close

Вход

Забыли?

вход по аккаунту

?

Frequencies of epstein-barr virus В Эinducible IgM anti-IgG B lymphocytes in normal children and children with juvenile rheumatoid arthritis.

код для вставкиСкачать
959
I
FREQUENCIES OF EPSTEIN-BARR VIRUSINDUCIBLE IgM ANTI-IgG B LYMPHOCYTES IN
NORMAL CHILDREN AND CHILDREN WITH
JUVENILE RHEUMATOID ARTHRITIS
SHERMAN FONG, JOHN J. MILLER Ill, TEKRY L. MOORE, CONSTANTINE D. TSOUKAS,
JOHN H. VAUGHAN, and DENNIS A. CARSON
The relative frequencies of IgM antiIgG autoantibody (rheumatoid factor) producing cells induced by the
polyclonal B cell activator Epstein-Barr virus were
measured in peripheral blood lymphocyte cultures of
normal children and patients with juvenile rheumatoid
arthritis. The frequencies of rheumatoid factor precursor B cells in normal children were lower than adults,
but higher than neonates. The frequency increased with
the age of the donor. In seronegative children with the
systemic-onset or pauciarticular-onset types of juvenile
rheumatoid arthritis, the number of IgM antiIgG inducible B cells was not significantly different ( D 0 . 0 5 )
from age-matched controls. Patients with seropositive
juvenile rheumatoid arthritis or seropositive adult rheumatoid arthritis had significantly higher IgM antiIgG
precursor cell frequencies than age-matched normal
subjects (P<O.O1 and P<0.02, respectively). In contrast, the patients with seronegative polyarticular-onset
juvenile rheumatoid arthritis had an average precursor
frequency significantly lower than normal age-matched
-_.
-
Supported by National Institutes of Health Grants AG
02267, AM 25443, AM 21 175, AM 07144, AM 00364. and KK 00833.
Sherman Fong, PhD: Assistant Memher, Dept. of Clinical
Research, Scripps Clinic and Research Foundation; John J. Miller,
111, MD: Director, Rheumatic Disease Service, Children’s Hospital
at Stanford; Terry L. Moore, MD: Associate Professor, St. Louis
University School of Medicine; Constantine D. Tsoukas, PhD:
Fellow, Department of Clinical Research, Scripps Clinic and Research Foundation; John H. Vaughan, MD: Head. Division of
Clinical Immunology, Scripps Clinic and Research Foundation;
Dennis A. Carson, MD: Associate Member, Dept. of Clinical
Research. Scripps Clinic and Research Foundation.
Address reprint requests to Sherman Fong, PhD, Scripps
Clinic and Research Foundation, 10666 North Torrey Pines Road,
La Jolla. CA 92037.
Submitted for publication September 4, 1981; accepted in
revised form January 19, 1982.
Arthritis and Rheumatism, Vol. 25, No. 8 (August 1982)
controls (P<0.05), analogous to results previously noted
in adult seronegative rheumatoid arthritis. Thus, both
children and adults with seronegative polyarticular
rheumatoid arthritis had a deficiency in B cells that
produce IgM antiIgG and that are induced by EpsteinBarr virus. This distinguished them from seropositive
juvenile rheumatoid arthritis and rheumatoid arthritis
patients, normal subjects, and patients with the pauciarticular-onset and systemic-onset types of seronegative
juvenile rheumatoid arthritis.
In both normal adults and patients with rheumatoid arthritis (RA), Epstein-Barr virus (EBV) infection
of peripheral blood B lymphocytes (PBL) induces the
secretion of IgM antiIgG antibodies (I). The ability to
produce some IgM antilgG is present at birth in most
normal children, and the idiotype of the antilgG was
inherited in I family ( 2 , 3 ) . However, as determined by
limiting dilution analysis, the relative numbers of IgM
antiIgG precursor B cells in the blood of normal
subjects increase several-fold between birth and adulthood (2).
