Articles
IgG4-related disease in the Japanese population:
Lancet Rheumatol 2019;
1: e14–22
Published Online
August 6, 2019
http://dx.doi.org/10.1016/
S2665-9913(19)30006-2
See Comment page e2
*Consortium members are listed
at the end of the Article
Center for Genomic Medicine,
Kyoto University Graduate
School of Medicine (C Terao MD,
T Iwasaki MD, S Kawaguchi PhD,
T Kawaguchi MS,
I Yamaguchi MD, K Higasa PhD,
Y Kamatani MD,
Prof F Matsuda PhD),
Department of Rheumatology
and Clinical Immunology
(T Iwasaki, Prof T Mimori MD)
and Department of
Gastroenterology and
Hepatology (M Shiokawa MD,
K Kuriyama MD, Y Kodama MD,
Prof T Chiba MD), Kyoto
University, Kyoto, Japan;
Department of Internal
Medicine 2, School of Medicine
(Prof M Ota PhD) and Center for
Health Safety and
Environmental Management
(Prof S Kawa MD) Shinshu
University, Matsumoto, Japan;
Department of
Gastroenterology and
Hepatology Kansai Medical
University, Hirakata, Japan
(K Uchida MD,
Prof K Okazaki MD); Department
of Rheumatology and Clinical
Immunology, Sapporo Medical
University School of Medicine,
Sapporo, Japan
(M Yamamoto MD,
Prof H Takahashi MD);
Department of Endoscopy,
Yokohama City University
Hospital, Yokohama, Japan
(Prof K Kubota MD); Department
of Gastroenterology and
Hepatology, Kitano Hospital,
Osaka, Japan (S Yazumi MD);
Department of
Gastroenterology, Tokyo
Takanawa Hospital, Tokyo,
e14
a genome-wide association study
Chikashi Terao, Masao Ota, Takeshi Iwasaki, Masahiro Shiokawa, Shuji Kawaguchi, Katsutoshi Kuriyama, Takahisa Kawaguchi, Yuzo Kodama,
Izumi Yamaguchi, Kazushige Uchida, Koichiro Higasa, Motohisa Yamamoto, Kensuke Kubota, Shujiro Yazumi, Kenji Hirano, Yasufumi Masaki,
Hiroyuki Maguchi, Tomoki Origuchi, Shoko Matsui, Takahiro Nakazawa, Hideyuki Shiomi, Terumi Kamisawa, Osamu Hasebe, Eisuke Iwasaki,
Kazuo Inui, Yoshiya Tanaka, Koh-ichi Ohshima, Takashi Akamizu, Shigeo Nakamura, Seiji Nakamura, Takako Saeki, Hisanori Umehara,
Tooru Shimosegawa, Nobumasa Mizuno, Mitsuhiro Kawano, Atsushi Azumi, Hiroki Takahashi, Tsuneyo Mimori, Yoichiro Kamatani,
Kazuichi Okazaki, Tsutomu Chiba, Shigeyuki Kawa, Fumihiko Matsuda, on behalf of the Japanese IgG4-Related Disease Working Consortium*
Summary
Background IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune
pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of
IgG4-related disease, we did a genome-wide association study.
Methods We did a genome-wide association study of Japanese individuals, initially screening 857 patients with
IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants
from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to
July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed
diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was
done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and
genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms.
The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of
the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations
identified in these two genes were examined.
Findings We identified the HLA-DRB1 (p=1·1 × 10−¹¹) and FCGR2B (p=2·0 × 10−⁸) regions as susceptibility loci for
IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of
HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease
(p=1·7 × 10−¹⁴), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association
with increased FCGR2B expression (p=2·7 × 10−¹⁰) and was in weak linkage disequilibrium with rs1050501, a missense
variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated
with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035).
Interpretation Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have
important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related
disease and other immune-related disorders
Funding The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and
Development, and Kyoto University Grant for Top Global University Japan Project.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Introduction of immune complexes by other antibody isotypes, thus
IgG4-related disease is a newly recognised immuno­ inhibiting inflammatory reactions.2 Increased serum IgG4
pathological entity that is characterised by swelling in the concentra­tions were first reported in patients with auto­
affected organs, increased serum concentrations of total immune pancreatitis (IgG4-related pancreatitis),3 and sub­
IgG and IgG4, tissue infiltration of plasmacytes and se­quently in various diseases affect­ing different organs,
eosinophils, tissue fibrosis, and a good response to cortico­ such as IgG4-related sialadenitis (Mikulicz’s disease) or
steroid therapy.1 IgG4 is a subtype of imm­unoglobulin γ IgG4-related kidney disease.4 Patients with IgG4-related
with specific features, including anti-inflammatory activity disease are often positive for rheumatoid factor and have
because of its much weaker binding to complement anti­nuclear antibodies with substan­tially decreased con­
proteins and Fcγ receptors than IgG1. Another unique centrations of specific auto­antibodies, such as anti-SSA/Ro
feature of IgG4 is its ability to become bispecific through and anti-SSB/La, com­pared with patients with Sjögren's
exchange of one antigen-binding arm with that of another syndrome.1 Auto­antigens detected in patients with IgG4-
IgG4 molecule, which might interfere with the formation related dis­ease have been reported, includ­ing those against
www.thelancet.com/rheumatology Vol 1 September 2019
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Japan (K Hirano MD);

