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Excessive function of peripheral blood neutrophils from patients with behcet's disease and from hla-b51 transgenic mice.

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Number 3, March 1995, pp 426-433
0 1995, American College of Rheumatology
Objective. To elucidate the role played by HLAB51 in the neutrophil hyperfunction of Behqet’s disease,
we determined the superoxide production by purified
peripheral blood neutrophils from Behqet’s disease patients, from HLA-B51 positive healthy individuals, and
from HLA-B51 transgenic mice,
Methods. Neutrophil function was evaluated by
flow cytometric analysis, detecting the conversion of
2’,7’-dichlorofluorescin diacetate into dichlorofluorescein, induced by superoxide in the neutrophils.
Results. A significant correlation between the
neutrophil hyperfunction and the possession of HLAB51 phenotype, regardless of the presence of the disease,
was observed in humans. FMLP-stimulatedneutrophils
(without in vitro priming) from HLA-BS1 transgenic
mice, but not those from HLA-B35 transgenic mice or
from nontransgenicmice, produced substantial amounts
of superoxide.
Conclusion. The HLA-BS1 molecule itself may
be responsible, at least in part, for neutrophil hyperfunction in Behqet’s disease.
Presented in part at the 57th Annual Scientific Meeting of
the American College of Rheumatology, San Antonio, TX, November 10, 1993.
Supported in part by research grants from the BehGet’s
Disease Research Committee of Japan, Ministry of Health and
Welfare of Japan; the Uehara Memorial Foundation, Tokyo, Japan;
the Kanagawa Nanbyo Foundation, Kawasaki, Japan; and the Japan
Intractable Diseases Research Foundation, Tokyo, Japan.
Mitsuhiro Takeno, MD, PhD, Naomi Yamashita, MD,
PhD, Yutaka Mizushima, MD, PhD, Hidetoshi Kaneoka, MD, PhD,
Tsuyoshi Sakane, MD, PhD: St. Marianna University School of
Medicine, Kawasaki, Japan; Ai Kariyone, PhD, Masafumi Takiguchi, MD, PhD: University of Tokyo, Tokyo, Japan.
Address reprint requests to Tsuyoshi Sakane, MD, PhD,
Institute of Medical Science, St. Marianna University School of
Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216,
Submitted for publication April 13, 1994; accepted in revised form October 5, 1994.
Behget’s disease is a systemic inflammatory
disease characterized by recurrent signs and symptoms of oral aphthosis, genital ulcers, skin lesions, and
ocular involvement including uveitis. Aseptic neutrophi1 infiltration in the lesions is one of the most striking
pathologic features, and various in vitro tests of neutrophil function in patients with BehGet’s disease have
been shown to be abnormal (1-5). This suggests that
the excessive neutrophil function plays a vital role in
the development and clinical course of the disease.
Epidemiologic studies have demonstrated that
the disease is prevalent along the Silk Road: the Far
East of Asia, China, the Middle East, and along the
Eastern Mediterranean. These studies have also revealed that the HLA-B51 phenotype is strongly associated with Behget’s disease in these ethnic groups
(6-10). Chajek-Shaul and coworkers have reported
that neutrophil chemotaxis in patients with Behget’s
disease who possess the HLA-B51 antigen was significantly enhanced as compared with that in HLA-B51
negative patients (4).Furthermore, Sensi and coworkers have recently reported that HLA-B51 could exert
regulatory control on neutrophil functions (5). These
results suggested that the HLA-B51 gene is one of the
major genetic markers of neutrophil abnormalities in
the disease. However, it remains to be determined
whether the HLA-B51 molecule itself or its linked
gene products are involved in the neutrophil hyperfunction.
To elucidate the relationship between the hyperfunction of neutrophils and HLA-B51, we first
determined the level of superoxide produced by purified peripheral blood neutrophils, avoiding the in vitro
influences of immunocompetent lymphocytes and
HLA phenotypes, in patients and in healthy subjects.
We found that neutrophils from the patients produced
significantly higher amounts of superoxide than did
those from the healthy controls. Moreover, the higher
productivity of superoxide was closely related t o the
possession of HLA-BS I , regardless of Behqet’s disease. These results suggest that the abnormal hyperfunction of neutrophils in patients with Behqet’s disease is determined in part by the HLA-BSI molecule.
