intriguing to speculate that patients
with primary SS indeed might have a different pathogenetic background, depending on their HLA genetics.
1738
KERTTULA ET AL
We have recently shown that there were elevated
levels of antigen-primed CD45RO + T lymphocytes
(memory cells) in the peripheral blood of patients with
untreated celiac disease, and the elevation was especially
prominent in TCRyIS+ lymphocytes (18). Another finding in patients with untreated celiac disease was a
decrease in circulating Val + lymphocytes (18). Similar
to our results regarding patients with SS, the presence of
HLA-DQA1*0501 and DQB1*0201 alleles, encoding
the HLA-DQ2 molecule, seemed to be most important
in susceptibility to celiac disease (17). There have been
increased densities of Val + TCRyIS intraepithelial
lymphocytes detected in the small bowel mucosa of
patients with celiac disease (34). Moreover, 30% of
healthy family members of patients with celiac disease,
who have normal jejunal morphology, have been shown
to have increased levels of TCRyIS intraepithelial lymphocytes in the normal small intestine (19), indicating
this phenomenon to be genetically determined.
In the present study, we have shown that, in
comparison with other patients with SS, Finnish DQ2+
patients with primary SS show alterations in circulating
T cell subsets similar to those found in patients with
celiac disease. In fact, patients with SS seem to be prone
to developing gluten-sensitive enteropathy (10). Increased densities of V61 cells in small bowel mucosa and
decreased levels of these cells in the peripheral blood of
patients with celiac disease could reflect sequestration of
these cells in the epithelium. In SS, there are lymphocytic infiltrates in exocrine glands. However, the vast
majority of infiltrating T cells in salivary glands express
TCRaIP receptor (3.9, so it is not likely that increased
densities of Val cells could be found in exocrine glands.
Nevertheless, it would be of interest to know whether
patients with SS and the alleles HLA-DQA1*0501 and
DQB1*0201 also have increased densities of jejunal
Val + TCRyIG intraepithelial lymphocytes compared
with other patients with SS.
It is assumed that Val+ T cells may, on the
whole, reflect an important immunobiologic role in the
chronic inflammatory process. There is evidence that, in
addition to the small bowel mucosa in patients with
celiac disease, Val T cells are enriched in the synovial
membrane and synovial fluid in rheumatoid arthritis
(36,37). According to a recent study, these cells could
play a significant role in the destruction of joints in
rheumatoid arthritis, since they may be directly cytotoxic
to the cells that comprise the joint structure (38).
However, the actual pathogenetic role of TCRyIS cells
and their subpopulations in autoimmune disorders remains unclear.
+
In conclusion, our present and earlier studies
indicate that in Finnish patients, primary SS and celiac
disease share common disease-susceptible genes and
immunologic changes. In patients with SS, HLADQA1*0501 and DQB1*0201 alleles might be a marker
of more active immune responses. There is heterogeneity of HLA alleles in many diseases with autoimmune
features but, according to our present findings, it is
possible to speculate that patients who have the DR3DQ2 haplotype may have some immunologic features in
common despite having different diseases. It remains to
be seen whether changes in levels of circulating
CD45RO+ TCRyIS cells and V a l + TCRy/S cells can
be found in healthy individuals with the alleles HLADRB1*0301, DQA1*0501, and DQB1*0201.
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subsets, finnish, features, drb1, dqa1, patients, allele, hla, distinct, syndrome, sjgren, immunologic, circulating, cells, 17803910301, pdf0501, dqb10201, receptov, alteration
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