The EBV-induced IgM antilgG response of
PBL from adult patients with R A differs from control
subjects in two important aspects. First, as expected,
seropositive RA patients’ lymphocyte cultures produce significantly more IgM antilgG than normal lymphocyte cultures ( l , 4 ) . Second, PBL from adult patients with persistent seronegative RA produce
notably less IgM antilgG than normal lymphocytes (4).
The latter result suggests that I ) the peripheral bloods
of adult seronegative patients are deficient in an EBVinducible subset of IgM antiIgG precursor B cells,
without any generalized lack of response to the virus,
and 2) the deficiency might be a marker characterizing
FONG ET AL
960
seronegative RA as a disease entity distinguishable
from seropositive RA and other forms of arthritis.
It is now clear that juvenile rheumatoid arthritis
(JRA) encompasses a spectrum of diseases with overlapping clinical manifestations (5). Depending on the
assay used and the source of the patient population,
15-68% of JRA patients have detectable IgM antiIgG
antibodies in serum or in the IgM-containing fraction
isolated by acid-gel filtration (6). The purpose of the
present investigations was to determine the frequency
of EBV-inducible IgM antiIgG precursor B cells, both
in a large series of normal children of increasing age
and in patients with different onset-types of JRA. The
results show that the frequency increases progressively during normal childhood. Children with seropositive
JRA have significantly higher EBV-inducible IgM antiIgG frequencies in PBL than age-matched normal
subjects. In contrast, children with the seronegative
polyarticular-onset type of JRA, as defined by absence
of both overt and “hidden” rheumatoid factor, have
significantly lower frequencies of EBV-inducible cells
that produce IgM antiIgG in PBL than do patients with
seropositive polyarticular-onset JRA, patients with
seronegative systemic-onset or pauciarticular-onset
JRA, or normal children of the same age.
MATERIALS AND METHODS
Subjects. Blood samples were obtained from 21 children with polyarticular-onset JRA, 12 with pauciarticularonset JRA, 7 with systemic-onset JRA, 2 with systemic
lupus erythematosus, 1 with dermatomyositis, 1 with linear
scleroderma, 1 with progressive systemic sclerosis, 1 with
sarcoidosis, 1 with subcutaneous nodules, 1 with Raynaud’s
disease, 1 with thyroid carcinoma, and 1 with WiskottAldrich syndrome, as well as from 10 healthy children.
Additional blood samples came from 4 patients with adultonset seropositive RA and from 15 normal adults.
The diagnosis and classification of the JRA patients
met the criteria established by the Committee on JRA of the
American Rheumatism Association (7). All the children were
patients at the Pediatric Arthritis Clinic of St. Louis University at Cardinal Glennon Memorial Hospital in St. Louis,
MO or the Children’s Hospital of Stanford at Stanford, CA.
Clinical laboratory tests at these two institutions included
the latex fixation test (LFT) for rheumatoid factor (RF), a
test for antinuclear antibody (ANA), and Clq binding radioimmunoassay for immune complexes (8,9). Complementfixing IgM R F was analyzed by Dr. Terry L. Moore, as
previously described, both before and after acid-gel separation of serum on Sephadex G-200 (10,ll). Patients are
referred to as “hidden” RF positive if their complement
fixing IgM antiIgG titer was >]:I6 in the enriched IgM
fraction, but not in whole serum.
Cells and cell cultures. Two to 3 ml of heparinized
blood specimens were added to 5-ml vials that contained 2
ml of Lebovitz L-15 medium (Flow Laboratories, Inc,
Rockville, MD) with 0.01M Hepes buffer. On the day that
they were drawn, all blood specimens were sent by air
freight to La Jolla and were processed within 24 hours in
each case. Several duplicate samples obtained at different
times from the same subjects yielded comparable results.
Peripheral blood mononuclear cells were isolated immediately on amval by Ficoll-Hypaque density sedimentation
(12) and yielded an average cell viability of 80 2% (SEM),
as measured by trypan blue exclusion.