Research in context Department of Hematology
and Immunology, Kanazawa
Evidence before this study results identified both susceptibility and protective HLA alleles. Medical University, Uchinada,
Studies have suggested that genetic factors such as HLA, FCRL3, We also found a significant disease association with a SNP in Japan (Prof Y Masaki MD);
CTLA4, and KCNA3 could be involved in IgG4-related disease. FCGR2B, the only FCGR family member expressed in B cells. Center for Gastroenterology,
Teine-Keijinkai Hospital,
However, these studies used small-scale approaches to test rs1340976 showed the strongest association with expression of Sapporo, Japan
candidate genes, and no comprehensive genomic studies have FCγR2B and is in linkage disequilibrium with rs1050501, a (H Maguchi PhD); Department
been done to date. Also those studies lacked a replication set to functional missense variant associated with systemic lupus of Immunology and
validate the results and there is the risk that the associations erythematosus. rs1340976 was also associated with the clinical Rheumatology, Nagasaki
University Graduate School of
were overestimated because of an inevitable selection bias of phenotype of IgG4-related disease, such as the number of Biomedical Sciences, Nagasaki,
samples. We searched PubMed for articles published between swollen organs and IgG4 concentration at diagnosis. Moreover, Japan (T Origuchi MD); Center
April 1, 2009, and March 31, 2019, with the search terms our study provided comprehensive information on genetic for Health Care and Human
“IgG4-related disease” and “genome wide” with no restrictions variations in Japanese patients with IgG4-related disease. Sciences, University of Toyama,
Toyama, Japan
on language. We found no reports on genome-wide association
Implications of all the available evidence (Prof S Matsui MD); Department
studies of IgG4-related disease to date. of Gastroenterology and
Our results suggest common molecular pathways underlying
Metabolism, Graduate School
Added value of this study IgG4-related disease and other immune-related diseases, and a of Medical Sciences, Nagoya
We identified an association peak in the HLA-DRB1 gene. central role for HLA and FCGR2B in the pathogenesis of City University, Nagoya, Japan
This association corresponded to an aminoacid position in the IgG4-related disease. Our findings might help to identify (T Nakazawa MD); Department
of Gastroenterology, Kobe
β domain of the peptide-binding groove of the protein; important differences or similarities of the genetic landscape of
University Hospital, Kobe,
aminoacid variants at this position also occur in patients with IgG4-related disease among populations through trans-ethnic Japan (H Shiomi MD);
rheumatoid arthritis and systemic lupus erythematosus. Our comparisons. Department of Internal
Medicine, Tokyo Metropolitan
Komagome Hospital, Tokyo,
prohibitin,5 galectin-3,6 annexin A11,7 and laminin 511 E8.8 who were treated at 50 research institutions across Japan Japan (T Kamisawa MD);
However, the aetiology and patho­physiology of the disease (stage 1). Healthy individuals genotyped for the Nagahama Department of
Gastroenterology, Nagano
are still largely unclear. Prospective Genome Cohort for the Comprehensive
Municipal Hospital, Tomitake,
Previous studies have suggested the involvement Human Bioscience15 were used as the control group. In Japan (O Hasebe MD); Division
of genetic factors in IgG4-related disease. A haplotype stage 2, between April 30, 2014, and July 22, 2014, we of Gastroenterology and
consisting of MHC class II alleles HLA-DRB1*04:05 and recruited additional patients diagnosed with IgG4-related Hepatology, Department of
Internal Medicine, Keio
DQB1*04:01 was reported to be associated with auto­ disease from the same 50 research insti­tu­tions as in stage 1.
University School of Medicine,
immune pancreatitis.9 Involvement of the MHC class I As controls for stage 2, we used healthy individuals residing Tokyo, Japan (E Iwasaki MD);
locus was also suggested in this disease.10 However, in Nagahama City, Japan, who were included in a previous Department of
whether the primary association between the HLA locus expression quantitative trait loci (eQTL) mapping study.16 Gastroenterology, Second
Teaching Hospital, Fujita
and disease is attributed to the classical HLA alleles is There was no overlap between control samples used for Health University, Toyoake,
uncertain. Candidate gene studies showed associations stage 1 and stage 2. In both stages, clinical informa­tion was Japan (Prof K Inui MD); First
with several loci, including Fc receptor-like 3 (FCRL3),11 collected about patients with representative organ-specific Department of Internal
cytotoxic T-lymphocyte-associated 4 (CTLA4),12 and potas­ subsets of IgG4-related dis­ease, namely autoimmune pan­ Medicine, University of
Occupational and
sium voltage-gated channel subfamily A member 3 creatitis, IgG4-related siala­denitis, and IgG4-related kidney Environmental Health,
(KCNA3).13 However, the potential involvement of other disease (appendix pp 1–6). Basic clinical characteristics of Kitakyushu, Japan
genes has not been investigated because no genome-wide the patients (IgG4 concen­tration, age at diagnosis, com­ (Prof Y Tanaka MD); Department
association studies have been done to date. The identi­ plication of malignancies, and number of swollen organs of Ophthalmology, National
Hospital Organization
fication of genetic determinants that affect disease onset such as pancreas, parotid gland, and retroperitoneum) Okayama Medical Center,
and prognosis would help to clarify the genetic basis of were also recorded. Most patients were undergoing treat­ Okayama, Japan
IgG4-related disease. Whether IgG4-related disease has ment with steroids, but a few of them were being followed (K Ohshima MD); First
genetic characteristics that are distinct from those of other up without treatment. Department of Medicine,
Wakayama Medical University,
immune-related diseases is also of interest. With these A diagram of the study design and baseline characteristics Wakayama, Japan
goals in mind, we did a genome-wide association study in of study participants are shown in the appendix pp 7–8. (Prof T Akamizu MD);
Japanese patients with IgG4-related disease. In accordance with the Declaration of Helsinki, our Department of Pathology and
study was reviewed and approved by the ethics committee Laboratory Medicine, Nagoya
University Hospital, Nagoya,
Methods of each institution. All patients were fully informed of Japan (Prof Sh Nakamura MD);
Study design and participants the purpose and procedures of this study, and written Section of Oral and
In this genome-wide association study, we used a two- consent was obtained from each participant. Maxillofacial Oncology,
Division of Maxillofacial
stage, case-control design to identify novel and significant
Diagnostic and Surgical
genome-wide associations that confer susceptibility to Genotyping Sciences, Faculty of Dental
IgG4-related disease. Between Oct 27, 2008, and Dec 3, 2013, In stage 1, samples were genotyped with the Science, Kyushu University,
we recruited patients who fulfilled the international con­ Infinium HumanOmni5Exome, HumanOmni2.5Exome, Fukuoka, Japan
(Prof Se Nakamura DDS);
sensus of diagnostic criteria for IgG4-related dis­­ease14 and or HumanOmni2.5 arrays (Illumina; San Diego, USA),

