ARTHRITIS & RHEUMATISM
Vol. 48, No. 8, August 2003, pp 2240–2245
© 2003, American College of Rheumatology
In Primary Sjo ¨gren’s Syndrome, HLA Class II Is
Associated Exclusively With Autoantibody Production
and Spreading of the Autoimmune Response
Jacques-Eric Gottenberg,1Marc Busson,2Pascale Loiseau,3Julien Cohen-Solal,4
Virginia Lepage,3Dominique Charron,3Jean Sibilia,4and Xavier Mariette1
Objective. To reevaluate, in a large series of
patients with Sjo ¨gren’s syndrome (SS) recruited from 2
French centers, the question of whether HLA is associ-
ated with SS itself or with a pattern of secretion of
Methods. One hundred forty-nine white patients
fulfilling the American-European Consensus Group cri-
teria for SS were divided into 3 subgroups, according to
their anti-Ro/SSA and anti-La/SSB status, as follows:
group 1 (n ? 53), no antibody; group 2 (n ? 46),
anti-SSA only; group 3 (n ? 50), both anti-SSA and
anti-SSB. Patients were compared with 222 unrelated
healthy subjects representative of the white population
Results. Comparisons between the 149 SS pa-
tients and 222 controls confirmed the association of SS
with DRB1*03 (the frequency was 25% in patients
versus 10% in controls) and DQB1*02 (32% versus
22%). The association between HLA and SS was re-
stricted to patients with anti-SSA and/or anti-SSB; no
association with HLA was observed in patients in group
1 (no antibody). The frequency of HLA–DRB1*15 was
highest in group 2 (24%), compared with 11% in group
1 and 11% in controls, whereas the frequency of HLA–
DRB1*03 was highest in group 3 (44%), compared with
12% in group 1, 19% in group 2, and 10% in controls.
Group 2 and group 3 had more clinical and biologic
markers of activity than did group 1 but were not
clinically different. HLA alleles were not associated with
clinical features of the disease, and were associated with
only some biologic features: rheumatoid factor positiv-
ity, increased serum IgG, and thrombocytopenia were
associated with HLA–DRB1*03, and neutropenia was
associated with DQB1*01.
Conclusion. HLA class II markers confer genetic
susceptibility to Sjo ¨gren’s syndrome. The association
between HLA and SS is restricted to patients with
anti-SSA and/or anti-SSB antibodies; HLA is not asso-
ciated with SS in patients without these autoantibodies.
The absence of a difference in disease severity between
groups 2 and 3, as well as the restricted association of
HLA–DRB1*03 in group 3, strongly suggest that HLA
alleles predispose to autoantibody secretion, without
being associated with clinical outcome. HLA class II
phenotype might support epitope spreading: HLA–
DR15 favors anti-SSA synthesis, whereas HLA–DR3 is
associated with both anti-SSA and anti-SSB production.
Primary Sjo ¨gren’s syndrome (SS) is an auto-
immune disorder characterized by lymphocytic infiltra-
tion of salivary and lachrymal glands leading to xerosto-
mia and keratoconjunctivitis sicca, and systemic
production of autoantibodies (1). The condition is char-
acterized by numerous abnormalities of epithelial cells
that can express class II major histocompatibility com-
plex (MHC) and costimulation molecules (2,3) and
therefore can act as antigen-presenting cells to infiltrat-
ing lymphocytes, mainly of the CD4 type. The presented
autoantigens are mainly SSA/Ro, SSB/La, ?-fodrin and
?-fodrin, or cholinergic muscarinic receptors. Help from
1Jacques-Eric Gottenberg, MD, Xavier Mariette, MD, PhD:
Ho ˆpital de Bice ˆtre, Assistance Publique-Ho ˆpitaux de Paris (AP-HP),
INSERM EMI 0109, Le Kremlin Bice ˆtre, France;2Marc Busson, PhD:
INSERM U396 and Ho ˆpital Saint-Louis, AP-HP, Paris, France;
3Pascale Loiseau, MD, Virginia Lepage, MD, Dominique Charron,
MD, PhD: Ho ˆpital Saint-Louis, AP-HP, Paris, France;4Julien Cohen-
Solal, MD, Jean Sibilia, MD, PhD: Ho ˆpital de Hautepierre, Ho ˆpitaux
Universitaires de Strasbourg, Strasbourg, France.