The cells were infected with a dose of EBV-containing supernatant fluid from B95-8 marmoset lymphoblastoid
cells that had been previously titered to yield immunoglobulin secretion and cellular transformation in 100% of the
cultures by 28 days (1,2). The infected cells were incubated
at a density of 3 x 105 cells/ml in 96-well culture trays
(Corning Glass Works, Corning, NY) with 0.3 ml FWMI-1640
medium per well, supplemented with 10% fetal bovine serum
(FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 pg/
ml streptomycin (Flow Laboratories). The average number
of cultures obtained was 42 2 (SEM) for 60 individuals.
Ten cultures served as noninfected controls. The microcultures were incubated for 28 days, and the supernatant fluids
were analyzed for IgM antiIgG autoantibodies and total IgM
by solid-phase radioimmunoassay as previously reported (2).
The relative frequencies of EBV-inducible cells that
produced IgM antiIgG were based on the fraction of the total
lymphocyte cultures producing IgM antiIgG, determined
exactly as described previously (2). Positive cultures were
scored as those secreting 220 ng/ml of IgM antiIgG. The
relative frequencies were determined according to the equation for the Poisson distribution P(,,=e-@, where P(,) is the
proportion of nonresponding wells, X is the number of cells
cultured per well, and C$ is the relative responding cell
frequency (13,14).
In control experiments, monomeric IgG at concentrations up to 1 mg/ml did not affect the IgM-RF assay (15).
This result is indicative of the enhanced avidity of interaction between multivalent antigen and IgM antibody in the
solid-phase radioimmunoassay , as compared with the liquid
phase. Hence, it is extremely unlikely that the small quantities of IgG in the culture supernatants (approximately 2001,OOO ng/ml) masked the detection of cultures that secreted
IgM-RF.
*
*
RESULTS
Patient data. A summary of the clinical classification, sex, age, and laboratory data on all subjects is
shown in Table 1. Only 2 patients in the polyarticular
JRA classification had serum LFT titers >1:20. The
same 2 patients and 2 other children had complementfixing rheumatoid factor in the partially purified IgM
fraction. None of the pauciarticular- or systemic-onset
JRA patients had LFT titers >1:20, although 6 had
detectable complement-fixing rheumatoid factor in
their separated IgM-containing fraction. All JRA patients had active disease at the time the tests were
done.
IgM ANTI-IgG B LYMPHOCYTES IN CHILDREN
96 1
Table 1. Patient clinical classification, sex. age. and laboratorv data
No. patients with positive results/
total number tested
RF Activity
Clinical
classification
Females/
males
Polyarticular-onset JRA
Pauciarticular-onset JRA
Systemic-onset JRA
Other disease controls
Normal children
1813
715
215
713
515
Age
13
9
8
12
12
2
SD
4
2 5
2 2
f5
c5
2
LFT*
Hidden
RFt
ANA$
Clq
binding§
2/14
0112
017
013
0110
4/12
4/10
217
013
Oil0
519
6/12
015
1/3
0110
411 1
218
417
013
0/10
* Latex fixation test results positive (titer >1:20).
7 “Hidden” rheumatoid factor (RF), results positive (titer >1: 16).
$ Antinuclear antibody test results positive (titer > 1:40)(mouse liver substrate).
§
Liquid Clq binding assay (8), results positive >9.5%.
Frequencies of EBV-inducible cells that produce
IgM antiIgG. Table 2 shows the frequencies of EBVinducible IgM antiIgG B cells in the children with JRA
as compared with controls and children with other diseases. Two JRA patients whose PBL were seropositive
in unfractionated serum had significantly higher frequencies of cells that produce IgM antiIgG autoantibody than did normal age-matched controls (RO.01).
In contrast, seronegative polyarticular-onset JRA patients had IgM antiIgG precursor B cell frequencies
significantly lower than normal controls (P<O.OS).