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Department of Internal which have 2 300 979 single nucleotide polymorph­
Medicine, Nagaoka Red Cross isms (SNPs) in common. In stage 2, samples were
Hospital, Nagaoka, Japan
(T Saeki MD); Division of
genotyped with the Infinium HumanOmni5Exome or
Rheumatology and HumanOmni2.5Exome arrays (as the HumanOmni2.5
Immunology, Nagahama City array was discontinued), containing 2 310 564 SNPs in
Hospital, Nagahama, Japan common.
(H Umehara MD); Division of
Gastroenterology, Tohoku
As a standard quality-control process, we first searched
University Graduate School of for population outliers. The principal component analysis
Medicine, Sendai, Japan of genetic data from the Asian clusters in the International
(Prof T Shimosegawa MD); HapMap Project did not find such samples. We next
Department of
Gastroenterology, Aichi Cancer
removed outliers from analysis if there was a high degree
Center Hospital, Nagoya, Japan of kinship or if their principal component score was out
(N Mizuno MD); Department of of range (from –3 × IQR below the 25th percentile to
Rheumatology, Graduate 3 × IQR above the 75th percentile in one of the top
School of Medical Science,
Kanazawa University,
ten inferred axes of variation). This trimming step was
Kanazawa, Japan iteratively applied until there were no outliers to exclude
(M Kawano MD); Department of (appendix p 7, p 9). No samples were excluded due to low
Ophthalmology, Kobe Kaisei
call rates (<95%).
Hospital, Kobe, Japan
(A Azumi MD) We then checked the quality of our data on SNP
Correspondence to:
markers. SNPs with a success rate of less than 99% or
Dr Fumihiko Matsuda, Center for those showing a departure from Hardy-Weinberg equil­
Genomic Medicine, Kyoto ibrium, with p values of less than 1·0 × 10–⁶, or a minor
University Graduate School of allele frequency of less than 5%, were excluded from
Medicine, Sakyo-ku,
Kyoto 606–8507, Japan
further analyses. This quality-control step was applied to
fumi@genome.med.kyoto-u. the mixed pool of case and control samples in each study
ac.jp set separately. SNPs that were identified in both stages
See Online for appendix were used for the combined analysis. Hetero­geneity of
For the International HapMap the odds ratio (OR) between the two stages was calculated
Project see https://www. by Cochran’s Q Test by METAL.17 Detailed methods of the
genome.gov/10001688/
international-hapmap-project
whole-genome imputation are in the appendix (p 10).
Statistical analysis
The statistical power of the study according to different
frequencies of risk alleles and ORs was calculated by
the CaTS algorithm,17 assuming a disease prevalence
of 0·01%, a ratio of cases to controls of 0·5, and a
significance level of 5·0 × 10–⁸. With a sample size of
835 for our current study, we calculated that we would
have 71% or higher statistical power to detect a risk allele
with an OR higher than 1·5 and minor allele frequency
higher than than 0·3 (appendix p 11).
The two genome-wide association studies (stages 1
and 2) were analysed by logistic regression using sex and
the top ten principal components of the analysis in all
study participants as covariates in each study. In the
combined study, we included an indicator variable to
distinguish study stages as a covariate to minimise bias
between the two studies. The inflation of genome-wide
association study statistics was evaluated by a quantile-
quantile (Q-Q) plot. PLINK statistical software (ver­
sion 1.9)18 was used for the analyses. The heritability
explained by SNPs showing significant associations with
IgG4-related disease was estimated using the method by
So and colleagues19 on the basis of the liability threshold
model and assuming a disease prevalence of 0·01%.
The genome-wide significance threshold was set
through the Bonferroni correction at p=5·2 × 10–⁸ for the
e16
two genome-wide association studies (stages 1 and 2).
The significance threshold for HLA susceptibility alleles
was set at p=4·4 × 10–⁴, because 114 HLA alleles were
compared. For the aminoacid analysis, the significance
level thresholds after Bonferroni’s correction were set as
p=2·9 × 10–⁴ for the comparison of antigen-presentation
groove domains (G-DOMAINS; 174 aminoacid positions)
and p = 7·1 × 10–⁵ for comparison of the entire HLA
protein (707 aminoacid positions). Otherwise, p values
lower than 0·05 were regarded as significant.
Linkage disequilibrium was calculated by the PLINK
statistical software using the current genome-wide
association studies data unless specified. Haplotypes of
rs1340976 and rs1050501 were estimated with PLINK, and
associations were tested with Fisher’s exact test.
HLA alleles and aminoacid residues were predicted
with the SNP2HLA software (version 1.0.3)20 for both test
and control participants, with a Japanese HLA imputa­
tion reference panel.21 DRB1*14:01 alleles imputed by
SNP2HLA were replaced by DRB1*14:54 because of
a mistyping problem using the conventional typing
method.22 The dosage output, which accounts for impu­
tation uncertainty, was used for the association analyses.
For the calculation and visualisation of linkage disequil­
ibrium, we used the output of the best-guess genotype,
which was restricted to the integer values 0, 1, and 2.
The distribution of HLA alleles in the patient group was
compared with that of control participants as predicted by
SNP2HLA using multiple logistic regression models
with the PLINK software. HLA alleles with r²<0·5 were
removed from the analysis. Aminoacid sequences corres­
ponding to HLA alleles were aligned to the HLA locus.
The effect of aminoacid positions on disease risk was
evaluated using a logistic regression model (using the
R statistics package, version 3.2.3) on the basis of the
additive effects of dosages of HLA aminoacid residues
(omnibus test).23 We took the top ten principal compon­
ents, sex, and the indicator variable from stage 2 as
covariates in each association study. Linkage disequil­
ibrium of the haplotypes was visualised and examined
using a disentangle method.24 Aminoacid positions at
the antigen-presentation groove domains were defined
according to the unique renumbering of the international
ImMunoGeneTics information system.25 The protein
structure figure was generated using Protein Data Bank
with the UCSF Chimera package.26
Associations between genotypes and gene expression
(eQTL) were analysed using genotyping and microarray-
based expression data from 298 Japanese individuals16 by
linear regression analysis. A generalised linear regression
model was applied for the association of genotypes with
age, serum IgG4 concentrations, and the number of
swollen organs at diagnosis. The nucleotide sequence
of the Fcγ receptor IIb (FCGR2B) gene was determined
for 748 patients with IgG4-related disease and 618 con­
trol participants from both study stages with Illumina
MiSeq targeting a 15·8 kb DNA segment that spans the
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A
rs615698
HLA
10 10