Drs. Sibilia and Mariette contributed equally to this work.
Address correspondence and reprint requests to Xavier Mari-
ette, MD, PhD, Service de Rhumatologie, Ho ˆpital de Bice ˆtre, 78 rue
du Ge ´ne ´ral Leclerc, 94275 Le Kremlin Bice ˆtre, France. E-mail:
Submitted for publication December 2, 2002; accepted in
revised form April 14, 2003.
CD4 cells leads to production of specific autoantibodies.
Anti-SSA/Ro antibodies may be detected alone, whereas
anti-SSB/La antibodies are always found in conjunction
with anti-SSA/Ro, suggesting a spreading of the auto-
antibody response, the origin of which is still unknown.
The MHC genes are the best documented genetic
risk factors for the development of autoimmune diseases
and could be directly involved in SS because of their
abnormal expression on the surface of epithelial cells,
which could favor presentation of SSA and SSB epitopes
to T cells, leading to specific help in autoantibody
production (4). Most previous studies suggested an
association between SS and the HLA–A1;B8;DR3/DQ2
haplotype (5–8). An association between this haplotype
and autoantibodies to SSA or SSB was also shown in
some studies (9–12). Until recently, however, the ab-
sence of consensual, objective diagnostic criteria for SS
in patients without anti-SSA/SSB antibodies did not
allow determination of whether this association was
linked to the disease itself or to a pattern of secretion of
autoantibodies. With the recently published consensual
American-European criteria for SS (13), which require a
focus score of ?1 on a lip biopsy specimen obtained
from a patient who is anti-SSA/SSB negative, it is now
possible to be confident of the diagnosis of SS in patients
without anti-SSA/SSB antibodies.
We took this opportunity to reinvestigate the
question of whether HLA is associated with SS itself or
with a pattern of secretion of autoantibodies, in a large
cohort of 149 patients fulfilling the American-European
Consensus Group criteria. The comparison between the
whole cohort of SS patients and controls confirmed the
known association of HLA with the disease. However,
after stratification for the presence of anti-SSA/SSB, the
HLA associations were restricted to autoantibody-
PATIENTS AND METHODS
Patients. One hundred forty-nine white patients with
primary SS according to the American-European Consensus
Group criteria (which include a focus score of ?1 or anti-SSA/
SSB positivity) (13) were consecutively recruited from 2
French reference centers for SS (the rheumatology depart-
ments of Le Kremlin Bice ˆtre and Strasbourg). They were
compared with 222 unrelated healthy subjects representative
of the white population in France, who were not specifically
screened for symptoms of SS; these subjects were previously
included in HLA studies in France (14).
All patients were examined for clinical features of
Sjo ¨gren’s syndrome, including enlarged parotid glands,
Raynaud’s phenomenon, arthralgia, synovitis, bronchopulmo-
nary involvement, purpura, myositis, neuropathy, and lym-
phoma. The erythrocyte sedimentation rate (ESR) was deter-
mined for each patient. Antinuclear antibodies were detected
by indirect immunofluorescence using the HEp-2000 substrate,
which consists of HEp-2 cells transfected with Ro 60 comple-
mentary DNA (15). Rheumatoid factor, complement compo-
nents C3 and C4, and serum IgA, IgG, and IgM levels were
measured by nephelometry. Anti-SSA/Ro and anti-SSB/La
were detected using a commercial enzyme-linked immunosor-
bent assay (ELISA) (Varelisa Ro and La antibodies; Pharma-
cia & Upjohn, Freiburg, Germany), which used both
baculovirus-expressed recombinant Ro 52 and Ro 60, coated in
an unspecified ratio. All positive results were confirmed by
either counterimmunoelectrophoresis using purified antigens
obtained from rabbit and rat thymus powder (Pel-Freez,
Rogers, AR) and from human spleen extract from our labora-
tory, or by double radial immunodiffusion.
Patients were divided into 3 subgroups according to
their anti-SSA/SSB status, as follows: group 1 (n ? 53), no
antibody; group 2 (n ? 46), anti-SSA only; group 3 (n ? 50),
both anti-SSA and anti-SSB.