Seronegative pauciarticular, systemic-onset, and
“hidden” RF positive JRA patients showed insignificant differences from normal subjects or disease con-
trols. For comparative purposes, the frequency of
EBV-inducible, IgM antiIgG B cells in adult RA
patients and normal adults is also listed in Table 2.
Quantities of IgM antiIgG antibody and total
IgM in cultures. Under the limiting dilution culture
conditions described, IgM antiIgG autoantibody responses were confined to only a fraction of the individual culture wells. Shown in Table 3 are the average
levels of IgM antiIgG and of IgM detected in the
positive and negative wells. Similar levels of EBVinducible IgM antiIgG antibodies and of IgM were
secreted in positive cultures in all the groups tested.
Moreover, wells positive and negative for IgM antiIgG
antibodies secreted similar levels of IgM. The “hid-
Table 2. Frequencies of EBV-inducible cells that produce IgM antiIgG in the peripheral blood of
normal healthy children and patients with juvenile rheumatoid arthritis*
Groups and number of subjects tested
1.
2.
3.
4.
5.
6.
7.
8.
9.
Normal children (n = 10)
Seronegative$ pauciarticular-onset JRA (n = 8)
Seronegative$ systemic-onset JRA (n = 6)
Seronegative$ polyarticular-onset JRA (n = 17)
“Hidden” seropositive JRA§ (n = 7)
Seropositive polyarticular-onset (n = 2)
Other disease controls (n = 10)
Adult seropositive RA (n = 4)
Normal adult (n = 15)
Frequency of cells that
produce IgM antiIgG in
PBL 2 SEM
4.2 2 1.4 x
6.3 ? 3.8 x lo-‘
8.4 f 6.4 X
1.6 2 0.5 X
12.2 2 5.1 X
28.5 2 17.5 x
5.7 ? 3.0 x
15.0 ? 3.0 X
7.6 2 1 . 1 X
P valuest
>O. 1
>O. 1
<0.05
>0.05
<0.01
>o. 1
<0.02
-
* EBV = Epstein-Barr virus; PBL = peripheral blood lymphocytes; SEM = standard error of the
mean; JRA = juvenile rheumatoid arthritis; RA = rheumatoid arthritis.
t P values determined by Student’s t-test, compared with normal age-matched controls.
$ Seronegative as determined by the latex fixation test or by the hemolytic assay for hidden
rheumatoid factor testing.
5 Seropositive by the hemolytic assay for hidden rheumatoid factor testing. This group includes 4
pauciarticular, 1 systemic-onset, and 2 polyarticular JRA patients.
FONG ET AL
962
tests than do children with earlier onset of disease. For
this reason, it was necessary to compare the EBVinducible IgM antiIgG precursor frequencies in JRA
patients with an age-matched control population.
In comparison with the other 3 groups studied
(normal children, patients with other chronic inflammatory diseases, and children with seronegative JRA
of any onset type), the overtly seropositive JRA
patients had significantly elevated EBV-inducible IgM
antiIgG precursor B cell frequencies (28.5 t 17.5 per
106 PBL, P<O.Ol). Subjects with a positive complement-fixing antiIgG in the IgM-containing fraction
partially depleted of IgG by acid-gel filtration had a
somewhat higher frequency of EBV-inducible IgM
antiIgG B cells from the normal age-matched controls,
but this difference did not reach statistical significance. This group consisted of the so-called hidden
rheumatoid factor patients among whom normal or
aggregated IgG obscured the determination of accurate IgM antiIgG concentrations in whole serum (6). It
probably includes patients like those found by Ziff et a1
(17,18) in early experiments to be positive for antiIgG
only in euglobulin fractions of serum. In inhibition
studies, the hidden IgM RF isolated from JRA patients
has specificity similar to IgM RF-plaque-forming cells
in adult subjects (19,20). In children, hidden RF titers
correlate with the presence of active disease and
immune complexes as detected by Clq solid-phase
assay (6,21).
The EBV-inducible IgM antiIgG precursor cell
den” RF seropositive JRA patient group secreted
slightly higher levels of IgM ( l Y 0 . 0 5 ) in noninfected
control cultures than the other groups tested.
