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Departments of
* Dermatology,
Internal Medicine III, and
Medical Statistics, Biometry, and Epidemiology, University of Erlangen-Nurnberg, Erlangen, Germany
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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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Involvement of Th cells in the pathogenesis of PV has been suggested by several epidemiological studies showing that HLA-DRB1*0402 is associated with PV in Jewish populations, and HLA-DQB1*0503 is associated with PV in non-Jewish populations (6, 7, 8, 9). The HLA class II alleles, HLA-DRB1*0402 and HLA-DRB1*1401 (in linkage disequilibrium with DQB1*0503), are also prevalent in drug-induced pemphigus (10).
Both Dsg3-reactive Th1 and Th2 cells have been identified by independent investigations in patients with active PV (11, 12, 13, 14) and pemphigus foliaceus (15). Attempts aimed at quantitating Dsg3-reactive Th1 and Th2 responses in a cohort of PV patients by ELISPOT were not successful due to low precursor frequencies in PV patients receiving immunosuppressive treatment (16). Autoreactive T cells recognized epitopes of the ECD of Dsg3 and were restricted by HLA-DRB1*0402 and HLA class II alleles that were identical or homologous (with regard to peptide binding motifs) to HLA-DRB1*0402 or HLA-DQB1*0503. A previous study suggested that autoreactive T cells of PV patients recognized distinct Dsg3 peptides with conserved anchor motifs required for binding to HLA-DRB1*0402 (17).
A critical role of autoreactive T cells in the induction and regulation of Ab production has been suggested by a recent study (18). By use of ELISPOT assay, anti-Dsg3 autoAb secreted by autoreactive B cells were detected upon in vitro stimulation of peripheral lymphocytes from PV patients with Dsg3. In contrast, activation of autoreactive B cells was virtually absent upon depletion of the peripheral lymphocytes from CD4+ cells (18). In addition, the adoptive in vivo transfer of splenocytes from Dsg3-/- mice immunized with Dsg3 into Dsg3+/+ recombinase-activating gene 2-/- mice led to the induction of Dsg3-specific autoAb accompanied by mucosal erosions characteristic for PV. Transfer of either Dsg3-reactive T or B cells into Dsg3+/+ recombinase-activating gene 2-/- mice did not lead to autoAb production and a PV phenotype, demonstrating that the interaction of both Dsg3-reactive T and B cells was required to induce autoAb production (19).
To better understand the pathogenic role that T cells play in the immune pathogenesis of PV, we assessed in this study whether distinct autoreactive Th cell subsets were associated with the clinical activity of PV and whether T cell recognition of Dsg3 was restricted by specific (i.e., PV-associated) HLA class II alleles. Peripheral Dsg3-reactive Th1 and Th2 cells from 28 PV patients and 25 healthy controls were isolated and quantitated by MACS secretion assay. Furthermore, HLA class II restriction of Dsg3-autoreactive Th cells from patients and healthy donors was thoroughly characterized. The findings of this study suggest that Dsg3-reactive Th2 cells are restricted to patients with PV, and that distinct (i.e., PV-associated) HLA class II alleles are critical for T cell recognition of Dsg3 in PV patients and healthy donors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Heparinized blood samples (40–80 ml) were obtained from a total
of 28 adult patients with acute-onset (n = 9), chronic
active (n = 8), and remittent PV (n =
11) who were seen at the Dermatology Department of University of
Erlangen as well as from 25 healthy control individuals. The clinical
diagnosis of PV was confirmed by 1) histopathology (suprabasal
acantholytic blisters), 2) direct immunofluorescence microscopy
(epidermal intercellular IgG and/or C3 deposits in perilesional skin),
and 3) detection of circulating autoAb by indirect immunofluorescence
microscopy (intercellular IgG binding to epithelial cells of monkey
esophagus) and/or the presence of autoAb against Dsg3 that were
detected by a commercial ELISA (MDL, Naka-ku Nagoya, Japan; Table I
). PV patients with cutaneous blisters
had also autoAb against Dsg1 (Table I). Acute-onset PV was defined as
the de novo development of blisters/erosions on previously unaffected
mucosal surfaces and/or skin; all the studied patients with acute PV
had not yet received immunosuppressive therapy. Chronic active PV was
defined as the expansion/persistence of existing blisters or erosions
on mucosal surfaces and/or skin; some of these patients had already
received immunosuppressive treatment. Patients with remittent PV had
not experienced new mucosal blisters/erosions for 
6 mo before the
study (Table I). HLA class II genotyping was performed in all patients
and controls. The determination of HLA-DRB1 and DQB1 alleles was
conducted at high resolution by enzyme-linked probe hybridization assay
(Biotest, Dreieich, Germany) using locus-specific PCR products as
templates. All PV patients and healthy control donors gave written
consent to participate in this study.
