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Sclerodermapossible significance of silent alleles at the C4B locus.

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71 1
BRIEF REPORT
SCLERODERMA: POSSIBLE SIGNIFICANCE OF SILENT ALLELES
AT THE C4B LOCUS
EVA MOLLENHAUER, REINHOLD SCHMIDT. MELANIE HEINRICHS, and CHRISTIAN KI‘RNER
Scleroderma (progressive systemic sclerosis,
PSS) is a systemic connective tissue disorder characterized by proliferative vascular lesions, obliterative
microvascular lesions, and residual atrophy with fibrosis of multiple organs such as skin, gastrointestinal
tract, heart, lung, and kidney.
The etiology of PSS is unknown. Immune
mechanisms have been suspected due to such findings
as hyperimmunoglobulinemia, circulating immune
complexes, antinuclear antibodies, mononuclear cell
infiltrates in the skin, and aberrant T cell.subpopulations.
In addition, a scleroderma-like disease may
occur in graft-versus-host reactions. Yet, association
studies of PSS and HLA region antigens revealed
heterogeneous results. The following antigens have
been found to be increased: A9, B8, B27 ( I ) , A9 (2), B8
(3,4), Dwl (9,DR3 (4), and DR5 (4,6). However, no
associations have been found (7,s).
In our study we investigated 17 patients with
PSS for the following markers of the major histocompatibility complex (MHC): HLA-A, B, C, DR, Bf, C2,
and C4 (see Table 1). The diagnosis of the disease was
based on criteria given by the American Rheumatism
Association .(9). For comparison, I44 healthy individuals from the Bonn, West Germany area were also
studied as controls.
.~
From the Institute of Legal Medicine and Medical Clinic,
University of Bonn, West Germany.
Supported in part by a grant from Deutsche Forschungsgemeinschaft (Ki 164-15-2).
Submitted for publication August 1 , 1983; accepted in revised form January 10, 1984.
Arthritis and Rheumatism, Vol. 27, No. 6 (June 1984)
We observed increased HLA antigen frequencies, with borderline significance: Bw35 (x2 = 9.45,
Pcorr [30] = 0.06), DR5 (x2 = 6.87, Pcorr [81 = 0.071,
and DR4 (x’ = 3.53, Pcorr [8] > 0.4). No associations
were found for C2 and Bf.
A strong association, however, was found for
the nonexpressed allele B*QO at the I3 locus of the
fourth component of human complement (10). Among
these 17 patients, 3 B*QO,QO homozygotes were
noted, compared with 3 homozygotes among 144 control subjects (x’ = 10.27, P = 0.001, Fisher’s test P =
0.016). These patients lack C4B alpha chains (11).
Thus, C4B*QO homozygosity might prove to be a
marker of a diffuse form of scleroderma, though nei-
Table 1. Markers of the major histocompatibility complex in
patients with progressive systemic sclerosis
Patient
number
1
2
3
4
5
6
7
8
9
10
I1
12
13
14
15
16
17
Marker
A
Cw
B
DR
C2
2.3
2
1,24
2,3
1,32
2,11
2.26
1,25
1.3
2,ll
2,26
1,23
2,3
2,9
11,24
2,29
1,2
2,4
2
4
4
27.35
27.61
14,35
35.44
61,57
1,4
1
1,5
6,6y
1,4
7,x
1
1
44,56
1,5
* S = slow; FS
-
1
1,4
4,5
35
8.18 3,6y
2.4
7,8
4,6y
4
35
2
51,52 2,5
- .
17,44 4,7
6
44.47 4,7
4
7,35 5,8
4
18,63 5,7
4.5
3,5 44,x
17,39
-
-
= fastlslow.
1
I
1
I
1
RfC
S
S
S
FS
S
S
S
1
S
S
1
S
1
1
1
S
S
FS
S
FS
1
1
1
I
S
S
C4A,B
A2,3 HI,QO
A3,4 B1,2
A2,3 B1,2
A3,3 BQ0,QO
A3,6 BI,1
A3,3 B1,l
A3,3 H I , Q O
A3,QO H I , I
A3,QO €31.1
A4,QO B1,QO
A3.3 B1,l
A3,6 RQ0,QO
A1,3 BQO.QO
A3,QO B l , l
A3,3 H1,QO
A3,QO B l , l
A3,6 B1,l
BRIEF REPORTS
712
Table 2. C4A and B allele frequencies of scleroderma patients
C4 alleles
Number
A1
A2
A3
A4
A5
A6
AQO
1
2
19
2
2
6
0.0882
0.1472
B1
18
0.6471
0.0294
0.0588
0.6176
0.0588
-
Total
B11
B2
B3
B5
BS 1
BQO
Frequency
2
I .moo
0.0588
-
12
Total
0.2941
1 .oOOo
ther t h e B*QO (gene frequency = 0.1146 among 144
control subjects, x2 = 3.56, P > 0.04) nor t h e other
C4A* a n d B* frequencies deviate from those of our
controls (see Table 2).