Age-associated development of IgM antiIgG precursors. We have previously shown that the frequency
of EBV-inducible IgM antiIgG cells was lower in
neonates (1.5 t 0.5 per 106 PBL) than in young adults
(20-40 years old, 8.0 k 1.8 per lo6 PBL) and aged
adults (75-90 years old, 7.2 ? 1.3 per lo6 PBL) (2).
Figure 1 extends this analysis to pre- and postpubertal
normal children. As can be seen, children between the
ages of 12 to 18 years exhibited higher frequencies
than children between the ages of 3 to 11. The data are
consistent with a gradual age-associated increase in
the frequency of IgM antiIgG autoreactive B cells.
DISCUSSION
The frequency of EBV-inducible IgM antiIgG
autoreactive B cells in the peripheral blood of normal
humans increased gradually from birth to young adulthood (2). Thus, healthy children (average age 12 ? 4
years) had an estimated frequency of 4.2 ? 1.4 IgM
antiIgG precursor B cells per lo6 PBL, a value 52% of
that detected in young adults. Moreover, children 1218 years old had a higher frequency than children
between the ages of 3 to 11.
The percentage of latex fixation-positive JRA
patients is related to the age of disease onset (16).
Children between the ages of 12 and 16 years have a
higher incidence of positive results on latex fixation
Table 3. Average levels of IgM antiIgG and total IgM produced by EBV-stimulated peripheral blood lymphocytes*
X IgM antilgG ngiml
f
+ EBV
Clinical
classification
I . Normal children (n
2. Seronegativet
3.
4.
5.
6.
7.
IgM antiIgG
positive wells
=
10)
pauciarticularonset JRA (n = 8)
Seronegativet systemiconset JRA (n = 6)
Seronegativet polyarticularonset JRA (n = 17)
“Hidden” RF seropositive
JRAt (n = 7)
Seropositive polyarticularonset JRA (n = 2)
Other disease controls
(n = 10)
73
f
2.5
56 2 6
X IgM ng/ml t SEM
SEM
-
IgM antiIgG
negative
wells
511 t 2
513
+ EBV
EBV
- EBV
Controls
IgM antiIgG
positive wells
IgM antiIgG
negative
wells
Controls
<I0
758 t 174
799 t 178
18 f 6
2
<10
1111 f 202
1072 f 172
517 t 3
<I0
894 t 1.57
848 t 170
98 t 20
48
?
63
* 11
48
f9
57 f 1
<I0
927
129
720
f
50 t 6
511 t 3
<10
994 t 179
99.5
* 107
511
1
< 10
983 f 17
932
?
515 f 3
<lo
1240 2 239
216 2 174
63
* 13
f
f
103
90
1000 t 105
20
f
f
9
10
284 t 126
60
f
31
64t6
* EBV = Epstein-Barr virus; % = mean; SEM = standard error of mean; JRA =juvenile rheumatoid arthritis; R F = rheumatoid factor.
t Seronegative as determined by the latex fixation test or by the hemolytic assay for hidden rheumatoid factor testing.
t Seropositive by the hemolytic assay for hidden rheumatoid factor testing. This group includes 4 pauciarticular-onset, 1 systemic-onset, and 4
polyarticular-onset JRA patients.
IgM ANTI-IgG B LYMPHOCYTES IN CHILDREN
neonates
n:ll
3-11
12-18
20-40
n=6
n:4
n:8
75-90
n=10
AGE in Y E A R S
Figure 1. Relative frequencies of EBV-inducible autoantibody-secreting lymphocytes as a function of age. Data shown for the
neonates, the young adults (20-40 years old), and the aged adults
(75-90 years old) were obtained from previously published information (2).
frequency in the polyarticular JRA patients seronegative for both overt and hidden RF had a mean of only
1.3 0.4 per lo6PBL, a value significantly lower than
age-matched controls and equivalent to the IgM antiIgG precursor frequency assayed in cord blood. This
deficiency in EBV-inducible cells that produce IgM
antiIgG did not result from a lack of polyclonal B cell
activation by EBV in the seronegative polyarticular
JRA patients. In contrast, seronegative patients with
the systemic-onset or pauciarticular-onset forms of
JRA did not differ notably in precursor frequencies
from normal children. The peripheral blood lymphocytes from all groups secreted equivalent amounts of
IgM after in vitro EBV infection and developed into
permanent B lymphoblastoid cell lines.