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The recombinant protein PVhis, a fusion protein consisting of the EC1–5 of Dsg3 linked to an E tag and a histidine tag, was used as a source of human Dsg3 (20). PVhis baculovirus was amplified in SF21 insect cells as described previously (13). For the production of Dsg3 protein, 3 x 108 High-Five insect cells were inoculated with PVhis baculovirus at a multiplicity of infection of 10. Culture supernatants of baculovirus-infected insect cells were collected after 4 days, and Dsg3 protein was purified from culture supernatants over nickel-nitrilotriacetic acid-linked agarose (Qiagen, Hilden, Germany) according to the manufacturer’s instructions.
Quantitation of Dsg3-reactive Th1 and Th2 cells by MACS cytokine secretion assay
Autoreactive T cells were isolated by MACS following the
manufacturer’s protocol (Miltenyi Biotec, Bergisch Gladbach, Germany).
In brief, autoreactive Th1 cells (secreting IFN-
) and Th2 cells
(secreting IL-4) were isolated from short term (16-h) cultures with
6–8 x 107 PBMC of PV patients/controls and
10 µg/ml Dsg3. Upon termination of the cultures, high affinity
anti-cytokine Ab were added that bound to the surface of the
cytokine-secreting T cells, and labeling with a secondary magnetic
bead-coupled Ab allowed for specific enrichment of IL-4- or
IFN--secreting T cells by passage over magnetic columns
(21) that were finally counted in a hemocytometer.
IFN--secreting Th cells were classified as Th1 cells and
IL-4-secreting Th cells as Th2 cells.
Propagation of Th1 and Th2 cells and proliferative T cell assays
Following isolation by MACS assay, Dsg3-reactive Th1 and Th2
cells were cloned by limiting dilution and were expanded by repeated
stimulation with 1% PHA (Life Technologies) and x-irradiated (50 Gy)
PBMC as APC as described previously (13, 22). For
proliferative assays, human T cells were cultured in a medium
consisting of RPMI 1640 (Life Technologies) with 10% heat-inactivated
pooled human serum (Life Technologies), 100 U/ml of penicillin, 100
µg/ml of streptomycin, and 20 mM L-glutamine. Th cells
(5 x 104) were cultured in duplicate with
5 x 104 x-irradiated (50 Gy) autologous
PBMC in 200-µl round-bottom microtiter plates (Costar, Cambridge, MA)
for 72 h at 37°C in 5% CO2. T cell
proliferation was determined by the incorporation of
[3H]thymidine (DuPont, Mechelen, Belgium) that
was added for the last 18 h of the culture. T cell proliferation
was expressed as a stimulation index (SI), which is the ratio of
[3H]thymidine uptake (cpm) in cultures with Ag
to that in cultures without Ag. SI values >3 were considered
significant. In addition, 100 µl of supernatants were removed from
each culture for the analysis of immunoreactivity against IL-4 and
IFN- according to the manufacturer’s instructions (BD PharMingen,
Heidelberg, Germany).
HLA restriction assays
Cloned T cells (5 x 104) were cocultured for 72 h with 5 x 104 x-irradiated (80 Gy) autologous or HLA-matched B lymphoblastoid cell line (B-LCL) cells and 10 µg/ml of Dsg3 for 72 h, and T cell proliferation was determined by the incorporation of [3H]thymidine (DuPont) that was added for the final 18 h of the culture (23). For the HLA blocking experiments, mAb against HLA-DR (clone L243), HLA-DQ (clone SK10), or HLA-DP (clone B7/21; at 50 ng/well; all from BD PharMingen) were added to the cocultures with Dsg3-reactive T cell clones and B-LCL as APC. Again, the proliferative T cell response to Dsg3 was determined by the incorporation of [3H]thymidine (DuPont) that was added for the final 18 h of the culture.