rs1340976
8 FCGR2B 8

–Log10 (observed p)
–Log10 (p)

6 6

4 4

2 2

0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 19 21 X 0 2 4 6
18 20 22
Chromosome –Log10 (expected p)

B
HLA-DRB1 rs615698

10
–Log10 (p)

10 Conditioned on rs615698
–Log10 (p)

0
29·2 30·0 31·0 32·0 33·0 33·6
(Mb)

F GHA J L E C B TNF C2 C4 DR DQ DM DP
MHC class I* MHC class III MHC class II†

Figure 1: Combined genome-wide association analysis of DNA from patients with IgG4-related disease and regional association in the HLA locus
(A) Manhattan plot and quantile-quantile plot of the combined genome-wide association study. (B) Regional association results in the HLA locus. The nominal
association on rs615698 is indicated in the upper panel and its conditional association is indicated in the lower panel. Blue plots indicate typing data, and red plots
indicate imputed data.*Letters represent HLA genes (eg, HLA-F, HLA-G, etc). †Letters represent HLA genes (eg, HLA-DR, HLA-DQ, etc).

gene and its 5ʹ upstream region. For this purpose, Results

an oligo­ nucleotide pair, which specifically amplifies
FCGR2B, was designed. PCR was done using the Tks
Gflex enzyme (Takara Bio; Kyoto, Japan; appendix p 12).
Copy-number variation in the FCGR region was estim­
ated by the paralogue ratio test using 591 case samples
and 608 control samples (appendix p 13). The estim­ated
dosage of copy-number variation was compared between
patients and control participants by Fisher’s exact test.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report. The corresponding author had full access to
all the data in the study and had final responsibility for
the decision to submit for publication.
Our genome-wide association study was done in
two stages; stage 1 included 644 patient samples and
1532 control samples, and stage 2 included 191 patient and
257 control samples. We initially genotyped DNA from a
total of 857 patients with IgG4-related disease (655 in
stage 1, 202 in stage 2), and from 2082 samples from
control participants (1784 in stage 1, 298 in stage 2), and
high-quality data were available from a total of 835 patients
and 1789 control samples (appendix p 7). Geno­typing data
on seven patients were removed from stage 1 of the
analysis because of a high degree of kinship. Additionally,
we removed 308 outliers in the principal component
analysis (four patient samples and 252 control samples in
stage 1; 11 patient samples and 41 control samples in
stage 2) in a trimming step of five iterations (appendix p 9).