Recently, t h e following C 4 alleles were shown
to b e markers on t h c M H C f o r t h e following diseases:
C4B4 (now B3) in patients with type I diabetes mellitus
(12), C4B2.9 in patients with adult rheumatoid arthritis
(13), C4A*4B*2 in multiple sclerosis (14), C4B2 in
Alzheimer’s disease (15), C4A*QO and B*QO in systemic lupus erythematosus (16), a n d most recently,
C4A*QO and rare variants in subacute sclerosing
panencephalitis (Rittner e t al: in preparation). Whether our finding may b e relevant t o endothelial cell
damage d u e t o immune, inflammatory, a n d fibrotic
characteristics of scleroderma remains to be demonstrated in family studies, as well as studies with larger
numbers of subjects.
Acknowledgments. We want to thank Beate Stradmann, Ingrid Tduberecht, and Sabine Zaschke for their
excellent technical assistance.
REFERENCES
1. Rabin BS, Rodnan GP, Bassion S, Gill TJ 111: HL-A
antigens in progressive systemic sclerosis (letter). Arthritis Rheum 18:381-382, 1975
2. Clements PJ, Opelz G, Terasaki PI, Mickey R, Furst D:
Association of HLA antigen A9 with progressive systemic sclerosis. Tissue Antigens 1 1 :357-361, 1978
3. Hughes P, Gelsthorpe K , Doughty RW, Rowell NR,
Rosenthal FD, Sneddon IB: The association of HLA-B8
with visceral disease in systemic sclerosis. Clin Exp
Immunol 31:351-356, 1978
4. Black CM, Welsh KI, Batchelor JK: HLA antigens in
scleroderma. Submitted for publication
5. DiBartolomeo AG, Rabin BS, Rodnan GP: HLA-D
antigens in progressive systemic sclerosis (scleroderma). Immunol Commun 10:733-740, 1981
6. Gladman DD, Keystone EC, Baron M, Lee P, Cane D,
Mervert H: Increased frequency of HLA-DRS in scleroderma. Arthritis Rheum 242354-856, 1981
7. Majskv A, Kobikovk M , Stava Z:HLA and scleroderma. Tissue Antigens 14:359-360. 1979
8. Lynch CJ, Singh G, Rabin BS, Rodnan GP: Histocompatibility antigens in progressive systemic sclerosis (abstract). Arthritis Rheum 23:713, 1980
9. Masi AT, Rodnan GP, Medsger T A Jr, Altman RD,
D’Angelo WA, Fries JF, LeRoy EC, Kirsner AB, Mackenzie AH, McShane DJ, Myers AK, Sharp GC: Preliminary criteria for the classification of systemic sclerosis
(scleroderma). Arthritis Rheum 23:581-590, 1980
10. Awdeh ZL, Alper CA: Inherited structural polymorphism of the fourth component of complement. Proc
Natl Acad Sci USA 77:3576-3580, 1980
11. Roos MH, Mollenhauer E, DCmant P, Rittner C: A
molecular basis for the two locus model of human
complement component C4. Nature 2982354-856, 1982
12. Bertrams J, Hintzen U, Schlicht V, Schoeps S: C4:
another marker for type I diabetes. Lancet i:41, 1982
13. O’Neill GJ, Nerl CW, Kay PA, Christiansen FT, Cluskey MC, Dawkins RL: Complement C4 is a marker for
adult rheumatoid arthritis. Lancet i:214. 1982
14. Schriider R , Zander H, Andreas A, Mauff G: Multiple
sclerosis: immunogenetic analysis of sibpair doublecase
families. 11. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6 and GLO polymorphisms.
Immunobiology 164: 160-170, 1983
15. Nerl CW, Mayeux R , O’Neill GJ: Complement C4
allotypes in Alzheimer’s disease. Lancet ii: 1343, 1982
16. Fielder AHL, Walport MJ, Batchelor JR, Rynes RI,
Black CM, Dodi SA, Hughes GRV: Family study of the
major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of
C4A and C4B in determining disease susceptibility. Br
Med J 286:425-428, 1983
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locus, silent, allele, c4b, sclerodermapossible, significance
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