Thus, among the subsets of JRA patients analyzed, only the overtly seropositive and seronegative
polyarticular groups yielded EBV-inducible IgM antiIgG precursor cell frequencies significantly different
from age-matched controls. Indeed, the results in the
seropositive JRA and seronegative polyarticular JRA
subgroups were remarkably similar to the findings
previously reported in adult seropositive RA and seronegative RA, respectively (4).
*
963
It is possible that many cases of RF-positive
polyarthritis of childhood are the juvenile equivalent
of classic adult seropositive RA. There are notable
clinical similarities between the 2 syndromes (22).
Besides the raised numbers of EBV-inducible IgM
antiIgG precursor cells in each disease, both are
associated with an increased frequency of HLA-DR4,
compared with control populations (23,24).
The relative deficiency in EBV-inducible B
cells that produce IgM antiIgG in the peripheral blood
of patients with both seronegative polyarticular-onset
JRA and seronegative adult RA suggests an immunologic relationship between these 2 diseases. With
modern radioimmunoassay techniques, only rarely
have IgG antiIgG antibodies been detected in persistently seronegative patients (25 and DA Carson, unpublished). The incidence of HLA-DR4 is not increased in either population (23,26).
The exact reasons for the deficiency in EBVinducible IgM antiIgG precursors in seronegative polyarticular RA patients of all ages remain unresolved.
Genes related to the primary sequence of IgM antiIgG
antibodies are inherited in some (and possibly many)
individuals but are unlinked to the HLA locus (3). A
few EBV-inducible IgM antiIgG precursor B cells are
detectable at birth in nearly all normal subjects (2).
The gradual increase in precursor cell frequency between infancy and young adulthood in normal subjects
could be the consequence of immunizations, childhood infections, or an internally programmed maturation of the immune system. In any one or all of these
aspects, seronegative RA patients could differ from
their normal counterparts.
In this regard Van Snick has recently shown
that the ability to make antiIgG antibodies in mice is
genetically controlled (27). However, even in genetically high responding strains, the elicitation of autoantibody depended on the particular environmental conditions under which the animals were maintained
(28,29). Similarly complex interactions between genes
and the environment probably govern EBV-inducible
IgM antiIgG production in humans.
To summarize, the frequencies of IgM antiIgG
precursor B cells inducible by EBV increased with age
in normal children. Patients with seropositive JRA had
higher precursor frequencies than age-matched normal
controls. Children with seronegative systemic-onset ,
pauciarticular-onset, and hidden rheumatoid factor
seropositive JRA had IgM antiIgG precursor cell frequencies appropriate for their ages. However, children
with polyarticular-onset seronegative JRA, like their
adult counterparts, had EBV-inducible, IgM antiIgG
FONG ET AL
964
precursor cell frequencies significantly lower than
normal. Our conclusions are 1) that seropositive JRA
is probably the childhood variant of adult seropositive
RA, and likewise 2) that polyarticular-onset seronegative JRA and adult seronegative RA are closely related
or identical diseases, different from seropositive RA
and from the pauciarticular-onset and systemic-onset
types of JRA.
ACKNOWLEDGMENTS
The authors wish to thank Ms Lee A. Frincke and
Ms Lynne Olds for their technical assistance, and Ms Shari
Brewster and Ms Anna Milne for their preparation of the
manuscript.