These observations prompted us t o generate
HLA-BS 1 transgenic (Tg) mice t o examine the direct
involvement of HLA-BSI in in vivo and in vitro
functions of neutrophils. Although active lesions mimicking Behqet’s disease were not observed in any
HLA-B51 Tg mouse, neutrophils from HLA-BS1 Tg
mice responded t o FMLP without additional stimuli,
and produced excessive amounts of superoxide; however, neither the HLA-B35 Tg nor the non-Tg mice
showed this response. These findings suggest that the
HLA-BS 1 molecule itself affects neutrophil function,
which may play pivotal roles in pathogenesis and
clinical course of Behqet’s disease.
Patients and controls. Twenty-nine Japanese patients
with BehCet’s disease (16 male and 13 female), 14 of whom
were HLA-B5I positive and 15 were B51 negative, were
evaluated. The diagnosis was made based on the criteria
proposed by the BehCet’s Disease Research Committee of
Japan (1 I ) . Twenty-four age- and sex-matched healthy Japanese individuals, 9 of whom were HLA-1351 positive and 15
B51 negative, served as controls. HLA phenotypes were
determined using a standard complement-dependent microlymphocytotoxicity test with internationally recognized
Preparation of human peripheral blood neutrophils.
Whole blood from patients and healthy donors was drawn
into tubes containing heparin. Peripheral blood neutrophils
were separated after centrifugation, at the interface between
2 Ficoll gradients of specific gravities 1.077 and 1 . 1 19. The
purity of the neutrophils, determined by flow cytometric
scattergram, was typically more than 97%.
Measurement of superoxide production by human
peripheral blood neutrophils. We measured neutrophil superoxide production according to the method described by Bass
and coworkers (12), with slight modification. Briefly, purified neutrophils were gently diluted in Ca2’ -free and Mg2-‘free phosphate buffered saline (PBS) in a polypropylene tube
(Corning, Corning, NY), and incubated with 5 pM 2‘,7‘dichlorofluorescin diacetate (Eastman Kodak, Rochester,
NY) for 15 minutes at 37°C. After centrifugation, the neutrophils were resuspended in PBS, and an additional 15minute incubation at 37°C was performed in the presence of
1 pglml FMLP (Sigma, St. Louis, MO) or 100 nglml phorbol
myristate acetate (PMA; Wako Pure Chemicals, Osaka,
Japan). Cells generating superoxide in their cytoplasm became fluorescent from the conversion of 2‘,7’-dichlorofluo-
Log Fluorescence Intensity
Figure 1. Representative flow cytometric profiles of superoxideproducing neutrophils in A, unstimulated and B, FMLP-stimulated
(1 pglml FMLP for 20 minutes) purified neutrophils. Superoxideproducing fluorescent neutrophils were determined by flow cytometry. A discriminating line was drawn at the point where <2% of
unstimulated neutrophils could be assessed as positive. After FMLP
stimulation, neutrophils that showed a shift to the right were
considered positive (hatched area).
rescin diacetate into dichlorofluorescein. Contaminating red
blood cells were lysed with 0.83% ammonium chloride.
The cytoplasmic content of superoxide in individual
cells correlates with the intensity of fluorescence. Flow
cytometric analysis was performed utilizing a flow cytometer
(Cytron Absolute; Ortho, Rantan, NJ). The percentage of
superoxide-producing neutrophils was calculated as the
number of fluorescence-positive cells divided by the total
number of cells examined. Figure 1 shows a representative
flow cytometric profile of superoxide-producing neutrophils.
Mice. Inbred C3H/He mice were purchased from
Charles River Japan (Tokyo, Japan). HLA-B51 Tg C3H/He
mice bearing the 6.4-kilobase Eco RI fragment of the HLAB*5101 heavy chain gene from a healthy Japanese individual
were produced and characterized as previously described
(13). HLA-B35 Tg mice bearing HLA-B*3501 were also
molecules. Similar results were obtained in B35 Tg mice, but
not in non-Tg mice (Figure 2). The magnitudes of mean
fluorescence intensity of flow cytometric analyses were 8.23,
14.46, and 2.91 in lymphocytes and 10.35, 13.56, and 6.52 in
neutrophils from B51 Tg mice, B35 Tg mice, and non-Tg
mice, respectively. The specificity in HLA transgenic mice
was determined by a complement-dependent cytotoxicity
test using HLA-B51 and HLA-B35 antisera obtained from
multiparous women (data not shown).
