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Major histocompatibility complex genes in systemic lupus erythematosus, Sjögren's syndrome, and polymyositis
Major Histocompatibility Complex Genes in Systemic Lupus Erythematosus, Sjiigren’s Syndrome, and Polymyositis FRANKC. ARNEIT,M.D., ROSEGOLDSTEIN, M.D., MADELEINEDUN, M.D., JOHND. REVEILLE,M.D. Houston, kxas
Current concepts about the roles of human leukocyte antigen (HLA) and complement genes in predisposing to connective tissue diseases are reviewed. Precise localization of disease conferring alleles and epitopes is confounded by two major phenomena: (1) clinical and serologic heterogeneity of the diseases and associations of several different HLA alleles with different and often overlapping autoantibody responses; and (2) linkage disequilibrium of many potentially relevant gene loci located on the disease-associated HLA haplotypes. Using molecular genetic tools in serologitally homogeneous patient populations, and across racial lines, the Ro (S&A) and La (SS-B) autoantibody responses in systemic lupus erythematosus and Sjiigren’s syndrome appear to associate most strongly with HLA-DQ alleles, whereas the anti-Jo-l autoantibody in myositis correlates best with HLA-DRw52. A gene deletion of C4A within HLA predisposes to systemic lupus erythematosus in both white and black patients.
From the Divrsion of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, and Department of Dermatology, The University of Texas Medical School at Houston, Houston, Texas. This study was supported by grants from the Arthritis Foundation, Texas Gulf Coast Chapter, and an Arthritis Foundation Clinical Research Center Grant. Requests for reprints should be addressed to Dr. Frank C. Arnett, University of Texas Medical School, P.O. Box 20708, Houston, Texas 77225.
38
December
23, 1988
The American Journal of Medicine
enes encoding effector molecules of the immune G system are being increasingly implicated in the development of such autoimmune disorders as systemic lupus erythematosus (SLE), Sjogren’s syndrome, and polymyositis. The strongest disease associations described thus far have been with class II alleles of the major histocompatibility complex (MHC), and with genetic deficiencies of complement components, especially C2 and C4, whose genes also map within the human leukocytic antigen (HLA) region [Il. Family studies suggest, however, that MHC and complement genes alone cannot fully explain multiple cases of the same or, as is more often the case, different autoimmune diseases in the same kindred [2]. HLA haplotypes are not shared among affected relatives, including sibs, any more often than expected by normal Mendelian segregation. Also, healthy relatives who have serum autoantibodies and/or abnormalities of lymphocyte function do not necessarily share HLA haplotypes or alleles with their affected family members 111.Formal genetic analyses of such families suggest the presence of a dominant, non-HLA linked, “autoimmune trait.” MHC alleles appear to act epistatically with this as yet undefined genetic factor and promote expression of the autoimmune disease “phenotype” 121. Thus, different HLA antigens show associations with different diseases in families and in unrelated groups of patients. Given the caveat that the MHC is probably not the only genetic system involved, the elucidation of the precise MHC alleles and their roles in the expression of SLE, Sjdgren’s syndrome, and polymyositis is nevertheless an important task. “Epitopes” on certain HLA molecules have been identified that appear to confer susceptibility to several other autoimmune diseases, such as rheumatoid arthritis, pemphigus vulgar-is, and type I diabetes mellitus [3,4]. Identification of similar nucleotide or peptide sequences relevant to SLE, Sjogren’s syndrome, and polymyositis is confounded by two major problems. DISEASE HETEROGENEITY Clinical and serologic heterogeneity characterize each of these diseases, and there is considerable overlap among them (Figure 1). Multiple autoantibodies to DNA and RNA complexes are the rule, with some antibody systems being disease-specific (anti-dsDNA and anti-Sm in SLE.; antiJo- and other translationrelated specificities m polymyositis) and others crossing nosologic lines (anti-R0 and anti-La in both SLE and Sjbgren’s syndrome and rarely polymyositis) [l]. Several of these autoantibodies correlate strongly with certain disease features, suggesting that they
Volume 85 (suppl 6A)
SYMPOSIUM
ON IMMUNOGENETICS
OF THE RHEUMATIC
SLE
PRIMARY SS
High
Figure 1. Schematic representation of the clinical, serologic, and immunogenetic overlap of SLE and primary Sjdgren’s syndrome (SS). Ro = antibodies to Ro (.%-A); La = antibodies to La @S-B); Sm/RNP = antibodies to Sm (Smith) and/or nuclear ribonucleoprotein; EBA = antibodies to epidermolysis bullosa acquisita antigen; SCLE = subacute cutaneous lupus crythematosus.