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SNP characteristics Set 1
Chromo­ Position Allele* Gene Frequency of p value OR
some (A1/A2) A2 allele (case (95% CI)
vs control)
rs1340976 1 161661489 C/A FCGR2B/FCRLA 0·51 vs 0·61 6·4 × 10–⁸ 0·60
(0·50–0·72)
rs615698 6 32574190 A/G HLA-DRB1/DQA1 0·40 vs 0·49 2·2 × 10–⁶ 0·64
(0·53–0·77)
OR=odds ratio. SNP=single nucleotide polymorphism. *A1 and A2 denote reference and non-reference alleles in the NCBI Build37 reference sequence.
Table 1: Genetic variants showing genome-wide significance in the combined study
In stage 1, the strongest signal associated with
IgG4-related disease was detected in the MHC locus
(p=8·2 × 10–¹⁴ for rs477515; appendix p 14). In stage 2,
we detected no significant associations for this locus,
although there was a peak showing a suggestive associ­
ation in the MHC locus (peak at rs204989, p=1·1 × 10–⁶;
appendix p 14). We then examined the overall associ­
ations between variants and disease by combin­ ing
the data from the two stages. No population struc­
ture was observed (λ=1·02, figure 1A). The strongest
association with disease was obtained for rs615698
(p=1·1 × 10–¹¹) in the vicinity of the HLA-DRB1 gene in the
MHC locus (figure 1A). rs201755244, which is located
adjacent to a T-nucleotide stretch (GCCTGGCCT[C→T]
TTTTTTTTTTTTCT), showed the strongest association
in the FCGR2B locus (data not shown). We examined the
accuracy of the rs201755244 genotyping using the whole-
genome sequencing results from 384 control participants
in this study and found that there was a multi-allelic
polymorphism of the number of T nucleotides in the
stretch, but that the C→T substitution did not exist (ie,
SNP array was not accurate for rs201755244). rs1340976
showed the second strongest association in the FCGR2B
locus (p=2·0 × 10–⁸) with IgG4-related disease (table 1),
and its genotyping results showed 99·5% concordance
between the SNP array and whole-genome sequencing
results. Therefore, we removed rs201755244 and used
rs1340976 for further analysis. There was no hetero­
geneity in the OR of rs615698 between the two stages
(p=0·52), whereas rs1340976 showed a weak hetero­
geneity (p=0·015). The SNP markers with p values
smaller than 1·0 × 10–⁵ are listed in appendix pp 15–17. An
additional genome-wide association study using imputed
geno­types repeatedly showed associations in these two
reg­ions, and there were no additional significant peaks
(appendix p 18).
After conditioning on rs615698, no other markers
showed significance (p≥8·8 × 10–⁵, figure 1B). In the
FCGR2B region, no further association was observed
after conditioning for rs1340976 (p3 ·5 × 10–⁵, figure 2A).
These two variants combined accounted for 0·5% of the
heritability of susceptibility to IgG4-related disease. We
then studied whether these variants were associated with
a specific subtype of IgG4-related disease, autoimmune
e18
Set 2 Combined set
Frequency of p value OR Frequency of p value OR (95%
A2 allele (case (95% CI) A2 allele (case CI)
vs control) vs control)
0·54 vs 0·60 0·32 0·83 0·52 vs 0·62 2·0 × 10–⁸ 0·62
(0·59–1·19) (0·52–0·73)
0·39 vs 0·55 5·9 × 10–³ 0·61 0·40 vs 0·50 1·1 × 10–¹¹ 0·53
(0·43–0·87) (0·44–0·63)
pancreatitis or Mikulicz’s disease. The results showed
that both variants were associated with both disease
subphenotypes (appendix p 19). We also examined associ­
ations between the susceptibility variants and clini­
cal parameters of IgG4-related disease and found that
rs1340976 was associated with number of swollen organs
at diagnosis (p=0·011) and IgG4 concentrations at
diagnosis (p=0·035; appendix p 20).
We next did an association study for the variations
of HLA alleles and aminoacid residues, estimated with
SNP2HLA, in the HLA-A, HLA-B, HLA-C, HLA-DPA1,
HLA-DPB1, HLA-DQB1, and HLA-DRB1 proteins. Sig­
nificant associations were observed in DRB1*04:06,
DRB1*09:01, and DQB1*03:03 (table 2 and appendix
pp 21–24). Among them, DRB1*09:01 and DQB1*03:03
showed high linkage disequilibrium (r²=0·88; appendix
p 25). The omnibus test identified the strongest associ­
ation at position 7 of the β domain of the peptide binding
groove of HLA-DRB1 (hereafter DRB1-GB-7; p=1·7 × 10¹⁴,
figure 3). After conditioning on DRB1-GB-7, no other
positions remained significant (p≥2·6 × 10–³). A mul­
tiple logistic regression analysis showed that a valine
at position 7 of the β domain of the peptide binding
groove was associated with risk for IgG4-related disease
(p=8·7 × 10–¹⁹; table 2), whereas aspartic acid at this
position was protective (p=1·5 × 10–⁶).
In stage 2, expression analysis of quantitative trait loci
in healthy controls showed that the risk allele (the
C nucleotide variant) of rs1340976 was associated with an
increased expression of FCγR2B (p=2·7 × 10–¹⁰, figure 2B).
Much weaker associations were observed for the express­
ion of FCγR2A (p=0·046) and FCγR2C (p=0·043), but not
for the other three FCγR family members whose genes
cluster adjacent to FCGR2B (appendix p 26), suggesting
that FCGR2B was the primary locus associated with this
SNP. Furthermore, eQTL mapping showed that rs1340976
was most significantly associated with FCγR2B expression
from SNPs in a 250-kbp region that encompass the
FCγR gene (ie, chromosome 1 161·45 Mb to 161·70 Mb;
figure 2C). We next tried to identify rare or unknown
com­ mon causative variants in FCGR2B through the
nucleo­­
tide sequencing of 748 patient samples and
618 control samples from both study stages. An association
analysis of 114 SNPs and seven bi-allelic insertions or
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A
10
FCGR2B rs1340976
–Log10 (p)

