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HLA antigens in juvenile arthritis.

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35
HLA ANTIGENS IN JUVENILE ARTHRITIS
Genetic Basis for the Different Subtypes
OYSTEIN FORRE, JAN H . DOBLOUG, HANS M. HOYERAAL, and ERIK THORSBY
Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the
DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients53%
and 17%, respectively (P < O.O25)-compared with
27% in healthy Norwegians. An increased frequency of
the HLA-DR4 antigens was also found in polyarticular
onset JA (50% compared with 27%, P < 0.05). The
frequency of both the HLA-B27 (21%) and the DR5
antigen (21%) was increased in the whole patient group
compared with controls (10% and 9%, respectively, P <
0.01). The DR5 antigen was also increased in the
systemic onset patients (40%, P < 0.05). Both the DR5
and the DR8 antigens were increased in the pauciarticular onset group (P < 0.05 and P < 0.01, respectively).
The results support the view that seropositive and
seronegative JA are different disease entities and also
that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the
DR4 antigen and IgM rheumatoid factor suggests that
the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.
Juvenile arthritis (JA) is a heterogenous disease
currently divided into different subtypes based on
different onset symptoms ( I ) . Like rheumatoid arthritis (RA) in adults, the disease can also be grouped into
seropositive and seronegative forms. Although several
From the Institute of Immunology and Rheumatology and
the Tissue Typing Laboratory, Rikshospitalet, The National Hospital, and Oslo Sanitetsforening’s Rheumatism Hospital, Oslo, Norway.
Address reprint requests to gystein Fprre, MD, Institute of
Immunology and Rheumatology, Fr. Qvamsget I, Oslo I, Norway.
Submitted for publication November 19, 1981; accepted in
revised form June 8. 1982.
Arthritis and Rheumatism, Vol. 26, No. 1 (January 1983)
studies of HLA antigen distributions have been performed on J A patients (2-5), it is unknown whether
various subtypes of JA are associated with different
genetic markers (HLA antigens) reflecting different
pathogenetic mechanisms.
Previous investigations have shown that genes
regulating the immune response toward certain antigens-immune response (Ir) genes-are located within
the H-2 region of the major histocompatibility complex
in the mouse (6,7). In parallel, Ir genes in humans may
be located within the HLA gene complex (8). Increased frequency of certain HLA antigens in patients
with autoantibody production may therefore imply
that the corresponding HLA gene or a closely associated gene may regulate the immune response against
the autoantigen. Such HLA genes may therefore also
be involved in the pathogenesis of and the susceptibility to certain disease states.
We have performed HLA typing and looked for
antigen associations to the various subtypes of JA,
focusing on the seropositive and seronegative forms of
the disease. Different HLA antigen distributions were
observed in the various subtypes, suggesting that
different immune mechanisms are involved in the
pathogenesis of the various JA subtypes.
PATIENTS AND METHODS
Patients. Seventy-seven patients with JA according
to the criteria of Brewer et a1 (9) were studied. The 52 girls
and 25 boys, all Norwegians, were hospitalized at Oslo
Sanitetsforening Rheumatism Hospital. Seventeen (22%) of
the patients were seropositive with titers >32 in the WaalerRose agglutination test for IgM rheumatoid factor (RF) and
titers >32 in the RA latex agglutination test for IgM RF.
Only patients who had repeatedly been negative were classi-
F0RRE ET AL
36
Table 1. Distribution of HLA-DR antigens and HLA-B27 in different types of juvenile arthritis
~~
~~
JA patients with a history
of chronic iridocyclitis
Onset type of JA
HLA
antigen
DR 1
DR 2
DR 3
DR 4
DR 5
DR 6
DR 7
DR 8
827
15)
4/11
(n = 62)
51/11
% all
patients
(n = 77)
25/52
10
0
10
25
50t
13
40
7
13
13
8
19
24
29
23
15
II
15
23$
6
18
27
25
21f
14
9
20f
210
% polyarticular
5/5*
% pauciarticular
(n = 47)
18/29
0
30
40
20
40t
0
30
0
0
6
19
26
I5
21t
17
6
28$
268
% systemic
(n = 10)
(n = 20)
2/18
% present
(n
10
15
5
10
20
=
0
40
13
% absent
% normal
frequency
(n = 200)
21
20
19
27
9
8
10
11
10
* n = number in each group. Numbers indicate male/female ratio.
f P < 0.05.
f P < 0.01.