Statistical analyses
In addition to descriptive uni- and bivariante statistics, the
association between the clinical activity of PV and Dsg3-reactive Th
response and the autoAb profile, respectively, was statistically tested
with the Kruskal-Wallis test (Fig. 2). In view of sparse and skewed
data, which render asymptotic test results unreliable, exact
p values were computed. Correlation was analyzed using the
Spearman rank correlation coefficient. The statistical software package
SAS (version 8.2, SAS Institute, Cary, NC) was used for data
analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The majority (23 of 28) of the studied PV patients expressed
either HLA-DRB1*0402 (39%) or HLA-DQB1*0503 (43%), HLA class II
alleles that are prevalent in PV (Table I
). Independent from the
clinical activity and the immunosuppressive treatment of PV, all PV
patients mounted detectable Th2 responses against Dsg3, ranging from
3.2–9.6 cells/105 PBMC (Fig. 1A). Statistical analysis
revealed that there were no significant differences in the Th2
frequency in acute-onset, chronic active, or remittent PV (Fig. 2A). In contrast,
Dsg3-reactive Th1 responses that were also identified in all the PV
patients varied in frequency in the studied subgroups (Fig. 1A). The eight patients with chronic active PV mounted
Dsg3-reactive Th1 cell responses that were significantly higher than
those in the groups of PV patients with acute-onset and remittent
disease (Fig. 2A). Since variation in Th1 frequency among
the three disease classes was significant (p =
0.016) and variation in Th2 frequency was not
(p = 0.36; Fig. 2A) we sought to
assess whether the Th1/Th2 ratio related to the levels of Dsg3-reactive
IgG. In fact, there was a strong correlation between the Th1/Th2 ratio
and IgG1 (0.82), IgG4 (0.66), as well as total IgG autoAb (0.73)
reactive with Dsg3, which was significant (p <
0.0001) for all these parameters (Fig. 2B). Noteworthy,
there was no correlation between the ratio of Dsg3-responsive Th1/Th2
cells and IgG titers against Dsg1 (0.05; p = 0.82) that
were present in some of the patients’ sera. There was also no
relationship between the frequency of Dsg3-reactive Th1 cells and
Dsg3-reactive IgG in the healthy donors, since Dsg3-reactive autoAb
were not detected (not shown).
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Thirteen of 28 randomly chosen healthy donors carried the
PV-prevalent HLA class II alleles, HLA-DRB1*0402 and/or HLA-DQB1*0503,
while the remaining 15 donors expressed PV-unrelated HLA class II
alleles (Fig. 1B). None of the healthy donors had
circulating autoAb against Dsg3 as determined by ELISA or immunoblot
with recombinant Dsg3, as described recently (24). All
healthy carriers of the PV-associated HLA class II alleles,
HLA-DRB1*0402 and HLA-DQB1*0503 (Co18 carried both HLA alleles),
exhibited T cell reactivity against Dsg3 that was exclusively of the
Th1 type (Fig. 1B). In these healthy donors, Dsg3-reactive
Th1 cells were detected at frequencies similar to those of the PV
patients (Fig. 1B). In contrast, none of the healthy
carriers of PV-unrelated HLA class II alleles exhibited Dsg3-specific
Th1 or Th2 responses (Fig. 1B).
Cytokine profile of long term cultured Dsg3-reactive Th1 and Th2 cell clones isolated by MACS secretion assay
The Ag specificity and cytokine profile of Dsg3-reactive Th1 and
Th2 cell clones that were isolated by MACS secretion assay was
investigated upon in vitro culture of T cells. MACS-selected Th1 cell
clones (n = 13) from three PV patients continued to
secrete IFN-, but no IL-4, upon stimulation with Dsg3 (Fig. 3A), while autoreactive Th2
cell clones (n = 18) from three PV patients secreted
IL-4, but no IFN-, upon in vitro challenge with Dsg3. Shown in Fig. 3A are representative data for five Th1 and four Th2 clones
from the PV patient PV1. Accordingly, a total of 16 Dsg3-reactive Th1
clones from three Dsg3-reactive healthy donors maintained their
cytokine profile (i.e., secretion of IFN-, but not IL-4) upon in
vitro challenge with Dsg3; shown in Fig. 3B are
representative data for nine Th1 clones from the healthy donor Co16.
Upon long term culture (i.e., more than third Ag stimulation), most
autoreactive T cell clones from PV patients and healthy controls showed
a decreased proliferative in vitro response to Dsg3 (Fig. 3, A and B). Noteworthy, all the Th clones retained
their cytokine profile, i.e., Th1 clones produced exclusively IFN-
and Th2 clones secreted IL-4, but no IFN-. There may have been a
potential bias toward the selection of Th1 cells that produced high
amounts of IFN-, but not of Th1 cells that produced low amounts of
IFN-. We have not performed titration studies to evaluate the
efficacy of the MACS secretion assay to detect Th1 cells that produce
little IFN-. However, selective isolation of T cells that produced
high IFN- seems rather unlikely, since the MACS-selected Th1 clones
produced variable amounts of IFN- (Fig. 3).