Measurement of superoxide production by peripheral
blood neutrophils from Tg and non-Tg mice. We measured
superoxide production by murine neutrophils, utilizing the
same method as used for humans, except that several
stimuli, including 1 pg/ml FMLP, 100 nglml PMA, and 100
pdml opsonized zymosan (Sigma), were used. Whole blood
white cells rather than purified neutrophils were used because of the technical difficulties in obtaining purified peripheral neutrophils from the limited amount of white cells
from a single mouse. Flow cytometric analyses were performed on neutrophils by gating out lymphocytes and monocytes from neutrophils. The magnitudes of stimulant-induced
superoxide production were evaluated by determining the
relative fluorescence intensity ratio, calculated as the mean
fluorescence intensity of stimulated neutrophrls divided by
that of unstimulated neutrophils.
Clinical and histologic examination. The existence of
the clinical signs and symptoms typically seen in humans
with BehGet's disease-skin lesions, oral aphthae, genital
ulcers, and ocular lesions-was carefully documented ip the
HLA-B Tg mice. Histologic studies were also performktl on
those tissues and organs.
Statistical evaluation. Statistical significance was examined using the unpaired Student's t-test.
Log Fluorescence Intensity
Figure 2. Expression of HLA-B transgene products on peripheral
blood lymphocytes (A) and neutrophils (B)from HLA-B transgenic
(Tg) mice. Peripheral blood cells were stained with fluorescein
isothiocyanate-conjugated w6/32 monoclonal antibody specific for
HLA class I molecules. After lysis of red blood cells, flow cytometric analysis was performed, with gating forward scatter and side
scatter. Profiles of positive cells from an HLA-B51 Tg mouse
a B35 Tg mouse (- - -), and a non-Tg mouse (. *
generated following the same procedures. The characterization of HLA-B35 Tg mice will be described in detail elsewhere (Kariyone A et al: manuscript in preparation). All Tg
and non-Tg mice were bred and maintained under the same
conditions. B51 Tg, B35 Tg, and non-Tg C3H/He mice
were killed at ages 7-12 weeks for the in vitro neutrophil
function tests.
To determine the expression of HLA-B transgene
products in Tg mice, peripheral lymphocytes and neutrophils
were stained with fluorescein isothiocyanate-conjugated
w6/32 monoclonal antibody, which has monomorphic specificity for the conformational elpitope of HLA class I molecules, and analyzed utilizing a flow cytometer. Figure 2
shows that peripheral lymphocytes as well as neutrophils
from B51 Tg mice expressed the HLA class I heavy chain
Superoxide production by purified peripheral
blood neutrophils from patients with Behget's disease.
Highly purified peripheral blood neutrophils were
stimulated with 1 pg/ml FMLP. The percentages of
superoxide-producing neutrophils were calculated as
described in Patients and Methods. The level of superoxide production by neutrophils from the patients was
significantly higher than that from controls (mean ?
SEM 53.8 ? 5.6% and 37.0 ? 5.9%, respectively; P =
The same data were analyzed according to the
presence or absence of HLA-B51. Neutrophils from
positive individuals, regardless of the presence of
Behset's disease, produced much higher levels of
superoxide than did those from B51 negative individuals, and the statistical significance of the difference
was higher (mean 2 SEM 67.3 t 6.8% and 41.2 ?
10.6% in B51 positive and B51 negative patients [n =
291, P = 0.017; 52.6 ? 12.2% and 25.5 ? 4.7%,
respectively, in controls [n = 241 P = 0.021; and 63.0
( N = 1 I ) (N=9)
( N S O ) (N=23)
Figure 3. FMLP-induced superoxide production by peripheral
blood neutrophils from patients with BehGet's disease and from
healthy controls. Superoxide-producing neutrophils from HLA-BS I
negative and HLA-BSI positive subjects were determined by flow
cytometry. Values are the mean and SEM 96 positive for superoxide.
