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ß Protein Dimer, the Class II MHC Molecule Associated with Protection from Insulin-Dependent Diabetes Mellitus1
*
Virginia Mason Research Center and
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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ß dimer in SDS may play a role in IDDM
protection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß dimers have the property of being resistant to
denaturation in SDS to varying degrees (1). However, in
HLA-DM-deficient cells this SDS-resistant property is generally lost
(2, 3, 4, 5, 6). Peptides eluted from MHC class II allelic proteins
on HLA-DM-deficient cells are predominantly derived from invariant
chain instead of being derived from multiple protein sources
(7, 8, 9). This phenotype is consistent with the function
described for HLA-DM as a peptide editor (10, 11, 12, 13).
Peptides such as the class II-associated invariant chain peptide,
CLIP3, are removed by HLA-DM, and peptides
with slower intrinsic rates of dissociation are added to MHC class II
proteins. In addition, the SDS-stability property of MHC class II
ß dimers can be induced by the addition of specific peptides
(7, 9, 14, 15). Thus, the SDS-stability property of MHC
class II allelic proteins is associated with loss of invariant chain
and binding of antigenic peptides.
The significance of the SDS stability of MHC class II ß dimers in
a physiologic context is suggested by the observation that the HLA-DM
mutants are defective in the processing and presentation of exogenous
Ags (4, 5, 6, 16). A correlation between SDS stability and
t1/2 has also been suggested, such that MHC
class II allelic proteins that are more SDS stable have a longer
t1/2 (1, 17). Carrasco-Marin et al.
demonstrated that the unique MHC class II molecule found in the mouse
model for insulin-dependent diabetes mellitus (IDDM), the nonobese
diabetic (NOD) mouse, is less SDS stable than other I-A alleles
(1).
In human IDDM, there is a hierarchy of genetic associations, in which
HLA-DQA1*0301/DQB1*0302 is the predominant HLA class II allele
associated with susceptibility in IDDM and HLA-DQA1*0102/DQB1*0602 is
the predominant HLA class II allele associated with protection, even in
individuals that carry HLA-DQA1*0301/DQB1*0302 (18, 19, 20).
Other HLA-DQ genotypes such as HLA-DQA1*0301/DQB1*0301 and
HLA-DQA1*0102/DQB1*0604 are not associated with IDDM, even though these
later genotypes are structurally very similar to the susceptible
allele, HLA-DQA1*0301/DQB1*0302, and protective allele,
HLA-DQA1*0102/DQB1*0602, respectively. We have analyzed the SDS
stability properties for these and other HLA class II allelic proteins
expressed in EBV-transformed B lymphoblastoid cell lines (B-LCL), PBLs,
and a HLA-DM-negative cell line, and find an unusually stable phenotype
for the ß dimer encoded by the IDDM-dominant protective
allele, HLA-DQA1*0102/DQB1*0602.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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EBV-transformed B-LCLs from the Xth International Histocompatibility Workshop include MGAR (DQA1*0102/DQB1*0602), AMAI (DQA1*0102/DQB1*0602), HOM-2 (DQA1*0101/DQB1*0501), DEU (DQA1*0301/DQB1*0301), BSM (DQA1*0301/DQB1*0302), COX (DQA1*0501/DQB1*0201), OMW (DQA1*0103/DQB1*0603), HHKB (DQA1*0103/DQB1*0603), EMJ (DQA1*0102/DQB1*0604), and WT47 (DQA1*0102/DQB1*0604) (21). Other EBV-transformed B-LCLs used in this study include LG2 (DQA1*0101/DQB1*0501), PF97387 (DQA1*0301/DQB1*0301), PRIESS (DQA1*0301/DQB1*0302), and MAT (DQA1*0501/DQB1*0201), and were HLA typed by high resolution oligonucleotide typing (Puget Sound Blood Center, Seattle, WA). BLS-1 was a gift from Janet Lee (Memorial Sloan Kettering Cancer Center, New York, NY) (22). BLS-1 is a HLA class II-null EBV-transformed B-LCL generated from the cells of a patient with bare lymphocyte syndrome (BLS), complementation group B (22, 23). Cells were grown in Iscove’s-modified Dulbecco’s medium with L-glutamine and 25 mM HEPES buffer (Life Technologies, Gaithersburg, MD) supplemented with 10% FBS, 1 mM sodium pyruvate, 50 U/ml penicillin, and 50 µg/ml streptomycin. PBLs were isolated by Ficoll-Hypaque gradient and were HLA typed by high resolution oligonucleotide typing.