HLA typing. HLA typing was performed using a
serologic method for HLA–A and HLA–B, and HLA class II
typing was performed using a molecular technique. Serologic
typing for HLA–A and HLA–B was performed using the
standard microlymphocytotoxicity method with monoclonal
antibodies (One Lambda, Canoga Park, CA), which defined
the 24 HLA–A and the 48 HLA–B antigens. For HLA class II
typing, HLA–DRB1 and HLA–DQB1 medium resolution
genotyping was performed using polymerase chain reaction
single-strand oligonucleotide reverse dot-blot kits (InnoLipa
DRB key and InnoLipa DQB kits, respectively; Innogenetics,
Statistical analysis. The distribution of HLA types was
compared between patients and controls and between the
different patient subgroups and controls. An association be-
tween clinical or biologic features of the disease and HLA was
also investigated. The chi-square test was used to calculate the
significance of the difference between groups. Analysis was
performed using HLASTAT2000 software, which was devel-
oped by INSERM U396 (program available on request to
email@example.com) and has already been used in
other HLA studies (14). Allele frequencies were estimated
using the maximum-likelihood method (16). Comparisons be-
tween the 3 groups for phenotype frequencies of each HLA
allele were made, and each P value was corrected (Pcorr),
multiplying by the number of tested alleles at each considered
locus. The relative risk (RR) according to Haldane’s method
was also calculated for each allele (17).
Clinical and biologic characteristics. The study
group comprised 15 men and 134 women. The mean ?
SD age at diagnosis was 56 ? 13 years, and the mean ?
SD age at first symptom was 45 ? 7 years. Thirty-nine
patients (26%) had enlarged parotid glands, 49 (33%)
had Raynaud’s phenomenon, 115 (77%) had arthralgias
and/or synovitis, 5 (3%) had myositis, 18 (12%) had
bronchopulmonary involvement, 13 (9%) had purpura,
ASSOCIATION OF HLA AND PRIMARY SS2241
16 (11%) had neuropathy, and 6 (4%) had lymphoma.
Twenty-one patients (14%) were neutropenic, 8 (5.3%)
were thrombocytopenic, and 22 (15%) had a monoclonal
component (Table 1). The mean ? SD ESR was 30 ? 27
mm/hour. Sixty-eight patients (46%) had positive rheu-
matoid factor. Mean serum IgA, IgG, and IgM levels
were 2.9 gm/liter, 14.7 gm/liter, and 1.5 gm/liter, respec-
tively. Of the 149 patients, 96 (64%) had anti-SSA
antibody, and 50 (33%) had both anti-SSB and anti-SSA
antibodies (Table 1). No patient had anti-SSB antibodies
in the absence of anti-SSA antibodies. Thus, the follow-
ing 3 subgroups of approximately equal size were stud-
ied: patients in group 1 (n ? 53) had no antibody,
patients in group 2 (n ? 46) had anti-SSA only, and
patients in group 3 (n ? 50) had both anti-SSA and
anti-SSB. One hundred thirty-seven patients (92%) had
a focus score of ?1, including 100% of the patients in
Analysis of the whole group of SS patients. There
was no significant difference in autoantibody status or
HLA type between patients referred to Le Kremlin
Bice ˆtre and to Strasbourg; thus, the patients were
pooled. Comparisons between the 149 patients with SS
and the 222 controls confirmed the association of SS
with both DRB1*03 and DQB1*02: the frequency of
DRB1*03 was 25% in patients versus 10% in controls
(RR 3.8, Pcorr? 10?7), and the frequency of DQB1*02
was 32% in patients versus 22% in controls (RR 2.2,
Pcorr? 6 ? 10?4) (Table 2). These alleles are in linkage
disequilibrium on the A1;B8;DR3/DQ2 haplotype. No
other HLA class I or class II marker was significantly
associated with the disease.
Analysis of the subgroups. Association of HLA
with autoantibody secretion. HLA distribution in patients
in group 1 (SS patients without any antibody) was not
significantly different from that in controls. The fre-
quency of HLA–DRB1*15 was highest in group 2
(24%), compared with 11% in group 1 (RR 4.1, Pcorr?
0.019), and 11% in controls (RR 3.5, Pcorr? 0.0001)
(Table 3). The frequency of HLA–DRB1*03 was highest
in group 3 (44%), compared with 12% in group 1 (RR
15, Pcorr? 10?7), 19% in group 2 (RR 8.1, Pcorr?