REFERENCES
1. Slaughter L, Carson DA, Jensen FC, Holbrook TL,
Vaughan JH: In vitro effects of Epstein-Barr virus on
peripheral blood mononuclear cells from patients with
rheumatoid arthritis and normal subjects. J Exp Med
148: 1429-1434, 1978
2. Fong S, Tsoukas CD, Frincke LA, Lawrance SK,
Holbrook TL, Vaughan JH, Carson DA: Age-associated
changes in Epstein-Barr virus-induced human lymphocyte autoantibody responses. J Immunol l26:9 10-9 14,
1981
3. Pasquali J-L, Fong S, Tsoukas CD, Vaughan JH, Carson
DA: Inheritance of immunoglobulin M rheumatoid-factor idiotypes. J Clin Invest 66:863-866, 1980
4. Pasquali J-L, Fong S, Tsoukas CD, Hench PK, Vaughan
JH, Carson DA: Selective lymphocyte deficiency in
seronegative rheumatoid arthritis. Arthritis Rheum
241770-773, 1981
5. Hanson V, Kornreich HK, Bernstein B, King KK,
Singsen BH: Three subtypes of juvenile rheumatoid
arthritis: correlations of age at onset, sex, and serological factors. Arthritis Rheum (suppl) 20: 184-186, 1977
6. Moore T, Dorner RW, Weiss TD, Baldassare AR,
Zuckner J: 19s IgM hidden rheumatoid factor in juvenile
rheumatoid arthritis. Pediatr Res 14: 1135-1 138, 1980
7. Brewer EJ, Bass J, Baum J, Cassidy JT, Fink C, Jacobs
J, Hanson V, Levinson JE, Schaller J, Stillman JS:
Current proposed revision of JRA criteria. Arthritis
Rheum (suppl) 20:195-199, 1977
8. Miller JJ 111, Osborne CL, Hsu Y: Clq binding in serum
in juvenile rheumatoid arthritis. J Rheumatol7:665-670,
1980
9. Zubler RH, Lange G, Lambert PH, Miescher PA: Detection of immune complexes in unheated sera by a
modified '2sI-Clq binding test. J Immunol 1 16:232-235,
1976
10. Moore TL, Zuckner J, Baldassare AR, Weiss TD,
Dorner RW: Complement-fixing hidden rheumatoid factor in juvenile rheumatoid arthritis. Arthritis Rheum
21:935-941, 1978
11. Robbins D, Moore TL: Lack of hidden complement
fixing IgM rheumatoid factor in adult seronegative rheumatoid arthritis. Ann Rheum Dis 39:64-67, 1980
12. Boyum A: Separaton of leukocytes from blood and bone
marrow. Scand J Clin Lab Invest (suppl 97) 21:7789,1968
13. Lefkovits I: Induction of antibody-forming cell clones in
microcultures. Eur J Immunol2:360-366, 1972
14. Halsall MK, Makinodan T: Analysis of the limitingdilution assay for estimating frequencies of immunocompetent units. Cell Immunol 11:456-465, 1974
15. Pasquali J-L, Fong S, Tsoukas CD, Slovin SF, Vaughan
JH, Carson DA: Different populations of rheumatoid
factor idiotypes induced by two polyclonal B cell activators, pokeweed mitogen and Epstein-Barr virus. Clin
Immunol Immunopathol21:184-189, 1981
16. Hanson V, Rexler ED, Kornreich H: The relationship of
rheumatoid factor to age of onset in juvenile rheumatoid
arthritis. Arthritis Rheum 12:82-86, 1969
17. McEwen C, Ziff M, Carmel P, Di Tata D, Tanner M: The
relationship to rheumatoid arthritis of its so-called variants. Arthritis Rheum 1:481-496, 1958
18. Ziff M, Brown P, Lospalluto J, Badin J, McEwen C:
Agglutination and inhibition by serum globulin in the
sensitized sheep cell agglutination reaction in rheumatoid arthritis. Am J Med 20500, 1956
19. Moore TL, Dorner RW, Weiss TD, Baldassare AR,
Zuckner J: Specificity of hidden 19s IgM rheumatoid
factor in patients with juvenile rheumatoid arthritis.
