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Immunogenetic studies of juvenile dermatomyositishla-dr antigen frequencies.

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IMMUNOGENETIC STUDIES OF JUVENILE DERMATOMYOSITIS:
HLA-DR ANTIGEN FREQUENCIES
J.M. FRIEDMAN. L.M. PACHMAN, M.L. MARYJOWSKI, R.M. RADVANY. W.E. CROWE. V. H A N S O N .
J.E. L E V I N S O N , and C.H. S P E N C E R
Juvenile dermatomyositis (JDMS) is a chronic
inflammatory disease of unknown etiology that occurs
in children and is characterized by a typical rash and
symmetric proximal myopathy often associated with
soft tissue calcifications. We have previously reported
a greater than expected frequency of HLA-B8 among
16 white patients with JDMS (1). In order to confirm
this finding and to investigate its relationship to the
pathogenesis of this rare disease, we undertook a
multicenter collaborative investigation of immunoge- -
_-
From the Division of Clinical Genetics, Departments of
Obstetrics and Gynecology and of Pediatrics and the Cecil H. and
Ida Green Center for Reproductive Biology Sciences. University of
Texas Health Science Center. Dallas; the Departments of Pediatrics
and Surgery, Northwestern University Medical School and the
Children's Memorial Hospital, Chicago; the University of Cincinnati Medical Center, Cincinnati; the University of Southern California Medical School and the Los Angeles Children's Hospital, Los
Angeles.
Supported by grants from the U.S. Public Health Service.
National Institutes of Health (AM21589 and RR-00199). and the
Illinois Chapter of the Arthritis Foundation.
J.M. Friedman. MD, PhD: Associate Professor of Obstetrics and Gynecology and of Pediatrics, University of Texas Health
Science Centcr at Dallas; L.M. Pachman. MD: Professor of Pediatrics, Northwestern University Medical School; M.L. Maryjowski.
RN: Immunology Clinician. Children's Memorial Hospital; R.M.
Radvany. PhD: Assistant Professor of Surgery, Northwestern University Medical School: W.E. Crowe. MD: Assistant Professor of
Medicine and Pediatrics, University of Cincinnati; V. Hanson. MD:
Professor of Pediatrics. University of Southern California School of
Medicine: J.E. Levinson. MD: Professor of Medicine and Pediatrics. University of Cincinnati; C.H. Spencer, MD: Assistant Professor of Pediatrics. Louisiana State University Medical Center.
Address reprint requests to J.M.Friedman. MD. PhD,
Division of Clinical Genetics. Department of Obstetrics and Gynecology. University of Texas Health Science Center at Dallas, 5323
Harry Hines Boulevard, Dallas, TX 75235.
Submitted for publication October 5, 1981; accepted in
revised form July 9 , 1982.
Arthritis and Rheumatism, Vol. 26. No. 2 (February 1983)
netic factors in JDMS. We here report the results of
typing for HLA-DR antigens in this series of patients.
PATIENTS AND METHODS
Juvenile dermatomyositis patients. One hundred
patients with JDMS were located through a review of
the records of pediatric rheumatology clinics at Children's Memorial Hospital (Chicago), University of
Michigan Hospital (Ann Arbor), Los Angeles Children's Hospital, Texas Scottish Rite Hospital (Dallas),
and Children's Hospital Medical Center (Cincinnati).
Ninety of these patients, including I I of our original
series of 16 ( I ) , were considered to have definite
JDMS according to the criteria of Bohan and Peter (2).
Each patient had the typical rash and 3 or 4 of the
following additional features: symmetric limb-girdle
muscle weakness, histologic evidence of myositis
shown by muscle biopsy, elevated serum concentration of skeletal muscle enzymes, and characteristic
electromyographic abnormalities. The age at onset of
disease in these patients ranged from 1-21 years, with
a mean of 8.0 years. HLA-DR typing was performed
on 51 patients including 17 from Chicago, 18 from Los
Angeles, and 16 from Cincinnati.