Characteristics of the study population with primary Sjo ¨gren’s syndrome*
(n ? 53)
(n ? 46)
(n ? 50)
(n ? 149)
Enlarged parotid glands†
Peripheral nerve involvement
Mean ESR, mm/hour**
* Except where indicated otherwise, values are the number (%). Group 1 ? no antibody; group 2 ?
anti-SSA only; group 3 ? both anti-SSA and anti-SSB. ESR ? erythrocyte sedimentation rate.
† Pcorr? 0.022, group 1 versus group 3; Pcorr? 0.031, group 1 versus groups 2 and 3.
‡ Pcorr? 0.006, group 1 versus group 3; Pcorr? 0.004, group 2 versus group 3.
§ Pcorr? 0.007, group 1 versus group 3; Pcorr? 0.06, group 1 versus groups 2 and 3.
¶ Pcorr? 0.031, group 1 versus group 2; Pcorr? 0.032, group 1 versus group 3; Pcorr? 0.012, group 1 versus
groups 2 and 3.
# Pcorr? 0.024, group 1 versus group 3; Pcorr? 0.051, group 1 versus groups 2 and 3.
** Pcorr? 0.038, group 1 versus group 2; Pcorr? 0.0001, group 1 versus group 3.
Significantly different HLA allele frequencies in patients
(n ? 149)
(n ? 222)Pcorr
5 ? 10?6
6 ? 10?4
* Except where indicated otherwise, values are the number (%). Allele
frequencies were calculated using the maximum-likelihood method.
SS ? Sjo ¨gren’s syndrome; RR ? relative risk.
2242GOTTENBERG ET AL
0.0001), and 10% in controls (RR 20, Pcorr? 10?15).
HLA–B8 and HLA–DQ2, which are in linkage disequili-
brium with HLA–DRB1*03, were also significantly in-
creased in group 3 compared with group 1, group 2, and
Association of anti-SSA/SSB with clinical and bio-
logic features of disease activity and severity. Enlarged
parotid glands, lung involvement, and skin manifesta-
tions were more frequent, and the mean ESR was
higher, in groups 2 and 3 together compared with group
1 (Table 1). The differences in these parameters be-
tween groups 2 and 3 were not statistically significant,
except that the frequency of lung involvement was
higher in group 3.
Association of HLA alleles with clinical features of
the disease. No correlation between HLA and clinical
features of SS was observed. Concerning the association
between HLA markers and biologic results, HLA–
DRB1*03 was not associated with a higher mean ESR
(33 mm/hour in patients with HLA–DRB1*03 versus 28
mm/hour in patients without HLA–DRB1*03; Pcorr?
0.29). However, some biologic features associated with
disease severity were associated with the DRB1*03/
DQB1*01 haplotype. There was a slight association
between DRB1*03 and thrombocytopenia (defined as
?150 ? 109platelets per liter) and between DQB1*01
and neutropenia (defined as ? 1 ? 109neutrophils per
liter): 50% of patients with ORB1*03 were thrombocy-
topenic versus 24% of controls (Pcorr? 0.04), and 10%
of patients with DQB1*01 were neutropenic versus 1%
of controls (Pcorr? 0.016). HLA–DRB1*03 was also
significantly associated with rheumatoid factor positivity
(RR 3.01, Pcorr? 0.014) and a higher mean IgG level
(16.2 gm/liter in patients versus 13.2 gm/liter in controls;
This study included a racially homogeneous
group of 149 patients with primary Sjo ¨gren’s syndrome,
who were carefully selected according to the American-
European Consensus Group criteria. Findings in this
series of 149 patients confirm the previously described
association between SS and the HLA class II markers
DR3 and DQ2 (5–8), which are in linkage disequili-
brium with HLA–A1 and HLA–B8, in white SS patients.
For example, Kang et al (7) also reported an increased
frequency of the HLA–A1;B8;DR3/DQ2 haplotype in
white patients. In addition, an association with DR2
(now called DRB1*15) has been reported in Scandina-
vian patients (18), and an association with DR5 has been
reported in Greek patients (19). Last, the HLA–
DRB1*0301/*1501 heterozygote genotype was observed
to be increased in a population of white patients in
This study represents the largest ever performed
in which an association between HLA and SS (as defined
by strict consensus criteria) was investigated, and thus
allows individualization of 3 subgroups of equal size (no
antibody, anti-SSA only, both anti-SSA and anti-SSB) in
a population in which every patient equally fulfilled the
American-European Consensus Group criteria for Sjo ¨-
gren’s syndrome. Thus, every patient in the group with-
out anti-SSA or anti-SSB had a focus score of ?1.