Generation of BLS-1 cell lines expressing HLA-DQ and HLA-DR alleles
BLS-1 cell lines expressing HLA-DQA1*0101/DQB1*0501 (encodes DQ0501), HLA-DQA1*0102/DQB1*0602 (encodes DQ0602), HLA-DQA1*0102/DQB1*0604 (encodes DQ0604), HLA-DQA1*0501/DQB1*0201 (encodes DQ0201), HLA-DQA1*0301/DQB1*0301 (encodes DQ0301), HLA-DQA1*0301/DQB1*0302 (encodes DQ0302), HLA-DRA1*0101/DRB1*0101 (encodes DR1), HLA-DRA1*0101/DRB1*0301 (encodes DR3), and HLA-DRA1*0101/DRB1*0401 (encodes DR4w4) were generated by retroviral-mediated gene transfer as previously described (24). Briefly, the DQA and DRA cDNAs were cloned into the retroviral vector pLHCL6 and the DQB and DRB cDNAs were cloned into the retroviral vector pLNCL6. PE501 fibroblasts (5 x 105) were plated in 60-mm plates and the next day 10 µg of retroviral vector DNA containing the cDNA of interest was transfected by calcium phosphate precipitation. PG13 fibroblasts (5 x 105) were plated in 60-mm plates and the next day supernatants (10 to 1000 µl) from the PE501 transfected cells were used to infect PG13 fibroblasts in the presence of 4 µg/ml polybrene. Infected PG13 fibroblasts were selected with 1 mg/ml G-418 sulfate (pLNCL6 vector) or 300 µg/ml hygromycin (pLHCL6 vector) and drug resistant colonies were isolated and expanded. Viral titer of the isolated colonies was determined using canine cf2th fibroblast cells. PG13 virus-producing cells (5 x 105) were plated in 60-mm plates and the next day were irradiated and cocultivated with BLS-1 cells (2 x 106) in the presence of 4 µg/ml polybrene for 24 h. The infected cells were transferred to 100-mm plates and 2 h later to flasks to separate the infected BLS-1 cells from the fibroblasts. 1 mg/ml G-418 sulfate (pLNCL6 vector) or 300 µg/ml hygromycin (pLHCL6 vector) was used for selection, and BLS-1 cell lines stably expressing HLA-DQ and HLA-DR were characterized by flow-cytometric analysis with anti-HLA-DQ and -DR mAbs.
Antibodies
SPVL3 hybridoma cells were obtained from DNAX Research Institute
of Molecular and Cellular Biology (Palo Alto, CA). SPVL3 mAb (IgG2a)
recognizes monomorphic epitopes specific to HLA-DQ dimers
(25). Purified 1a3 mAb (IgG2a) was purchased from
Biodesign International (Kennebunk, ME). 1a3 mAb recognizes monomorphic
epitopes on HLA-DQ dimers (26). GS200.1 hybridoma cells
were kindly provided by Susan Radka NexStar Pharmaceutical, Boulder,
CO). GS200.1 mAb (IgG2a) is a dimer-specific Ab that recognizes, of the
HLA-DQ allelic proteins included in this analysis, DQ0501, DQ0602,
DQA1*0103/DQB1*0603 (encodes DQ0603), DQ0604, and DQ0302
(27). 2H3 hybridoma supernatant was kindly provided by
Thomas Dyrberg (Gentofte, Denmark). 2H3 is an anti-peptide mAb
(IgG1) directed to amino acid residues 39–52 of the ß-chain of
HLA-DQ and recognizes the same HLA-DQ allelic proteins as GS200.1
(28). L243 hybridoma cells were purchased from American
Type Culture Collection (Rockville, MD). L243 mAb (IgG2a) recognizes a
monomorphic epitope on HLA-DR dimers (29). DA6.147
hybridoma cells were a kind gift of Veronica Van Heyningen (Edinburgh,
Scotland). DA6.147 mAb recognizes an epitope on the -chain of HLA-DR
monomers and dimers (30). SPVL3, GS200.1, and L243 ascites
were prepared and mAbs were purified using protein A-Sepharose (Sigma,
St. Louis, MO). Abs were isotyped with a dipstick mouse mAb isotyping
kit (Life Technologies). A mouse IgG2a isotype control mAb, specific
for trinitrophenol, was purchased from PharMingen (San Diego,
CA).