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In light of the preferential detection of HLA-DRB1*0402 and
HLA-DQB1*0503 in the studied PV patients and Dsg3-reactive healthy
donors, we sought to assess whether these PV-associated HLA class II
alleles restricted T cell recognition of Dsg3. Dsg3-reactive Th cell
clones from PV patients and Dsg3-reactive healthy donors were
cocultured with autologous HLA-DRB1*0402+ or
HLA-DQB1*0503+ B-LCL as APC and Dsg3. T cell
clones 1–5 from DRB1*0402+ PV patients PV10 and
PV18 were stimulated by Dsg3 in the presence of DRB1*0402 homozygous
B-LCL as APC (Fig. 4A). In
addition, T cell clones 3–5 were stimulated by Dsg3 with DQB1*0503
homozygous B-LCL as APC (Fig. 4A). T cell clones 6–10 from
HLA-DQB1*0503+ PV patients PV1 and PV21 were
stimulated by Dsg3 with DQB1*0503+ as well as
with DRB1*0402+ B-LCL as APC (Fig. 4B). Dsg3-responsive T cell clones 11–14 from
DRB1*0402+ donor Co16 were only stimulated in the
presence of DRB1*0402+ B-LCL as APC (Fig. 4C). Similarly, T cell clones 15–18 from
DQB1*0503+ donors Co23 and Co24 were stimulated
only with DQB1*0503+ B-LCL as APC (Fig. 4D).
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. In the PV patients, two distinct
restriction patterns were identified. The proliferative response of the
Dsg3-reactive T cell clones 1–5 from DRB1*0402+
PV patients PV10 and PV18 that recognized Dsg3 with
DRB1*0402+ (Fig. 5A) or
DQB1*0503+ (Fig. 5B) B-LCL as APC was
almost completely inhibited by anti-DR (Fig. 5A) and
anti-DQ Ab (Fig. 5B), respectively. Accordingly, the
proliferative response of the Dsg3-reactive T cell clones 6–10 from
DQB1*0503+ PV patients PV1 and PV21 that
recognized Dsg3 with DRB1*0402+ (Fig. 5C) and DQB1*0503+ (Fig. 5D) B-LCL as APC was almost completely inhibited by
anti-DR (Fig. 5C) and anti-DQ Ab (Fig. 5D), respectively. In contrast, Dsg3-reactive Th1 clones
11–14 from HLA-DRB1*0402+ healthy donor Co16
were only stimulated by Dsg3 with DRB1*0402 homozygous B-LCL as APC,
and their proliferative response was blocked by anti-DR Ab (Fig. 5E). Dsg3-reactive Th1 clones 15–18 from
HLA-DQB1*0503+ healthy donors Co23 and Co24 were
stimulated by Dsg3 only with DQB1*0503 homozygous APC, and their
proliferative response was blocked by anti-DQ Ab (Fig. 5F).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4-secreting Dsg3-reactive T cells were indeed of the Th1 and Th2
types, respectively, because they retained a polarized cytokine profile
upon long term in vitro culture. The selection of Th1 and Th2 cells was
specific for Dsg3-responsive T cells, since we were unable to isolate
either Th1 or Th2 cells from PBMC of Dsg3-unresponsive healthy donors
that had been cultured in vitro with Dsg3 for 16 h before MACS
secretion assay (Fig. 1B). This observation clearly
demonstrates that both autoreactive Th1 and Th2 cells are present in
PV, although at different frequencies during the course of the
disease. These findings extend previous studies that derived both
Dsg-reactive Th1 and Th2 clones from the peripheral blood of patients
with PV (11, 12, 13, 14, 23). Their detection, however, requires
assay systems of adequate sensitivity, as demonstrated herein compared
with ELISPOT analysis (16). In this report we demonstrate that T cell recognition of Dsg3 in several PV patients and Dsg3-responsive healthy controls is restricted by the PV-associated HLA class II alleles, DRB1*0402 and DQB1*0503. We found that only APC expressing HLA-DRB1*0402 and HLA-DQB1*0503 were capable of presenting Dsg3 to autoreactive Th1 and Th2 clones and that their proliferative response was blocked by anti-DR and anti-DQ Ab, respectively. Therefore, HLA-DRB1*0402 and HLA-DQB1*0503 appear to be the major HLA class II alleles involved in restriction of T cell responses against Dsg3 peptides, thus confirming previous evidence of DRB1*0402 as a restriction element for the presentation of Dsg3-derived peptides (11, 12, 23).