10 Conditioned on rs1340976
–Log10 (p)

0
161·45 161·50 161·60 161·70 161·80 161·90
(Mb)
FCGR2A FCGR2C FCGR2B FCRLA ATF6

FCGR3A FCGR3B FCRLB

HSPA6 HSPA7 RPL31P11 DUSP12

B C
p=2·7×10–10 8 10
rs1340976
1·5

8
6
–Log10 p(lgG4-RD susceptibility)

1·0
–Log10 p(FCGR2B expression)
Expression of FCγR2B

6
0·5
4

4
0

2
–0·5 2

–1·0
0 0
CC (51) CA (141) AA (105) 161·65 161·67 161·69
(Mb)
rs1340976 variants

Figure 2: Regional association analysis and eQTL analysis in the FCGR2B locus
(A) Regional association in the FCGR2B region based on the results of the combined genome-wide association study. Nominal association on rs1340976 is indicated in
the upper panel and conditional association is indicated in the lower panel. Blue dots indicate typing data, and red dots indicate imputed data. (B) Correlation between
eQTL analysis of rs1340976 with the expression of FCγR2B. (C) Results of eQTL mapping of FCGR2B combined with the association analysis. Open circles indicate
associations with susceptibility to IgG4-related disease, whereas inverted triangles show associations with FCGR2B expression. eQTL=expression of quantitative trait loci.

deletions showed 34 variations with nominal significance
(p < 0·05), although none of them reached genome-wide
significance (appendix pp 27–30). rs1340976 was in weak
linkage disequilibrium with rs1050501 (r²=0·16, Dʹ=0·98),
a missense variant (Ile232Thr) that was shown to impair
the function of FCγR2B and was associated with
sys­temic lupus erythematosus.27,28 The haplotype con­
sisting of the rs1340976 C allele and rs1050501 T allele
showed a strong association with the risk for IgG4-related
disease (p=3·3 × 10–⁶, appendix p 31). Association of
rs1050501 with IgG4-related disease risk was not attrib­
uted to linkage disequilibrium with rs1340976 because it

www.thelancet.com/rheumatology Vol 1 September 2019 e19

 Articles

A B
HLA-DRA Gα domain
20
DRB1-GB-7
–Log10 (p)

10

0
1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92
20
Conditioned on DRB1-GB-7
–Log10 (p)

10

0
1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92 1 92
1

A1

A2

B
GA

GA
GA

GA

-G

-G

-G

-G
G

B1

B1

A1

B1
A-

C-

B-
A-

C-

B-

DR

DQ

DP
DP
HLA-DRB1 Gβ domain

Figure 3: Association of aminoacid residues and the location of DRB1-GB-7

(A) Manhattan plot of the results of omnibus tests on aminoacid residues across HLA genes. The nominal association is indicated in the upper panel and the
conditional associations is indicated in the lower panel. (B) Location of GB-7 in the 3D structure of HLA-DRB1. Key aminoacid positions are highlighted as spheres.
DRB1-GB-7=position 7 of the β domain of the peptide binding groove of HLA-DRB1.