Flow cytometric analysis
EBV-transformed B-LCLs and BLS-1 HLA class II cell lines (0.5 x 106 cells) were washed with 1% FBS in PBS (staining buffer), resuspended in 30 µl of L243, SPVL3, 1a3, GS200.1, or IgG2a isotype control mAb at a concentration of 0.033 µg/ml to 10 µg/ml in staining buffer, and incubated on ice for 45 min. Cells were washed with staining buffer, resuspended in 15 µl of 10 µg/ml fluorescein FITC goat anti-mouse IgG, F(ab')2 (Jackson ImmunoResearch, West Grove, PA), and incubated on ice for 45 min. The cells were washed with staining buffer and resuspended in 500 µl of staining buffer for analysis on a Becton Dickinson FACSort using CELLQuest Software (San Jose, CA).
SDS-stability assay
Cell lysates were prepared from EBV-transformed B-LCLs (1 x 106 cells), BLS-1 HLA class II expressing cell lines (1 x 106 cells), and PBLs (1 x 107 cells). Briefly, cells were washed in PBS, resuspended in 50 µl cell lysis buffer (50 mM Tris-HCl, pH 7.5, 0.15 M NaCl, 5 mM EDTA, 1% Nonidet P-40, 1 mM PMSF, 1 µg/ml pepstatin A, 1 µg/ml leupeptin), incubated on ice for 30 min with vortexing, microfuged at 14,000 rpm for 10 min, and supernatants collected. Supernatants (10 µg protein EBV-transformed B-LCL, 25 µg protein BLS-1 HLA class II cell line, 40 µg protein PBL) were diluted 1:1 in 2x sample buffer with 0.4% SDS (0.125 M Tris-HCl, pH 6.8, 20% glycerol, 0.4% SDS, 0.005% bromphenol blue) and incubated at room temperature for 30 min. As a control, supernatants were diluted 1:1 in 2x sample buffer with 4% SDS (0.125 M Tris-HCl, pH 6.8, 20% glycerol, 4% SDS, 0.005% bromphenol blue, and 10% 2-ME) and boiled for 2 min. Samples were loaded on a 4-20% Tris-glycine gel (Novex, San Diego, CA), electrophoresed in running gel buffer (25 mM Tris, 190 mM glycine, 0.1% SDS), and transferred to Immobilon-P (Millipore, Bedford, MA). The membrane was blocked in 5% nonfat dry milk in Tris-buffered saline 0.05% Tween-20 (TBST) at room temperature for 1 h and washed three times in TBST. The membranes were incubated with primary Ab solution for 1 h at room temperature. The primary Ab solutions were purified GS200.1 or 1a3 mAb diluted to a concentration of 5 µg/ml in TBST, SPVL3, or L243 hybridoma supernatant diluted 1:1 in TBST, 2H3 hybridoma supernatant diluted 1:5 in TBST, and DA6.147 hybridoma supernatant diluted 1:4 in TBST. The membranes were washed three times in TBST and incubated in 0.25 µg/ml goat anti-mouse horseradish peroxidase (Jackson ImmunoResearch) for 1 h at room temperature. The membranes were washed three times in TBST and proteins detected by enhanced chemiluminescence (Amersham, Arlington Heights, IL).