Surprisingly, the association between HLA and SS was
restricted to patients with anti-SSA and/or anti-SSB; no
association with HLA was observed in the subgroup of
patients in whom these autoantibodies were absent.
Patients with anti-SSA expressed the DRB1*15/
DQB1*01 haplotype with a higher frequency, whereas
patients with both anti-SSA and anti-SSB more fre-
quently expressed the DRB1*03/DQB1*02 haplotype.
The association between anti-SSB and this haplotype
was entirely responsible for the association found be-
tween A1;B8;DR3/DQ2 and Sjo ¨gren’s syndrome, be-
cause this haplotype was not associated with either of
the other subgroups. Because of the very close linkage
between DRB1*15 and DQB1*01, as well as between
DRB1*03 and DQB1*02, it was impossible to determine
HLA allele frequencies in SS patient subgroups and
(n ? 53)
(n ? 46)
(n ? 50)
(n ? 222)
* Values are the number (%). Allele frequencies were calculated using
the maximum-likelihood method. Group 1 ? no antibody; group 2 ?
anti-SSA only; group 3 ? both anti-SSA and anti-SSB. SS ? Sjo ¨gren’s
† Pcorr? 0.0001, group 3 versus group 4 (relative risk [RR] 3.8).
‡ Pcorr? 10?5, group 3 versus group 1 (RR 7.3); Pcorr? 0.001, group
3 versus group 2 (RR 6.5); Pcorr? 10?10, group 3 versus group 4 (RR
§ Pcorr? 0.019, group 2 versus group 1 (RR 4.1); Pcorr? 0.0001, group
2 versus group 4 (RR 3.5).
¶ Pcorr? 10?7, group 3 versus group 1 (RR 15); Pcorr? 0.0001, group
3 versus group 2 (RR 8.1); Pcorr? 10?15, group 3 versus group 4 (RR
# Pcorr? 10?5, group 3 versus group 1 (RR 9.7); Pcorr? 0.0001, group
3 versus group 2 (RR 6.8); Pcorr? 10?7, group 3 versus group 4 (RR
ASSOCIATION OF HLA AND PRIMARY SS2243
whether the closest association involved the DR or the
DQ locus. Independently from anti-SSB, HLA–
DRB1*03 was also associated with 2 prominent features
of primary SS: rheumatoid factor positivity and in-
creased serum polyclonal IgG level.
Accordingly, Harley et al (9) suggested a corre-
lation between HLA and the level of hypergammaglobu-
linemia and autoantibodies in SS, by showing that het-
erozygotes for DQ1 and DQ2 had the highest level of
anti-SSA and anti-SSB antibodies. Most studies in the
literature about HLA predisposition in primary SS also
disclosed an association between DRB1*03/DQB1*02
and the presence of autoantibodies, but with anti-SSA as
well as with anti-SSB (8–12). However, only 1 of these
studies had a large enough number of patients to permit
individualization of subgroups with anti-SSA only (10).
In the study by Harley et al (as in ours), the latter
subgroup was associated with the DR15/DQ1 haplotype
(DR15 was formerly known as DR2), whereas DR3/
DQ2 was associated with the presence of precipitating
anti-SSB. Among patients with anti-Ro/SSA, the pres-
ence of anti-SSA antibody was confirmed by either
double radial immunodiffusion or counterimmunoelectro-
phoresis. Positivity by these techniques, which detect
precipitins, implies the mandatory presence of anti–Ro
60 antibody. Thus, we could be sure that all of the
patients with anti-Ro/SSA had anti–Ro 60 antibodies,
and that this specificity was associated with HLA–DR15.
However, it was not possible to look for a possible
association between HLA and anti–Ro 52 antibody,
because the ELISA could not differentiate between
anti–Ro 52 antibody alone and both anti–Ro 52 and
anti–Ro 60 antibodies.