IgG4-related disease, is in strong linkage disequilib­

Allele frequency p value OR (95% CI) Corresponding HLA alleles*
rium with DQB1*04:01, in accordance with a previous
Case Control report.9 Notably, non-obese diabetic mice transgenic for
DRB1*04:06 0·063 0·025 1·9 × 10–⁵ 2·58 (1·67–3·98) ·· HLA-DRB1*04:05 are prone to autoimmune pancreatitis.30
DRB1*09:01 0·068 0·135 6·0 × 10–⁹ 0·43 (0·32–0·57) ·· DRB1-GB-7 was also reported to be the primary suscept­
DQB1*03:03 0·079 0·145 6·8 × 10–⁸ 0·47 (0·36–0·62) ·· ibility position (DRB1 codon 11) for rheumatoid arthritis.23
DRB1-GB-7 ·· ·· ·· ·· ·· Additionally, HLA-DRB1*04:05 is associated with other
Val 0·369 0·207 8·7 × 10–¹⁹ 2·01 (1·72–2·34) *04:03, *04:05, *04:06, *04:10 immune-related dis­orders such as type 1 diabetes31 and
Ser 0·327 0·327 ·· Reference *08:02, *08:03, *11:01, *12:01, *12:02, Crohn’s disease.32 DRB1*04:06 is associ­ated with insulin
*13:02 , *14:03, *14:05, *14:06 autoimmune syndrome.33 Although IgG4-related disease
Pro 0·180 0·214 0·23 0·89 (0·74–1·07) *15:01, *15:02, *16:02 and similar conditions might share peptide epitopes
Leu 0·054 0·077 8·3 × 10–² 0·80 (0·61–1·03) *01:01 crucial for their pathology, the specific molecular mech­
Asp 0·067 0·136 1·5 × 10–⁶ 0·57 (0·45–0·72) *09:01 anisms underlying such associations among distinct
disease entities are yet to be elucidated. The strong genetic
OR=odds ratio. *HLA alleles with a frequency of greater than 0·01 in either the case or control population are shown.
associations between HLA-DRB1 and IgG4-related disease
Table 2: Susceptible HLA alleles and amino acid residues associated with IgG4-related disease highlights the fun­damental role of the HLA locus in the
onset of immune-related diseases, as in asthma.34
persisted after conditioning on rs1340976 (p=1·0 × 10–³, FCγR2B is the only FCGR family member expressed in
OR=0·58). Copy-number variation in the Fcγ receptor IIIb B cells.35 It is also the only known inhibitory FCγ receptor
(FCGR3B) gene located in the vicinity of FCGR2B is and has important roles in the elimination of autoreactive
reportedly associated with autoimmune diseases includ­ B cells.36 In our study, rs1340976 showed the strongest
ing systemic lupus erythema­tosus.29 However, we did not disease association in the FCGR locus and had the highest
find any associations between the copy-number variation impact on FCγR2B expression as compared with other
and IgG4-related disease (appendix p 32). FCγR proteins, strongly suggesting that rs1340976 is
the primary variant associated with IgG4-related disease.
Discussion Mice overexpressing Fcgr2b did not show any apparent
We showed that the HLA-DRB1 and FCGR2B genes were phenotypes that are typically observed in patients with
major genetic determinants of IgG4-related disease in a IgG4-related disease.35 However, it is not possible to evalu­
representative Japanese population. Since IgG4-related ate the effect of murine Fcgr2b on IgG4-related disease
disease is also reported in other populations,4 it will be phenotypes, since mice do not naturally express a version
important to compare the effect of these genes on of the IGHG4 gene, which encodes IgG4. The associ­ation
IgG4-related disease in other ethnicities. between rs134097 and specific clinical phenotypes also
The strongest association of HLA-DRB1 with the risk for indicates an important role of FCGR2B in IgG4-related
IgG4-related disease among all surveyed genes was likely disease.
due to the aminoacid variation at position 7 of the β domain Patients with IgG4-related disease often have pheno­types
the peptide-binding groove of HLA-DRB1, which has opposite to those observed in patients with other auto­
a crucial role in antigen presentation. We showed that immune diseases (eg, an increased number of regu­latory
the risk allele of HLA-DRB1*04:05, the risk allele for T cells and augmentation of inhibitory cytokines such