General
Protein concentration was determined using the Bradford microassay with BSA as the standard (31). Protein m.w. markers for Western analysis were prestained low range SDS-PAGE standards (Bio-Rad, Hercules, CA) or BENCHMARK prestained protein ladder (Life Technologies).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The stability of HLA-DQ allelic proteins that encode susceptible
(DQ0302, DQ0201), neutral (DQ0501, DQ0301), and protective (DQ0602)
alleles in IDDM were examined in the SDS stability assay (Fig. 1
). The SDS stability of these HLA-DQ
allelic proteins in cell lysates from EBV-transformed B-LCLs were
measured by Western analysis with HLA-DQ dimer mAbs, SPVL3 (Fig.
1A), GS200.1 (Fig. 1B), and 1a3 (Fig.
1C). These Abs detect the intact ß dimer, at 58 kDa,
and do not react with separate - and ß-chains. All three HLA-DQ
dimer mAbs showed that the "IDDM protective molecule," DQ0602, was
the most SDS stable of the HLA-DQ allelic proteins examined (Fig.
1, A to C, lane 4). SDS stable HLA-DQ
dimers for DQ0501 and DQ0301 were also detected, at much lower
intensity than DQ0602. Fig. 1 does not show stable dimers for DQ0302
and DQ0201, however, upon longer exposure a dimer could be detected for
DQ0302. Similar results were obtained with a second panel of cells
encoding the same HLA-DQ allelic proteins (data not shown). Total
HLA-DQß expressed in these cells was examined with the 2H3 mAb under
denaturing conditions and was expressed at comparable levels in all
cell lines (Fig. 1D). HLA-DQ was not examined due to lack
of a suitable Ab. In addition, flow-cytometric analysis of the
EBV-transformed B-LCLs used in the SDS stability assay with SPVL3 (Fig. 2), GS200.1 (data not shown), and 1a3
(data not shown) mAbs also showed a similar level of HLA-DQ cell
surface expression. This suggests that the differences observed are due
to HLA-DQ dimer stability and not to differences in expression level or
polymorphic effects on Ab recognition.
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shows the results of
analyzing the SDS stability of DQ0602 (lanes 3
and 4), DQ0603 (lanes 5 and 6),
and DQ0604 (lanes 7 and 8) in cell lysates
from two different EBV-transformed B-LCLs for each HLA-DQ allelic
protein. The trend observed with the HLA-DQ dimer mAbs, SPVL3 (Fig.
3A), GS200.1 (Fig. 3B), and 1a3 (Fig.
3C) was a rank order of SDS stability that correlated with
protection in IDDM (DQ0602 > DQ0603 > DQ0604). Total
HLA-DQß expressed in these cells was examined with the 2H3 mAb under
denaturing conditions and was expressed at a similar level (Fig.
3D).
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HLA-DQ SDS stability was examined in cell lysates from PBLs, to
determine if the observations in EBV-transformed B-LCLs were relevant
to cells not grown and manipulated in culture. PBLs were isolated from
human blood homozygous for DQ0501, DQ0602, DQ0201, DQ0301, and DQ0302,
and analyzed in the SDS-stability assay with the HLA-DQ dimer mAbs,
SPVL3 (Fig. 4A) and GS200.1
(Fig. 4B). 1a3 was not used because it lacks the sensitivity
and specificity required to examine HLA-DQ in PBLs in which the
expression level is much lower than EBV-transformed B-LCLs (data not
shown). SPVL3 and GS200.1 both identified HLA-DQ ß dimer in the
DQ0602 cell lysate (Fig. 4, A and B, lane
4). A weak HLA-DQ ß dimer band was observed for DQ0501.
Analysis with 2H3 mAb under denaturing conditions showed that similar
amounts of HLA-DQß were present in each PBL cell lysate (Fig.
4C).