? 6.0% and 33.3 5 4.6%, respectively, among all
study subjects [n = 531, P < O.OOOl), (Figure 3).
When we compared superoxide production between B51 positive patients and B51 positive healthy
individuals, the difference did not reach to statistical
significance ( P = 0.263). Similar results were obtained
for B5I negative patients versus B51 negative healthy
individuals ( P = 0.09). PM A-induced superoxide production by purified peripheral blood neutrophils from
the patients and controls was also evaluated. There
were no statistically significant differences among
these populations (mean t SEM 90.0 t 14.0%, 75.0 f
8.3%, 92.7 ? 17.2%, and 82.2 t 5.04% in B51 positive
patients, B51 negative patients, B51 positive healthy
individuals, and B51 negative healthy individuals, respectively). These results. thus suggested that the
HLA-B5 1 antigen could regulate FMLP-induced neutrophil hyperfunction.
Superoxide production by peripheral blood neutrophils from HLA-B Tg imice. To clarify the direct
involvement of the HLA-lB51 molecule in neutrophil
hyperfunction, we generaced HLA-B Tg mice. We
examined superoxide production by peripheral blood
B51 Tg
B35 Tg
Log Fluorescence Intensity
Figure 4. Representative profiles of superoxide production by FMLP-stimulated ( 1 pg/ml for
I S minutes) neutrophils from 3 HLA-BSI transgenic (Tg) (A-C), 3 HLA-B3S Tg (D-F), and 3
non-Tg ( G I ) mice. Neutrophil fluorescence was assessed by flow cytometry of stimulated
and unstimulated (. . . .) neutrophils.
Log Fluoreseeme Intensity
Figure 5. Representative profile,s of superoxide production by
phorbol myristate acetate (PMA:. 100 ng/ml)-stimulated or opsonized zymosan (100 &ml )-stimulated neutrophils from HLA-B51
transgenic (Tg) (A and B), HLA-It335 Tg (C and D), and non-Tg (E
and F) mice. Neutrophil fluorescence was determined by flow
cytometry of stimulated 1-(
and unstimulated (. . neutrophils.
0 )
neutrophils from the Tg mice induced by FMLP,
PMA, or opsonized zymosatn to investigate the in vitro
function of the neutrophils. Prominent changes were
observed when the neutrophils were stimulated with
FMLP. In B35 Tg mice and non-Tg mice, the magnitude of superoxide production by FMLP-stimulated
neutrophils was comparable with that by unstimulated
neutrophils (Figure 4). In contrast, neutrophils from
B51 Tg mice responded vigorously to FMLP, producing high levels of superoxide without other stimuli
such as lipopolysaccharide or cytokines (Figure 4).
In contrast, neutrophils from not only the B51
Tg mice, but also the B35 Tg and non-Tg mice,
responded well to PMA (Figures 5A, C , and E) and to
opsonized zymosan (Figures 5B, D, and E), resulting
in high levels of superoxide production.
Figure 6 summarizes the relative fluorescence
intensity ratios of the stimulated neutrophils compared
with the unstimulated neutrophils from B51 Tg, B35
Tg, and non-Tg mice. The ratios in FMLP-stimulated
neutrophils from B5 1 Tg mice were significantly higher
than those in B35 Tg mice and those in normal non-Tg
mice (Figure 6A). The mean ? SEM ratios were 1.53
2 0.09, 1.07 2 0.02, and 1.11 2 0.04 in B51 Tg mice,
B35 Tg mice, and non-Tg mice, respectively (B51 Tg
mice versus B35 Tg mice P < 0.001; B51 Tg mice
versus non-Tg mice P < 0.001; and B35 Tg mice
versus non-Tg mice P = 0.488). However, there were
no differences in the distribution of the ratios of
PMA-stimulated or opsonized zymosan-stimulated
neutrophils among these 3 mouse groups (Figures 6B
and C). The ratios of PMA-stimulated neutrophils
were 3.72 2 1.40, 3.60 2 0.47, and 2.66 k 0.25 in B51
Tg mice, B35 Tg mice, and non-Tg mice, respectively
(B51 Tg mice versus B35 Tg mice P = 0.922; B51 Tg
A. n l L P
C. zymosan
Figure 6. Relative fluorescence intensity ratio of stimulated (with FMLP [A], PMA [B], or
zymosan [C]) neutrophils to unstimulated neutrophils from 13 HLA-B51 Tg, 12 HLA-B35 Tg,
and 17 non-Tg mice. The ratio was calculated by dividing the mean fluorescence intensity of
stimulated neutrophils by that of unstimulated ones. * = P < 0.01 versus other 2 groups, by
Student’s t-test. Values are the mean and SEM. See Figures 4 and 5 for concentrations of
stimuli and for definitions.