A recent study demonstrated that regions of SSB
were able to generate a T cell proliferative response
(21), provided these T cells were HLA–DR3/DQ2 re-
stricted. Thus, together, these results and the literature
data demonstrate that the association of HLA class II
with SS susceptibility is related exclusively to the pattern
of autoantibody diversification, rather than to the dis-
ease itself. Likewise, in animal models transfected with
human HLA class II, natural spreading of immune
response from Ro 60 to Ro 52 and La depended only on
the nature of the transgenic human HLA class II (22),
whereas the clinical course of the disease was not
modified (23). In accordance with previous reports (7),
this study did not show any association between HLA
class II and clinical features of SS, but demonstrated an
association between anti-Ro/La antibodies and extra-
glandular involvement and disease severity. Indeed,
patients with anti-Ro alone or patients with anti-Ro and
anti-La (groups 2 and 3) had a more severe disease than
did patients in whom these autoantibodies were absent
(group 1), but the group with anti-Ro alone and the
group with anti-Ro and anti-La did not differ clinically
from one another except in the frequency of lung
involvement (Table 1), whereas HLA–DRB1*03 allele
frequency was higher only in group 3. Thus, the absence
of a difference in disease severity between groups 2 and
3, as well as the restricted association of HLA–DRB1*03
in group 3, strongly suggest that HLA alleles predispose
to autoantibody secretion without being associated with
Anti-Ro and anti-La were first described in sera
from lupus patients. The role of HLA as a predisposition
factor in systemic lupus erythematosus (SLE) has been
widely studied. Reveille et al (24) showed that among
black Americans with lupus, the frequency of HLA–
DQA1*0401 was lower in patients with both anti-SSA
and anti-SSB than in patients with anti-SSA only. In
addition, the frequency of DQB1*0201 was higher in
patients with anti-SSA only than in white lupus patients
without anti-SSA. Scofield et al (25) found a cooperative
association between T cell receptor ? restriction enzyme
polymorphisms and HLA–DQB1*0201 and one of
DQA1*0101, *0102, *0103 alleles in SLE patients who
had anti-Ro antibodies only. Results of these studies
suggest that HLA essentially promotes autoantibody
responses in SLE. Whether the HLA association with
anti-Ro/La could be similar regardless of the disease
(SLE or primary SS) deserves further evaluation.
In SS, as in lupus, anti-SSA may be found alone
in serum, whereas anti-SSB antibodies are always de-
tected in association with anti-SSA. This is interpreted
as a spreading of autoimmune response from SSA to
SSB epitopes. Rischmueller et al (10) speculated that
anti-SSB antibody production requires efficient help to
B cells, which could be provided only by DR3/DQ2-
restricted T helper cells recognizing SSB determinants.
DR15/DQ1-restricted T helper cells recognizing SSA
determinants could stimulate anti-SSA antibody synthe-
sis but could not contribute to anti-SSB antibody syn-
thesis. This explanation may account for the differential
HLA association between anti-SSA and anti-SSB but
does not give any clue to the reason for the necessary
presence of anti-SSA in production of anti-SSB.
We suggest the following 3 hypotheses concern-
ing the role of HLA in autoantibody diversification: 1)
HLA–DR15/DQ1 might present only SSA epitopes,
whereas HLA–DR3/DQ2 could present both SSA and
SSB determinants; 2) SSB processing could require
anti-SSA synthesis first, then formation of an immune
2244 GOTTENBERG ET AL
complex composed of anti-SSA, SSA, and SSB, which
would be mandatory for SSB presentation to HLA–
DR3–restricted cells; 3) DR15/DQ1 (but not DR3/DQ2)
could be associated with the presence of an antiidiotypic
response to anti-SSB, which could neutralize anti-SSB
This study, which included 149 patients in a
homogeneous population of white patients with primary
SS according to the American-European Consensus
Group criteria, shows that HLA class II markers confer
genetic susceptibility to Sjo ¨gren’s syndrome but do not
influence the clinical course of the disease. The associ-
ation between HLA and SS is restricted to patients with
anti-SSA and/or anti-SSB antibodies. HLA is not asso-
ciated with SS in the subgroup of patients without any of
these antibodies. Furthermore, this study suggests that
HLA class II might support epitope spreading: HLA–
DR15 favors anti-SSA synthesis, whereas HLA–DR3
favors both anti-SSA and anti-SSB production.
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ASSOCIATION OF HLA AND PRIMARY SS2245