SDS stability of HLA-DQ and -DR allelic proteins in BLS-1
The greater SDS stability of DQ0602 relative to other HLA-DQ allelic proteins raised the question of whether DQ0602 would be SDS stable in a cell line deficient in peptide editing functions. The BLS-1 cell line does not express HLA-DM and thus would be expected to have a defect in SDS-stable HLA-DQ dimer formation as was previously shown for HLA-DR (4). To examine the SDS stability of DQ0602 in BLS-1, the DQA1*0102 and DQB1*0602 genes were transfected into BLS-1. BLS-1 cell lines that express DQ0501, DQ0604, DQ0201, DQ0301, and DQ0302 were also prepared to compare with DQ0602. Cell surface expression among the HLA-DQ allelic proteins on BLS-1 measured by flow cytometric analysis with HLA-DQ dimer mAbs, SPVL3, GS200.1, and 1a3, was similar (data not shown). Examination of the SDS stability of HLA-DQ in BLS-1 with the HLA-DQ dimer mAbs, SPVL3 (Fig. 5A), GS200.1 (Fig. 5B), and 1a3 (Fig. 5C), showed that DQ0602 was SDS stable in BLS-1 (Fig. 5, A to C, lane 4). A small amount of stable dimer was observed for DQ0604 (Fig. 5A, lane 5). Longer exposure times did not reveal detectable dimer for DQ0501, DQ0201, DQ0301, and DQ0302, whereas total HLA-DQß measured with 2H3 mAb was easily detectable for DQ0501, DQ0602, DQ0604, and DQ0302 (Fig. 5D).
The SDS stable dimer observed for DQ0602 in BLS-1 was not expected.
Therefore, to verify the significance of this result in our system, the
SDS stability of proteins encoded by HLA-DR alleles was examined. The
SDS stability of DR1, DR3, and DR4w4 in EBV-transformed B-LCLs and
BLS-1 was measured with DA6.147 (anti-HLA-DR monomer and dimer)
and L243 (anti-HLA-DR dimer). HLA-DR allelic proteins showed
significant amounts of SDS-stable dimer in EBV-transformed B-LCLs but
no detectable SDS-stable dimer in BLS-1, even though comparable levels
of HLA-DR were present in EBV-transformed B-LCLs and BLS-1 (data not
shown). These results support the notion that DQ0602 is exceptionally
SDS stable.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-chains
to remain as a heterodimer in the presence of SDS (33). In
the experiments presented herein, cellular lysates containing HLA-DQ
allelic proteins were incubated with 0.2% SDS at room temperature and
analyzed by Western blot analysis. Three different Abs that recognize
HLA-DQ ß dimer were used in these analyses, to mitigate the
possibility that HLA-DQ polymorphisms have a differential effect on
ß dimer recognition.
A comparison of the SDS stability of DQ0501, DQ0602, DQ0201, DQ0301,
and DQ0302 in EBV-transformed B-LCLs and PBLs revealed that DQ0602, the
IDDM protective molecule, is the most SDS stable in both
EBV-transformed B-LCLs and PBLs. Detectable ß dimer was observed
for the "IDDM neutral molecules," DQ0501 and DQ0301, and the least
amount of ß dimer was observed for the "IDDM susceptible
molecules," DQ0302 and DQ0201. Further comparison of DQ0602 to the
closely related DQ0603 and DQ0604 in EBV-transformed B-LCLs revealed
that the IDDM protective molecule, DQ0602, is the most SDS stable
followed by DQ0603 and then by DQ0604. These results suggest a
correlation between SDS stability of ß dimer and IDDM
susceptibility (Table I). This finding is
also consistent with our previous finding that DQ0302 was intrinsically
unstable, and a recent report that examined cell surface MHC class II
molecules and showed that DQ0302 is less SDS stable than DQ0602 in
EBV-transformed B-LCLs (34, 35).
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ß dimers, implying
that differences in the peptide-binding groove could result in
differences in SDS stability (7, 9, 14, 15).
Three-dimensional models of DQ0602, DQ0603, and DQ0604 based on the
crystal coordinates of DR1, reveal differences in the surface contour
of the peptide-binding groove (36, 37). Amino acids that
are polymorphic between DQ0602, DQ0603, and DQ0604 are listed in Table II. Differences at residues ß9, ß30,
and ß57, in particular, are likely to influence peptide binding at
binding pockets designated 6, 7, and 9. Since these polymorphic
differences imply a role for specific peptide binding, it was
surprising that DQ0602 was still SDS stable in the bare lymphocyte
syndrome cell, BLS-1. Even HLA-DR alleles, encoded by DR1, DR3, and
DR4w4, which have easily detectable SDS stable dimers in
EBV-transformed B-LCLs, were not stable in BLS-1. This observation, of
a MHC class II allelic protein being SDS stable in a HLA-DM-deficient
cell implies either an intrinsic structural stability to DQ0602 or a
key role for a ubiquitous peptide, such as CLIP, which does not require
HLA-DM for efficient binding. Similarly, SDS stable dimers have
previously been observed for murine I-Ak coexpressed with
invariant chain but not I-Ad coexpressed with invariant
chain in murine Ltk fibroblast cells (39).