8 P < 0.001.
fied as seronegative. Twenty-nine patients (38%) were positive for antinuclear antibodies. Ten (13%) had systemic
onset disease, 47 (61%) pauciarticular onset (4 or fewer
joints affected), and 20 (26%) had polyarticular onset (5 or
more joints involved). Fifteen patients (19%) had a history of
chronic iridocyclitis.
HLA typing. The HLA typing was performed by a
microcytotoxicity technique with 87 highly selected antisera
defining 13, 21,4, and 8 antigens, respectively, of the A, B,
C, and DR series, by techniques previously described (10).
The statistical significance was evaluated using 2 x 2
x2 analysis or Fisher’s exact test, depending on the expected
values. All the P values for DR antigen associations were
corrected for the 8 antigens investigated and for other
antigen associations that provided unexpected values.
RESULTS
A significant increase in t h t frequency of the
HLA-DR4 antigen was found in the 17 patients with
seropositive JA compared with 200 healthy controls
(53% versus 27%, P < 0.025). A non-significantly
reduced frequency of DR4 (17%) was found in the 60
seronegative patients. The DR4 antigen had a normal
frequency in the patient group taken as a whole (25%).
The frequency of both the HLA-B27 and the
DR5 and DR8 antigens was significantly increased in
the total patient group, 21% versus 10% (P < 0.01),
21% versus 9% (P < 0.01), and 20% versus 10% (P <
0.01), respectively (Table I). An increased frequency
of the HLA-B27, DR5, and DR8 antigens was found in
pauciarticular JA compared with normal controls: 26%
versus 10% ( P < O.Ol), 21% versus 9% (P < 0.025),
ahd 28% versus 11% (P < O.Ol), respectively.
Table 2 shows that the B27 antigen occurs in
older children with JA, while the DR5 antigen and the
DR8 antigen occur in younger patients (P < 0.05). In
the polyarticular form, the frequency of the DR4
antigen was 50% versus 27% in normal subjects (P<
0.05) and 15% (P < 0.01) in the pauciarticular onset
type of JA.
The DR4 antigen seems to occur in older children with pauciarticular onset JA (P < 0.05) (Table 3).
In patients with the systemic onset, the DR5 antigen
had a frequency of 40% versus 9% (P < 0.05). Forty
percent of patients with chronic iridocyclitis were
positive for the DR8 ant,igen versus 11% in the controls
(P< 0.05) (Table 1).
We also found a decreased frequency of DRI
among JA patients (6%) compared with the controls
(21%) (P< 0.01), which appeared most pronounced in
Table 2. The relationship between HLA-B27, DR5, and DR8 antigens, sex, and age of onset among patients with JA
Mean age in months (range)
No. patients (male/female)
Mean age in months (range)
Male
Female
B27 positive
104 (27-165)
12 (715)
B27 negative
42 (3-153)
32 (1 0122)
DR5 positive
69 (11-135)
10 (6/4)
% (63-148)
132 (27-165)
-
79 (16-120)
42 (4-135)
DR5 negative
53 (3-165)
33 (10123)
DR8 positive
76 (16-132)
12 (6/6)
89 (16-120)
38 (21-132)
DR8 negative
46 (3-165)
31 (10/21)
37
HLA ANTIGENS IN JA
Table 3. The onset age in HLA-DR4 positive and HLA-DR4
negative patients with pauciarticular onset type of JA
HLA-DR4
positive
No. patients
Mean onset age*
Range of age*
HLA-DR4
negative
Male
Female
Male
Female
1
114
5
132
(38-165)
15
78
(3-153)
22
42
(6-162)
-
* Ages given in months.
the systemic onset type of JA as well as in JA
accompanied by iridocyclitis.
DISCUSSION
In the present study an increased frequency of
the HLA-B27 antigen was found in the entire JA
patient group. This confirms earlier reports ( 1 1) and
supports the well known clinical observation that
some JA patients actually have reactive arthritis, and
that others later develop Bechterew’s syndrome (1).
Previously we demonstrated that the HLADR4 antigen is associated with IgM RF positivity in
patients with rheumatoid arthritis (12). This was later
confirmed in an international study (13). We therefore
proposed that the HLA-DR4 gene, or a closely associated gene, may serve as an Ir gene for autoantigens.
Increased frequency of the DR4 antigen was also
found in the seropositive form of JA. This further
supports our suggestion that the DR4 gene may act as
an Ir gene for autoantibody production against self
IgG .
Our findings also indicate that seropositive JA
constitutes a clinically, serologically, and genetically
separate disease entity which may be an early form of
seropositive RA in adults. In a previous study we
demonstrated an association of the HLA-DR4 antigen
to seropositive but not seronegative patients with
rheumatoid arthritis. To obtain enough patients to sort
out a similar association in JA, we included more
seropositive patients than would be expected in a
random sample of JA patients. This explains the high
proportion (17 of 77) of seropositive patients in the
present study.