mice versus non-Tg mice P = 0.363; and B35 Tg mice
versus non-Tg mice P = 0.097). The ratios of opsonized zymosan-stimulated neutrophils were 2.52 2
0.19,2.78 +- 0.23, and 2.63 +- 0.27 in B51 Tg mice, B35
Tg mice, and non-Tg mice, respectively (B51 Tg mice
versus B35 Tg mice P = 0.404; B51 Tg mice versus
non-Tg mice P = 0.793; and B35 Tg mice versus
non-Tg mice P = 0.727).
We failed to demonstrate any correlation between responsiveness to the stimulants and differences
in age or sex. These results indicated that peripheral
blood neutrophils from B51 Tg mice were more sensitive to FMLP stimulation than were those from B35 Tg
and non-Tg control mice.
Clinical manifestations and histologic examination of mice. We investigated whether B51 Tg mice
expressed clinical manifestations and pathologic
changes up to 12 weeks of age. Neither clinical nor
pathologic studies revealed any evidence of active
lesions resembling those seen in humans with Behset’s
disease (results not shown).
The significant association between Behset’s
disease and HLA-B51 has been reported in several
ethnic groups, especially among patients with ocular
and/or neurologic involvement (610). It is believed
that the principal biologic function of HLA molecules
is to present antigens to the antigen-specific T cells,
resulting in the triggering of the subsequent immunologic cascades. Therefore, the association suggests
that T lymphocytes may be involved in the pathogenesis and/or the modification of the clinical course of
the disease. One of us (TS) has reported the functional
aberration of a suppressor T cell subset derived from
patients with pre-active Behset’s disease (14). Kahan
et a1 later reported a defect of the suppressive function
in a CD4+ T cell subset (15). Recently accumulated
evidence indicates that T lymphocytes bearing T cell
receptor y/S (y/S T cells) are the major population in
the infiltrating lymphocytes and their numbers are
increased in peripheral blood (16,17). Their functional
importance has also been reported from cloning studies of y/S T cells raised by activation with streptococcal antigens, and their pathogenetic importance in
some patients with this disorder has been described
(18). Among the streptococcal antigens, heat-shock
proteins, especially the hsp65 family, might be one of
the major epitopes for T cell lines and clones (19,20)
43 1
and might be responsible: for uveitis in susceptible
rats (21).
Neutrophil infiltration is an initial characteristic
seen in skin and eye lesions of patients with BehFet’s
disease, and the hyperfunction of peripheral blood
neutrophils from such patients has been noted.
Chajek-Shaul et a1 reported the elevation of neutrophil
chemotaxis in HLA-BS 1 positive patients with Behset’s disease, and Sensi and coworkers showed enhanced neutrophil reactivity in HLA-B5 1 positive
healthy individuals (43). Our data showing the positive association of the neiitrophil hyperfunction with
the HLA-B51 phenotype. observed not only in humans but also in HLA-B Tg mice, directly demonstrate those previous observations.