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ß dimer and were present in
the majority of the cell lysates including the HLA-DQ-negative cell
line BLS-1. These bands in the m.w. range of 68–98 kDa, however, were
no longer detectable when the samples were boiled in the presence of
4% SDS and 10% 2-ME (data not shown). Thus, it is possible that some
of these higher m.w. bands may represent what has been previously
described as floppy dimer (14). A third possibility is
that the Abs recognize different forms of HLA-DQ in cellular lysates.
These different intermediate forms of HLA-DQ occur during cellular
trafficking of HLA-DQ from the endoplasmic reticulum to the cell
membrane, and thus would not be observed in the flow-cytometric assay
for cell surface HLA-DQ.
The physiologic correlates of SDS stability in class II MHC molecules
correspond to influences on Ag presentation (4, 16).
Peptide exchange, interactions with invariant chain and HLA-DM, and
binding of both endogenous and exogenously presented peptides are
likely to differ based on ß stability properties. It has also been
suggested that t1/2 may be a physiologic
correlate to SDS stability, based on observations of
[35S[methionine-labeled I-Ab,
I-Ad, and I-Ag7 in spleen cells
(1). More recently, however, this correlation was not
observed when [35S]methionine-labeled I-As
and I-Ag7 in spleen cells were compared (40)
and when cell surface-labeled DQ0302 and DQ0602 in EBV-transformed
B-LCLs were compared (35).
The results presented herein indicate that DQ0602 is an unusually
stable MHC class II molecule. Could this property of DQ0602 result in
dominant protection against IDDM? A number of potential mechanisms are
possible: 1) The increased stability of DQ0602 could result in
determinant capture of diabetogenic peptides, outcompeting susceptible
alleles such as DQ0302 and DQ0201 for peptide binding
(41). 2) The increased stability of DQ0602 could result in
deletion of diabetogenic T cells in the thymus whereas the same cells
would be positively selected by DQ0302 and DQ0201. Negative selection
of diabetogenic T cells by protective MHC class II molecules has indeed
been described in one TCR transgenic NOD mouse model (42)
but not another (43). 3) The increased stability of DQ0602
may divert the phenotype of diabetogenic T cells. This notion was
supported in a NOD I-E transgenic mouse in which protection from
diabetes was accompanied by a change in cytokine balance from Th1 to
Th2 (44). In addition, the strength of interaction between
MHC class II and TCR may be affected, modulating whether a T lymphocyte
undergoes proliferation, anergization, or apoptosis (45).
4) The increased stability of DQ0602 may allow for Ag presentation to
occur in a HLA-DM-independent fashion. Thus, Ag presentation could
occur in the context of DQ0602 but not other HLA class II proteins in
cells deficient in HLA-DM activity. In this regard, it is intriguing to
note that HLA-DM function was recently described to be blocked by
HLA-DO (46).
In conclusion, the correlation between SDS stability and IDDM susceptibility for HLA-DQ alleles suggests that the exceptional stability of DQ0602 plays a role in dominant protection and the poor stability of DQ0302 and DQ0201 plays a role in susceptibility. The SDS stability of DQ0602 in the absence of HLA-DM suggests a novel mechanism by which DQ0602 may elicit dominant protection in IDDM.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. William W. Kwok, Virginia Mason Research Center, 1000 Seneca St., Seattle, WA 98101. E-mail address:
3 Abbreviations used in this paper: CLIP, class II-associated invariant chain peptide; IDDM, insulin-dependent diabetes mellitus; NOD, nonobese diabetic; B-LCL, B lymphoblastoid cell line; DQ0501, protein product of the HLA-DQA1*0101/DQB1*0501 gene; DQ0602, protein product of the HLA-DQA1*0102/DQB1*0602 gene; DQ0604, protein product of the HLA-DQA1*0102/DQB1*0604 gene; DQ0201, protein product of the HLA-DQA1*0501/DQB1*0201 gene; DQ0301, protein product of the HLA-DQA1*0301/DQB1*0301 gene; DQ0302, protein product of the HLA-DQA1*0301/DQB1*0302 gene; DQ0603, protein product of the HLA-DQA1*0103/DQB1*0603 gene; BLS, bare lymphocyte syndrome.