DISEASES / ARNETT ET AL
-
levels Anti-R0
DQwllEQG2
of -
Vasculitis SCLE Neonatal
may play pathogenetic roles. For example, anti-R0 @S-A) usually accompanied by anti-La @S-B) occurs in patients with older onset SLE who usually develop sicca symptoms (secondary Sjogrens’ syndrome) and/ or characteristic photosensitive lesions, have a low incidence of lupus nephritis, and demonstrate hyperglobulinemia and serum rheumatoid factor activity [5]. Patients with primary Sjogren’s syndrome who have this same autoantibody profile often show these same features and are at risk for vasculitis and hematologic cytopenias [6]. Women who possess anti-R0 regardless of disease subset, may bear infants with congenital heart block or lupus dermatitis, probably by virtue of transplacental passage of antibodies 171. Lupus patients with antibodies to type 7 procollagen (epidermolysis bullosa acquisita) develop bullous skin lesions consequent to antibody attack on the basement membrane [3]. Polymyositis patients with autoantibodies to Jo-l (histidyl tRNA synthetase) almost invariably have inflammatory interstitial lung disease 191.Thus, these clinical disease entities appear to represent composites of multiple overlapping immune responses. Importantly! certain autoantibodies show stronger associations with HLA specificities than do their parent diseases (Table I). Lupus patients with antiepidermolysis bullosa acquisita are almost all HLADRt-positive [8]. Anti-Ro- and anti-La-positive patients, regardless of disease! are largely DR3- or DR2 [5,10,11]-positive, and the highest autoantibody levels are found in DQwllDQw2 heterozygotes. If anti-Ro-
lesions Lupus
positive lupus patients are removed from consideration, the HLA-DR3 and a large proportion of the HLA-DR2 associations with SLE itself are lost [51. Similarly, the anti-Ro/anti-La responses in primary Sjogren’s syndrome [lo] and the antiJo- response in polymyositis [12] account largely for the HLA-DR3 associations with these diseases. The HLA specificity that is maintained in antibody-negative patients with Sjogren’s syndrome or polymyositis is HLA-DRw52 [10,121. LINKAGE DISEQUILIBRIUM OF MHC GENES The second level of complexity falls within the MHC itself where primary disease and autoantibody associations are confounded by linkage disequilibrium. Two major extended HLA haplotypes bearing multiple gene loci account for most correlations with these diseases in white patients (Figure 2). The HLA-B8, DR3 haplotype carries DR-beta-I-encoding DR3, DR-betaIII-encoding DRw52a, the DQ-alpha and beta-alleles for DQw2, and a C4A gene deletion in the class III region resulting in the C4A null phenotype (C4AQO). The HLA-B’7, DR2 haplotypes carries DR-beta-1 encoding DR2, as well as DQ-alpha and -beta alleles encoding DQwl . Important questions arise from knowledge of the MHC infrastructure. First, which disease-associated alleles actually carry the disease conferring “epitopes” and which are only “piggybacked” because of linkage disequilibrium? Second, is it possible that there are several cis- and trans-associated effects, as suggested
December 23, 1988
The American Journal of Medicine
Volume 85 (suppl 6A)
39
SYhlF’OSIUMON IMMUNOGEN~CS OF THE RHEUMATICDISEASESI ARNEll ET AL TABLE I HlA Associations with Diseases and Autoantibodies Disease and Autoantibodies
RelativeRisks
HLA Associations
Systemic lupus erythematosus
DR3 DRZ, DQwl C4AQO
233 3
Anti-R0without anti-la Anti.Rowith an&La Highest anti-R0 levels
DR2, DQwl DR3 DQwlIDQwP
-
Anti-EEA
DR2, DQwl
13
AntiSm/nRNP
Negative association with DR3 and OQwllDQw2
Primary Sjogren’ssyndrome
0.18
DR3 DRw52 DRw52 DR3 DR2 OR2 and/or DR3 DR3 DQwllDQwP
Secondary Sjogren’ssyndrome Anti-R0 positives