Arthritis Rheum 24:1283-1290, 1981
20. Robbins DL, Moore TL, Carson DA, Vaughan JH:
Relative reactivities of rheumatoid factors in serum and
cells: evidence for a selective deficiency in serum rheumatoid factor. Arthritis Rheum 21 :820-826, 1978
21. Moore TL, Sheridan PW, Traycoff RB, Zuckner J,
Dorner RW: Immune complexes in juvenile rheumatoid
arthritis. Arthritis Rheum (suppl) 24: 101, 1981
22. Kredich DW: Polyarticular juvenile rheumatoid arthritis, Juvenile Rheumatoid Arthritis. Edited by JJ Miller
111. Littleton, MA, PSG Publishing Co, 1979, p 121
23. Hoyeraal HM, Forre 0, Dobloug JH, Thorsby E, Kass
E: HLA-antigens in juvenile rheumatoid arthritis patients: association between immunoglobulin M rheumatoid factor production and the HLA-DR4 antigen
(abstract). Paris, XVth International Congress of Rheumatology, 1981, p 673
24. Stastny P: Association of the B-cell alloantigen DRw4
with rheumatoid arthritis. N Engl J Med 298:869-871,
1978
25. Wernick R, Lospalluto J, Fink C, Ziff M: IgG and IgM
IgM ANTI-IgG B LYMPHOCYTES IN CHILDREN
rheumatoid factor levels in adult and juvenile rheumatoid arthritis by radioimmunoassay. Arthritis Rheum
23:761, 1980
26. Dobloug JH, Forre 0, Kass E, Thorsby E: HLA antigens and rheumatoid arthritis, association between
HLA-DRw4 positivity and IgM rheumatoid factor production. Arthritis Rheum 23:309-313, 1980
27. Van Snick JL: A gene linked to the Igh-c locus controls
965
the production of rheumatoid factors in the mouse. J
Exp Med 153:738-742, 1981
28. Van Snick JL, Masson PL: Age-dependent production
of IgA and IgM autoantibodies against IgG2a in a colony
of 129/Sv mice. J Exp Med 149:1519-1530, 1979
29. Van Snick JL, Masson PL: Incidence and specificities of
IgA and IgM anti-IgG autoantibodies in various mouse
strains and colonies. J Exp Med 151:45-55, 1980
Continuing Education
Vlll Panhellenic Congress of Rheumatology. The Congress will be held in Athens, Greece, November
25-27, 1982 at the Caravel Hotel. The subject of the Congress is “Rheumatic Diseases of Childhood.” For
further information contact Dr. Alex Andrianakos, Secretary, V l l l Panhellenic Congress of Rheumatology, 1
Pythias Street, Athens 809, Greece.
Fifth Annual Colorado Pain Symposium. The Symposium will be held in Aspen, Colorado, January 8-15,
1983 at the Continental Inn. The subject of the Symposium, which is sponsored by the Pain Control Center at
Boulder Memorial Hospital, is “The Surgical Management of Pain.” For further information contact Diana Buck,
Public Relations, Boulder Memorial Hospital, 31 1 Mapleton Avenue, Boulder, CO 80302; telephone 303441-0464.
Problems in Rheurnatology. This postgraduate course, sponsored by the Department of Internal
Medicine, University of South Florida College of Medicine, will be held March 10-13, 1983, at the Don CeSar
Beach Resort Hotel, St. Petersburg Beach, Florida. For further information, contact Bernard F. Germain, MD,
Course Director, Division of Rheumatology, University of South Florida College of Medicine, Box 19, Tampa, FL
33612.
Документ
Категория
Без категории
Просмотров
3
Размер файла
626 Кб
Теги
epstein, frequencies, virus, anti, children, norman, barry, igm, arthritis, igg, juvenile, lymphocytes, rheumatoid, эinducible
1/--страниц
Пожаловаться на содержимое документа