Received for publication April 14, 1998. Accepted for publication August 6, 1998.
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H. Quarsten, S. N. McAdam, T. Jensen, H. Arentz-Hansen, K. E. A. Lundin, and L. M. Sollid Staining of Celiac Disease-Relevant T Cells by Peptide-DQ2 Multimers J. Immunol., November 1, 2001; 167(9): 4861 - 4868. [Abstract] [Full Text] [PDF]
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A. Snijders, D. G. Elferink, A. Geluk, A. L. van der Zanden, K. Vos, G. M. T. Schreuder, F. C. Breedveld, R. R. P. de Vries, and E. H. Zanelli An HLA-DRB1-Derived Peptide Associated with Protection Against Rheumatoid Arthritis Is Naturally Processed by Human APCs J. Immunol., April 15, 2001; 166(8): 4987 - 4993. [Abstract] [Full Text] [PDF]
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S. Reichstetter, R. A. Ettinger, A. W. Liu, J. A. Gebe, G. T. Nepom, and W. W. Kwok Distinct T Cell Interactions with HLA Class II Tetramers Characterize a Spectrum of TCR Affinities in the Human Antigen-Specific T Cell Response J. Immunol., December 15, 2000; 165(12): 6994 - 6998. [Abstract] [Full Text] [PDF]
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S. Winer, L. Gunaratnam, I. Astsatourov, R. K. Cheung, V. Kubiak, W. Karges, D. Hammond-McKibben, R. Gaedigk, D. Graziano, M. Trucco, et al. Peptide Dose, MHC Affinity, and Target Self-Antigen Expression Are Critical for Effective Immunotherapy of Nonobese Diabetic Mouse Prediabetes J. Immunol., October 1, 2000; 165(7): 4086 - 4094. [Abstract] [Full Text] [PDF]
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 E. Zanelli, F. C. Breedveld, and R. R. P. de Vries HLA association with autoimmune disease: a failure to protect? Rheumatology, October 1, 2000; 39(10): 1060 - 1066. [Abstract] [Full Text] [PDF]
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R. A. Ettinger, A. W. Liu, G. T. Nepom, and W. W. Kwok {beta}57-Asp Plays an Essential Role in the Unique SDS Stability of HLA-DQA1*0102/DQB1*0602 {alpha}{beta} Protein Dimer, the Class II MHC Allele Associated with Protection from Insulin-Dependent Diabetes Mellitus J. Immunol., September 15, 2000; 165(6): 3232 - 3238. [Abstract] [Full Text] [PDF]
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W. W. Kwok, A. W. Liu, E. J. Novak, J. A. Gebe, R. A. Ettinger, G. T. Nepom, S. N. Reymond, and D. M. Koelle HLA-DQ Tetramers Identify Epitope-Specific T Cells in Peripheral Blood of Herpes Simplex Virus Type 2-Infected Individuals: Direct Detection of Immunodominant Antigen-Responsive Cells J. Immunol., April 15, 2000; 164(8): 4244 - 4249. [Abstract] [Full Text] [PDF]
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 K. M. Haan, W. W. Kwok, R. Longnecker, and P. Speck Epstein-Barr Virus Entry Utilizing HLA-DP or HLA-DQ as a Coreceptor J. Virol., March 1, 2000; 74(5): 2451 - 2454. [Abstract] [Full Text]
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D. J. Becker, R. E. LaPorte, I. Libman, M. Pietropaolo, and H.-M. Dosch Prevention of Type 1 Diabetes: Is Now the Time? J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 498 - 506. [Full Text]
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