HLA-DR typing and data analysis. HLA-DR
antigens were determined on B lymphocytes which
had been separated from peripheral blood by centrifugation on a Ficoll-Hypaque gradient (3) and nylon
wool filtration (4). The B lymphocytes were frozen at
-70°C in 10% DMSO until used. Cells were typed by a
minor modification ( 5 ) of the microcytotoxicity assay
of Terasaki and McClelland (6). Typing was performed
on all specimens within a 6-month time period, using
BRIEF REPORTS
215
Terasaki trays defining antigens HLA-DR 1 through
HLA-DR7. All specimens, except those from Los
Angeles, were also typed on local trays containing sera
standardized with cells from the 8th International
Histocompatibility Workshop. The same sera were
used to type all of the patients in this study, and at
least 4 different sera were used to define each specificity. On the local trays, these sera were used in
duplicate.
Data on normal population frequencies of the
HLA-DR antigens among healthy whites, blacks, and
Latin Americans were obtained from the joint report
of the 8th International Workshop (7). Population
groups 11 (United States whites), 2 (American blacks),
and 9 (Mexicans) were used. A panel of 30 local white
controls typed contemporaneously, a panel of more
than 300 normal whites, and more than 100 normal
blacks typed subsequently on the local typing trays
showed antigen frequencies which were not significantly different from the International Workshop values. The only exception was that HLA-DRw6 was
found more often than expected among the local white
controls (24%).
HLA antigen frequencies were compared in
patients and controls of similar ethnic origin by Fisher's exact test. Two-tailed probabilities of less than
0.05 after multiplication by 34 to correct for the
number of antigens (HLA-A, B, and DR) tested were
considered significant (8). Relative risks were estimated by Woolf's method (9).
all 3 ethnic groups studied, although it reached statistical significance only in whites and Latin Americans.
However, only 6 black JDMS patients were HLA-DR
typed. The estimated relative risk for JDMS in persons
with HLA-DR3 is 3.8 in whites (95% confidence
interval = 1.9-7.6), 12.9 in blacks (95% confidence
interval = 4.9-33.6), and 18.5 in Latin Americans
(95% confidence interval = 5.3-64.0).
DISCUSSION
Any demonstration of a population association
between a disease and genetic markers such as HLA
antigens depends critically on selection of an appropriate control group. In addition to being of the same
ethnic origin as the patients, the controls ideally
should be tested in the same laboratory as the patients
with the same reagents at the same time. Because of
the time required to amass the study group and because these patients were drawn from three different
large referral areas, no ideal control groups were
available to us. We therefore used as controls normal
Americans of simiIar ethnic origin who had been typed
by the same techniques during the 8th International
Histocompatibility Workshop. These controls, although not ideal, appear adequate because a group of
normal white and black individuals typed in our laboratory with the same reagents showed expected frequencies of all HLA-DR antigens except for HLADRw6, which is less well-defined and for which no
associations with JDMS are claimed.
We observed an association between HLADR3 and JDMS in whites and Latin Americans, and
probably in blacks as well. The estimated relative risk
of 3.8 for JDMS in whites with HLA-DR3 is only
slightly greater than the 2.8 relative risk we found in
this series for JDMS in whites with HLA-B8 (10). No
RESULTS
Table 1 compares the HLA-DR antigen frequencies in 51 patients with definite JDMS and in
healthy controls of similar ethnic origin. An association between HLA-DR3 and JDMS was observed in
Table 1. HLA-DR antigen frequencies in patients with juvenile dermatomyositis and in healthy
controls
Whites
HLA
antigens
DR 1
DR2
DR3
DR4
DR5
DRw6
DR7
Patients
(n = 36)
0.22
0.25
0.53*
0.25
0.28
0.11
0.25
Blacks
Controls
Latin Americans
(n = 979)
Patients
(n = 6)
( n = 168)
Patients
(n = 9)
Controls
(n = 88)
0.204
0.263
0.227
0.280
0.188
0.073
0.228
0.17
0.17
0.83
0.17
0.17
0.00
0.33
0.137
0.339
0.280
0.083
0.292
0.089
0.220
0.00
0.33
0.78t
0.22
0.22
0.00
0.22
0.08
0.15
0.16
0.28
0.27
0.06
0.23
* P < 0.01 (corrected for number of antigens tested).
t P < 0.05 (corrected for number of antigens tested).