e20 www.thelancet.com/rheumatology Vol 1 September 2019


as IL-10 and TGFβ,37). The increase of serum IgG4
concentrations in these patients might be associated with
these observations, since an increase in IgG4 is known to
inhibit allergic phenotypes.35,38 In this context, whether
rs1340976 is involved in IgG4 overproduction or whether
binding to FCGR2B has pathogenic consequences are
questions that remain to be addressed.
FCGR2B is known to be a major genetic factor of
systemic lupus erythematosus,27 and Fcgr2b-deficient mice
are prone to systemic lupus erythematosus.39 We found a
strong association signal in rs1050501, a causative variant
of systemic lupus erythematosus in which the C allele has
an aminoacid substitution at position 232 (Ile232Thr) in
the transmembrane domain. This alteration destabilises
the anchoring of FCGR2B in the cell membrane, resulting
in a reduced suppressive effect on the immune response.28
Importantly, in our study, the association of rs1050501
with IgG4-related disease involved the opposite T allele.
Our finding might suggest that increased expression
of stable cell-surface FCγR2B increases the risk for
IgG4-related disease. Similarly, the causative aminoacid
variation DRB1-GB-7-Val in patients with IgG4-related
disease was reported to be protective against systemic
lupus erythematosus.40 These opposing genetic associ­
ations of HLA and FCGR2B between IgG4-related disease
and systemic lupus erythematosus might help to explain
the differences between the two diseases, including in the
age at onset, sex, and affected organs.
Limitations of our study include insufficient statistical
power with a relatively small number of patient samples,
which might be the reason why variants of FCGR2B and
HLA-DRB1 accounted for only 0·5% of the genetic make-
up of IgG4-related disease. This is largely due to the
challenge of collecting DNA samples due to the rarity of
accurately diagnosed cases, which is a common problem
in genetic studies of rare diseases. The annual incidence
of IgG4-related disease is estimated to be 0·28–1·08
in 100 000 in the Japanese population.1 However, this is
likely to be an underestimate in view of the low awareness
and difficulty in diagnosing the disease. Nevertheless,
increased recognition of this disease will facilitate the
recruitment of a larger number of patients and thus the
identification of novel genetic determinants. In fact, our
statistical power calculation showed that we would need
more than 5000 patients with IgG4-related disease to
achieve more than 80% statistical power to detect a risk
allele with an OR lower than 1·3 or minor allele frequency
of less than 0·1 (appendix p 11). These results might also
reflect inherent limitations of genome-wide association
studies, in which rare variants with high impact cannot be
captured and no efficient statistical methods for evaluating
the com­binational effect of variants have been developed.
Moreover, a SNP array-based genome-wide association
study is not suitable for gene-based comparisons to
accumulate disease-related variants. Whole-genome or
whole-exome sequencing are options for circumventing
these shortcomings.
www.thelancet.com/rheumatology Vol 1 September 2019
Articles
IgG4 has a relatively weak anti-inflammatory effect and
is thought to suppress allergic reactions. How­ ever, a
study41 showed that IgG4 antibodies in patients with
IgG4-related disease are pathogenic and induce IgG4-
related disease-like symptoms in mice. It is yet to be
clarified whether IgG4 overproduction itself or the
antigen specificity of the IgG4 antibodies in patients (or
both) is important in the onset of the disease. Additionally,
there are likely to be other genetic and environmental
factors associated with the development of IgG4-related
disease. Future studies including the identification of
autoantigens in IgG4-related disease will improve our
understanding of its underlying molecular mechanisms.
Contributors
KOk, TC, SK, and FM designed and supervised the study. CT, MO, SK,
TKaw, IY, and KHig analysed the data. CT, TI, YKa, and FM wrote the
manuscript. MS, KKur, YKo, KU, MY, KKub, SY, KHir, YM, HM, TO, SM,
TN, HS, TKam, OH, EI, KI, YT, KOh, TA, ShN, SeN, TSa, HU, TSh, NM,
MK, AA, HT, TM, and the Japanese IgG4-Related Disease Working
Consortium recruited patients and collected their clinical information and
biological materials.
The Japanese IgG4-Related Disease Working Consortium
Atsushi Kanno, Yoshihiro Okabe, Shinji Katsushima, Tetsuro Inokuma,
Yukitaka Yamashita, Yoshitaka Nakai, Takayoshi Nishino, Kozo Kajimura,
Mitsushige Shibatoge, Naoki Kanda, Akio Ido, Masaya Ohana,
Ichiro Moriyama, Hiroshi Tatsuta, Kazuyoshi Matsumura, Keita Fujikawa,
Norimoto Gotoh, Takanobu Tsutsumi, Masakazu Shimizu, Kazuya Setoh,
Meiko Takahashi, Yasuharu Tabara, Jun Mimura, Takefumi Nakamura,
Toshiyuki Kimura, and Chiharu Kawanami.
Declaration of interests
YM reports grants from Kyowa Kirin Pharmaceutical Development,
Astellas, Eisai, Ono, Pfizer, Asahi Kasei, MSD, Daiichi-Sankyo, Taisho,
Taiho, Takeda, Chugai, Teijin, Nippon Kayaku, and Mochida outside the
submitted work. YT reports non-financial support and honoraria or
speakers fees funding from Astellas during the conduct of the study, grants
from Mitsubishi-Tanabe, Bristol-Myers Squibb, Eisai, Chugai, Takeda,
AbbVie, Astellas, Daiichi-Sankyo, Ono, MSD, and Taisho-Toyama, and
honoraria or speakers fees funding from Daiichi-Sankyo, Astellas, Eli Lilly,
Chugai, Sanofi, AbbVie, Pfizer, YL Biologics, Bristol-Myers Squibb,
GlaxoSmithKline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda,
Janssen, and Asahi Kasei outside the submitted work. NM reports grants
from Merck Serono, AstraZeneca, Zeria, NanoCarrier, Eisai, MSD,
Dainippon Sumitomo, ASLAN, Incyte, and Pharma Valley Center, personal
fees from Ono and Teijin, grants and personal fees from Yakult Honsha
and Taiho, and grants, personal fees, and non-financial support from
Novartis outside the submitted work. All other authors declare no conflicts.
Acknowledgments
This study was supported by in part by the Japanese Ministry of Health,
Labour, and Welfare (grant number #H22-Nanchi-084), the Japanese
Agency of Medical Research and Development (grant numbers
JP16EK0109070 and JP18EK0109283), and Kyoto University Grant for Top
Global University Japan Project. We are grateful to all of the patients for
their invaluable contributions.
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