Some of the autoreactive Th clones from the
HLA-DRB1*0402+ PV patients were also stimulated
by Dsg3 in the presence of both DRB1*0402+ and
DQB1*0503+ APC, and Th clones from the
HLA-DQB1*0503+ PV patients were also stimulated
by Dsg3 in the presence of both DQB1*0503+ and
DRB1*0402+ APC. These findings strongly suggest
that autoreactive T cells from PV patients recognize certain (not yet
identified) Dsg3 peptides that bind to both DRB1*0402 and
HLA-DQB1*0503. It is noteworthy that both HLA class II alleles share a
negative charge at a critical peptide binding site. Moreover, a recent
study from our laboratory showed in healthy donors that Dsg3 peptides
may also be presented by HLA class II alleles that share distinct
peptide binding motifs with the PV-associated HLA-DRB1*0402 or
DQB1*0503 alleles. Dsg3-reactive T cell clones from a Dsg3-reactive
healthy donor were restricted by HLA-DRB1*1102 that shares the
negatively charged residues, asparagic acid and glutamic acid, at
positions DR
70 and 71 with the PV-associated allele,
HLA-DRB1*0402, and by HLA-DQB1*0301 that shares asparagic acid at
position B57 with the PV-associated HLA-DQB1*0503 (14, 23). The importance of these distinct peptide binding motifs of
the aforementioned HLA class II alleles is supported by the
identification of Dsg3 peptides, such as peptide
DG190–204, that carry a positive charge at the
P4 pocket that may be critical for binding to the negatively charged P4
pockets of DRB1*0402 (DR70 and -71) and DQB1*0503 (DQ57)
(17, 25). The ongoing identification of immunodominant T
cell epitopes of Dsg3 will help to address the question of whether some
Dsg3 peptides promiscuously bind to both DRB1*0402 and DQB1*0503.
Of particular interest is the exclusive detection of Dsg3-reactive Th1
cells in healthy carriers of the PV-associated HLA class II alleles,
HLA-DRB1*0402 and HLA-DQB1*0503. In addition, Dsg3-reactive Th1 clones
derived from these Dsg3-reactive healthy donors were indeed restricted
by HLA-DRB1*0402 and DQB1*0503, respectively. This finding strongly
suggests that T cell recognition of Dsg3 in PV patients and healthy
individuals depends on the presentation of Dsg3 peptides by distinct
HLA class II alleles independent from the development of PV. This
observation extends a previous study from our group that detected
peripheral T cell responses to Dsg3 in a subset of healthy donors
(13). This finding is not unexpected, since T cells
specific for the autoantigens of multiple sclerosis, myelin basic
protein (MBP) and proteolipid protein, have been also identified
in healthy individuals and in the cord blood of newborns
(26, 27, 28). A recent study demonstrated that monozygotic
twins discordant for systemic sclerosis both carried
topoisomerase-specific, autoreactive T cells (29).
Autoreactive T cells from the twin with systemic sclerosis and the
healthy brother were able to promote the production of
topisomerase-specific autoAb by B cells from the diseased twin,
suggesting that lack of peripheral B cell tolerance was critical for
the development of the disease. The frequencies of Dsg3-autoreactive Th
cells in PV patients and Dsg3-reactive healthy individuals found in the
present study are comparable to those of MBP-reactive T cells
(
1/5000 T cells and 1–10/106 PBMC,
respectively) in patients with multiple sclerosis and MBP-reactive
healthy donors (30, 31). Moreover, autoreactive T cells
specific for pyruvate dehydrogenase were detected at a frequency of
4.5–8/105 PBMC in the peripheral blood of
patients with primary biliary cirrhosis by HLA class I tetramer
staining (32). Thus, the frequencies of autoreactive Th
cells specific for major human autoantigens seem to be in a similar
range in both patients and autoantigen-reactive healthy
individuals.