Controls
BRIEF REPORTS
216
association between HLA-B8 and JDMS was observed in blacks or Latin Americans (10). The fact that
the HLA-DR3 association, but not the HLA-B8 association, is apparent in all 3 ethnic groups tested
suggests that HLA-DR3 (or a gene in tight linkage
disequilibrium with HLA-DR3) predisposes t o the
development of JDMS. The association between
JDMS and HLA-B8 is probably due to linkage disequilibrium between HLA-B8 and HLA-DR3 in
whites (1 1).
An alternative interpretation of the association
between HLA-DR3 and JDMS is that an HLA-DR3related factor permits JDMS patients to survive long
enough to reach a pediatric rheumatology center. Our
patients were studied at times ranging from a few
weeks after disease onset to several years after onset,
so we cannot eliminate this possibility.
The HLA association reported here places
JDMS into company with several other diseases including dermatitis herpetiformis, celiac disease, myasthenia gravis, Sjogren’s syndrome, idiopathic Addison’s disease, insulin-dependentdiabetes mellitus, and
Graves’ disease, all of which have also been found to
be associated with HLA-B8/DR3 (12.13). All of these
conditions are of unknown but probably complex
etiology, and all exhibit manifestations of autoimmunity. This raises the possibility that JDMS may also be
an “autoimmune disease.” In a future paper in this
series (manuscript in preparation), we provide support
for this proposal by showing that patients with JDMS
have antinuclear antibodies, but not organ-specific
autoantibodies, more frequently than expected.
REFERENCES
1. Pachman LM, Jonasson 0, Cannon RA, Friedman JM:
HLA-B8 in juvenile dermatomyositis. Lancet 2:567568. 1977
2. Bohan A, Peter JB: Polymyositis and dermatomyositis.
N Engl J Med 292:344-347,403-407, 1975
3. Boyum A: A one-stage procedure for isolation of granulocytes and lymphocytes from human blood. Scan J Clin
Lab Invest (suppl 97) 2151-76, 1968
4. Danilovs JA, Ayoub G, Terasaki PI: B-lymphocyte
isolation by thrombin-nylon wool, Histocompatibility
Testing 1980. Edited by P Terasaki. Los Angeles,
UCLA Tissue Typing Laboratory, 1980, pp 287-288
5. Ting A, Mickey MR, Terasaki PI: B-lymphocyte alloantigens in Caucasians. J Exp Med 143:981-986, 1976
6. Terasaki PI, McClelland JD: Microdroplet assay of
human serum cytotoxins. Nature 204:998-1000, 1964
7. Baur MP. Danilovs JA: Population analysis of HLAA,B,C,DR, and other genetic markers, Histocompatibility Testing 1980. Edited by P Terasaki. Los Angeles,
UCLA Tissue Typing Laboratory, 1980, pp 955-960
8. Grumet FC. Coukell A, Bodmer JG, Bodmer WF.
McDevitt HO: Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. N Engl J
Med 285:193-196, 1971
9. Woolf B: On estimating the relation between blood
group and disease. Ann Hum Genet 19:251-253. 1955
10. Friedman JM, Pachman LM,Maryjowski ML, Jonasson
0, Radvany RM, Battles ND. Crowe WE, Fink CW.
Hanson V, Levinson JE. Spencer CH. Sullivan DB:
Immunogenetic studies of juvenile dermatomyositis:
HLA antigens in patients and their families. Tissue
Antigens (in press)
11. Baur MP. Danilovs JA: Reference tables of two and
three-locus frequencies for HLA-A,B.D,DR,BF, and
GLO, Histocompatibility Testing 1980. Edited by PI
Terasaki. Los Angeles. UCLA Tissue Typing Laboratory, 1980, pp 994-1210
12. Nerup J, Cathelineau C, Seignalet J, Thomsen M: HLA
and endocrine diseases, HLA and Disease. Edited by J
Dausset, A Svejgaard. Baltimore, Williams and Wilkins,
1977. pp 149-167
13. Friedman JM, Fialkow PJ: The genetics of Graves’
disease. Clin Endocrinol Metab 7:47-65. 1978
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