This study furthermore indicates that different
onset types of JA also represent different clinical and
genetic disease subtypes. The systemic onset type is
associated with the DR5 antigen, the pauciarticular
type with the B27, DR5, and DR8 antigens, and the
polyarticular onset type is associated with the DR4
antigen. The DR4 antigen frequency in polyarticular
JA is nearly the same as that in adults with RA
(approximately 50%). This most probably explains the
clinical observation of Morling et al (14) that children
with polyarticular JA develop classic or definite RA as
adults.
The various HLA antigen distributions observed in the different JA subtypes may indicate that
each subtype represents a genetically and clinically
separate disease state, each with a partly different
pathogenetic mechanism. Furthermore, the association between the DR4 antigen and IgM R F production
in both rheumatoid and juvenile arthritis may indicate
a genetic regulation of the immune response against
autoantigens in humans.
ACKNOWLEDGMENTS
The technical assistance of Anne Bratlie is appreciated. This work was supported by the Norwegian Hydro
Company, the Norwegian Research Council for Science and
the Humanities, and Astra Syntex Co., Norway.
REFERENCES
I . Ansell BM, Wood PHN: Prognosis in juvenile chronic
polyarthritis. Clin Rheum Dis 2:397-412, 1976
2. Gershwin ME, Opelz G, Terasaki PI, Castles JJ, Gorman TA: Frequency of HLA Dw3 in juvenile rheumatoid arthritis. Tissue Antigens 10:330-336, 1977
3. Glass DN, Litvin DA: Heterogeneity of HLA associations in systemic onset juvenile rheumatoid arthritis.
Arthritis Rheum 23:796-799, 1980
4. Glass D, Litvin D, Wallace K, Chylack L, Garovoy M,
Carpenter CB, Schur PH: Early-onset pauciarticular
juvenile rheumatoid arthritis associated with human
leukocyte antigen-DRw5, iritis, and antinuclear antibody. J Clin Invest 66:426-429, 1980
5 . Stastny P, Fink CW: Different HLA-D associations in
adult and juvenile rheumatoid arthritis. J Clin Invest
63;124-130, 1979
6. Munro A, Waldmann H: The major histocompatibility
system and the immune response. Br Med Bull 34:253258, 1978
7. Thorsby E: The human major histocompatibility complex HLA: some recent developments. Transplant Proc
9:616-623, 1979
8. Thorsby E, Albrechtsen D, Bergholtz B, Hirshberg H,
Solheim BG: Distribution of HLA-DR (human Ia-like)
antigens on human lymphoid cell sub-populations and
their role in T lymphocyte cell-interaction, Human Lymphocyte Differentiation: Its Application to Cancer. Edited by B Serrou, C Rosenfeld. INSERM Symposium No.
8, ElseviedNorth-Holland Biomedical Press, 1978, pp
22 1-229
9. Brewer EJ Jr, Bass J, Baum J, Cassidy JT, Fink C,
38
Jacobs J, Hanson V, Levinson JE, Schaller J, Stillman
JS: Current proposed revision of JRA criteria. Arthritis
Rheum 20:195-199, 1977
10. Albrechtsen D, Bratlie A, Nousiainen H, Solheim BG,
Winther N, Thorsby E: Serological typing of HLA-D:
predictive value in mixed lymphocyte cultures (MLC).
Immunogenet 6:91-100, 1978
11. Rachelefsky GS, Terasaki PI, Katz R, Stiehm ER:
Increased prevalence of W27 in juvenile rheumatoid
arthritis. N Engl J Med 290:892-893, 1974
12. Dobloug JH, Fgrre $3, Kiss E, Thorsby E: HLA anti-
FORRE ET AL
gens and rheumatoid arthritis: association between
HLA-DRw4 positivity and IgM rheumatoid factor production. Arthritis Rheum 23:309-313, 1980
13. Stastny P: Rheumatoid arthritis, Histocompatibility
Testing 1980. Edited by P Terasaki. Los Angeles,
UCLA Tissue Typing Laboratory, 1980, pp 681-686
14. Morling N, Hellesen C, Jakobsen BH, Platz P, Ryder
LP, Schwejgaard A, Thomsen M:HLA-A, B, C, D, DR
antigens and primed lymphocyte typing (PLT): defined
DP-antigens in juvenile chronic arthritis. Tissue Antigens 17:434-442, 1981
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