The findings of this study strongly suggest that there is a direct
relationship between the frequency of autoreactive Th1 and Th2 cells
and the titers of Dsg3-reactive IgG1 and IgG4 Ab. Moreover, in chronic
PV, the frequency of Dsg3-reactive Th1 cells was significantly
increased. This Th1 predominance is paralleled by a switch from the
Th2-regulated IgG4 to the Th1-regulated IgG1 Dsg3-reactive autoAb in
chronic PV as shown by previous studies (4, 24). Since all
patients with chronic PV received systemic glucocorticoids and
immunosuppressive adjuvants, the observed Th1 increase may have been
biased by the therapeutic regimen. This seems unlikely in light of a
recent serological study showing that there is, rather, a decrease in
Th1 cytokines (IFN-, TNF-
) in patients with Graves’ disease upon
systemic treatment with glucocorticoids (33). Moreover, an
independent study with ragweed- and tetanus toxoid-specific human
Th1 and Th2 clones showed that corticosteroids had a suppressive effect
on both Th1-derived (IFN-) and Th2-derived (IL-4, IL-5, IL-13)
cytokine expression (34).
A synergistic interplay of autoreactive Th1 and Th2 cells seems to be critical for promoting IgG1 and IgG4 secretion by Dsg3-reactive B cells in the pathogenesis of PV. This is supported by the finding that neither the frequency of Dsg3-reactive Th2 cells in PV patients nor that of Th1 cells in Dsg3-reactive healthy donors was directly related to the titers or the presence of Dsg3-specific IgG autoAb, respectively. Thus, even though Dsg3-reactive Th2 cells (which were restricted to the PV patients) are presumably critical for the development of PV, the simultaneous presence of both Th1 and Th2 related best to the titers of autoAb against Dsg3. Similarly, in patients with systemic sclerosis (scleroderma), both topoisomerase-specific Th1 and Th2 cells synergistically activated autologous B cells to produce topisomerase-specific autoAb (35); T cell help for Ab production was strictly dependent on the secretion of IL-2 and IL-6 (35). A similar observation was made in patients with systemic lupus erythematosus. Histone-specific autoreactive Th1 and Th0 cells were able to induce the secretion of anti-histone or anti-DNA autoAb upon in vitro coculture with autologous B cells (36). Autoreactive Th1 cells with a conserved TCR were identified in myasthenia gravis, suggesting a role for these cells in the pathogenesis of this autoimmune disorder (37, 38). However, there is only proof for a critical role of autoreactive Th2 cells in promoting anti-acetylcholine-specific autoAb production in myasthenia gravis (38). Our findings together with the mentioned in vitro studies strongly suggest that autoAb production in PV depends on both autoreactive Th1 and Th2 cells. We hope that ongoing in vitro coculture studies of autoreactive Th and B cells will help to clarify the role that these Th subsets play in the maintenance of autoimmunity vs tolerance against Dsg3.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael Hertl, Department of Dermatology, University of Erlangen, Hartmannstrasse 14, D-91054 Erlangen, Germany. E-mail address: michael.hertl{at}derma.imed.uni-erlangen.de
3 Abbreviations used in this paper: autoAb, autoantibody; Dsg1, desmoglein 1 (autoantigen of pemphigus foliaceus); Dsg3, desmoglein 3 (autoantigen of pemphigus vulgaris); ECD, extracellular domain; MBP, myelin basic protein; PV, pemphigus vulgaris; SI, stimulation index; B-LCL, B lymphoblastoid cell line.
Received for publication August 8, 2002. Accepted for publication November 4, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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allele associated with pemphigus vulgaris. Science 239:1026.This article has been cited by other articles:
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  C. Veldman, A. Pahl, S. Beissert, W. Hansen, J. Buer, D. Dieckmann, G. Schuler, and M. Hertl Inhibition of the transcription factor foxp3 converts desmoglein 3-specific type 1 regulatory T cells into th2-like cells. J. Immunol., March 1, 2006; 176(5): 3215 - 3222. [Abstract] [Full Text] [PDF]
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C. Veldman, A. Hohne, D. Dieckmann, G. Schuler, and M. Hertl Type I Regulatory T Cells Specific for Desmoglein 3 Are More Frequently Detected in Healthy Individuals than in Patients with Pemphigus Vulgaris J. Immunol., May 15, 2004; 172(10): 6468 - 6475. [Abstract] [Full Text] [PDF]
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C. M. Veldman, K. L. Gebhard, W. Uter, R. Wassmuth, J. Grotzinger, E. Schultz, and M. Hertl T Cell Recognition of Desmoglein 3 Peptides in Patients with Pemphigus Vulgaris and Healthy Individuals J. Immunol., March 15, 2004; 172(6): 3883 - 3892. [Abstract] [Full Text] [PDF]
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