Neutrophil functions are regulated and maintained by inflammatory cytokines such as interleukin- 1
(IL-l), IL-2, IL-6, IL-8, tumor necrosis factor (TNF),
granulocyte-macrophage colony-stimulating factor
(GM-CSF), and granulocyte CSF (G-CSF). Among
these cytokines, TNF ha:; been one of the primary
interests in this field, because the structural genes of
TNFa and TNFP are mapped within an HLA class I11
gene segment, and are in linkage disequilibrium with
HLA class I genes (22). Our initial observations of
cytokine production by purified neutrophils, but not
by lymphocytes, suggest thlat not TNF production, but
rather, IL-8 production rnight be regulated by the
HLA molecule (unpublished observation). DeForge et
a1 reported that mechanisms independent from TNF,
IL-1, or IL-6 also could regulate IL-8 secretion, and
that reactive oxygen metabolites regulate IL-8 production, suggesting circular or autocrine mechanisms between superoxide produci.ion and IL-8 (23). Taken
together, our results suggest that the abnormal hyperfunction of peripheral blood neutrophils in the patients
may be determined in part by an HLA-B51 molecule,
and may occur in an autocirine manner through excessive production of proinflannmatory cytokines by those
Several autoimmune diseases are closely associated with particular phenotypes of HLA. Generation
of HLA transgenic animals is one of the useful strategies for establishing animal models for human diseases. For example, HLrbB27 Tg rats have been
shown to have clinical features similar to those of
human HLA-B27-related syndromes including ankylosing spondylitis (24). Wle generated HLA-B5 1 Tg
mice as a candidate for an animal model to elucidate
the contribution of HLA m,oleculesto the disease. We
have shown here that FML,P-induced superoxide pro-
duction by neutrophils from HLA-B51 Tg mice is
significantly elevated compared with B35 Tg or non-Tg
mice. It is conceivable that the HLA molecules, which
are xenogeneic to mice, could nonspecifically stimulate neutrophils in Tg mice. However, this is not the
case, because this phenomenon occurred only in B51
Tg mice, and not in B35 Tg mice. The results suggest
that the HLA-B5 1 transgene product itself is directly
involved in neutrophil hyperactivity in these Tg mice.
In the present study, only FMLP-induced superoxide production by neutrophils was increased in
B51 Tg mice; PMA- or zyrnosan-induced superoxide
production was comparable with that in other mice.
The reason that neutrophills from B51 Tg mice are
more sensitive to FMLP stimulation is not yet clear.
Maximal superoxide production induced by FMLP
requires “priming” by cytokines such as G-CSF,
GM-CSF, and TNF (25). Our results suggest that
neutrophils in B51 Tg mice may be easily agitated
intrinsically to produce superoxide by stimuli that are
not potent enough to cause neutrophils from B35 Tg or
non-Tg mice to produce a large amount of superoxide.
Alternatively, neutrophil hyperfunction observed in
B51 Tg mice might represent an inherited abnormality
in their immune systems, thereby allowing them to
secrete excessive cytokines to prime neutrophils
in vivo.
Possession of the E:[LA-B51 molecule is not
sufficient to induce clinical disease among the Tg mice.
This is similar, however, to the relationship between
the human disease and HLA-B51. Even in Japan, the
area with the highest prevalence, Behset’s disease
occurs in only 1 in 1,000 individuals who have the
HLA-B5 1 phenotype (6). Although intrafamilial occurrences of Behset’s disease related to HLA-BS 1
have been observed (26,27:), the coincidence of Behset’s disease in monozygotiic twins is rarely reported.
These data indicate that 13LA-BSl is not a single
genetic factor which determines the occurrence of the
There is no HLA-B association in Caucasian
patients with Behset’s disease. Lehner and colleagues
emphasized the importance of heat-shock proteinresponsive lymphocytes for the onset of the disease in
Caucasian patients (19), whereas we believe the infiltration of peripheral blood neutrophils is the primary
phenomenon in Japanese patients with Behset’s disease. These facts might reflect that Behset’s disease is
not a single clinical entity, but rather, a clinical syndrome (21). The phenotype in combination with environmental factors, such as bacterial (28) or viral infec-
tions (29), may lead to the development and/or
exacerbation of the disease in humans.
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BehCet’s syndrome and recurrent oral ulcers. Lancet 2:13561360, 1982
New Manuscripts to be Sent to Dr. William P. Arend as of April 1
Dr. William P. Arend will officially assume the full responsibilities of Editor, Arthritis and Rheumatism, on July
1, 1995. However, as part of the transition from the Editorship of Dr. Peter H. Schur, Dr. Arend will handle the
review process for all new manuscripts submitted on or afler April 1, 1995. Any manuscripts submitted on or
afler that date should be sent to William P. Arend, MD, Editor, Arthritis and Rheumatism, University of
Colorado Health Sciences Center, Box B-117, 4200 E. Ninth Avenue, Denver, CO 80262.
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neutrophils, periphery, patients, hla, transgenic, behcet, mice, b51, disease, function, blood, excessively
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