Anti-Lapositives Highest anti-R0 and La levels Poiymyositis
Anti-Jo-l
ii
ii
4-10 ; i: -
DR3 DRw52
i
DRw52a
18
IA = epidermolysis bullosa acquisita
HLA-DQ
HLA-DR
CLASS
III
C4A.C4B I /
DQw2
DR3
DRw52a
C4AQO
--HLA-B
HLA-C
D
m I
1
ee
cw7
figure Other
Haplotypes
by the earlier studies [5,10,111, or are the relevant epitopes represented on multiple alleles and a dosage effect results? For example, the DR-beta-III allele DRw52 carried on DR3,5,w6 and w8 haplotypes correlates most strongly with the disease Sjogren’s syndrome, the DR-beta-1 alleles DR3 and DR2 are more strongly associated with the presence of Ro antibodies, and DQwl/DQw2 heterozygosity correlates with high autoantibody levels [16,111. Such questions can now be better addressed using newer molecular genetic techniques; however, the use of homogeneous patient populations, especially with respect to specific autoantibody responses, and across ethnic lines are most likely to be fruitful. Three examples in which we have recently used these approaches follow:
40
December
23,
1988
2. Schematic representation of gene loci within the MHC on three haplotypes associated with susceptibility to SLE.
C4AQO
The American Journal of Medicine
1. Studies of HLA class I and II antigens by serologic typing have shown no consistent associations with SLE in black subjects. Reveille et al (manuscript in preparation) recently examined class II alleles in black patients with lupus using restriction fragment length polymorphisms and found no disturbances in frequencies of DR or DQ alleles or their subtypes. With a C4 probe and the restriction enzymes Hind III and Taq I, however, a deletion of the C4A gene was found in 24 percent of 80 black patients with SLE and in only ‘7percent of ‘72 normal black subjects (relative risk, 4.2) 1133. Unlike white patients with SLE and a C4A deletion [14,15], only a fraction of black patients had the B8, DR3 phenotype. Nonetheless, all of the C4A-deleted black patients and control subjects had
Volume 85 (suppl 64
SYMF’OSIUM ON IMMUNOGENETICS
HLA-DR2 or DR3. Thus, this class III association provides the strongest genetic risk factor yet identified for SLE in black patients; however, possible confounding effects from linked DR2 and DR3 haplotypes remain. 2. Recent restriction fragment length polymorphism analyses of DR and DQ alleles in SLE and Sjogren’s syndrome patients having anti-R0 and antiLa antibodies have confirmed the previous associations in white subjects and shown a weaker correlation with DR3 in black subjects. DQwl. UDQw2.1 heterozygosity emerges as the strongest risk factor in both races (manuscript in preparation). 3. In similar studies of myositis, HLA-DR3 strongly correlates with disease in white patients but is not increased in black patients [12]. Instead, DRw52 is significantly increased in both races (relative risk, 4.7). Among antiJo- positive subjects, the DRw52a subtype is almost universally found and confers a relative risk of 18. Thus, disease and this abnormal immune response appear to localize to the DRbeta-III gene. Although such studies are likely to more precisely define the MHC contributions to these diseases, complete understanding must await more fundamental knowledge of other genes predisposing to autoimmunity per se, as well as non-germline events (environmental triggers and/or somatic mutations) suggested by lack of complete autoimmune disease concordance in monozygotic twins.
OF THE RHEUMATIC
DISEASES / ARNEll
ET AL
REFERENCES 1. Goldstern R, Arnett FC: The genetrcs of rheumatrc diseases in man Rheum Dis Clin N Am 1987; 13: 487-510. 2. Bias WB, Reveille JD, Beaty TH, Arnett FC: Evrdence that autormmunrty rn man IS a Mendelian dominant ban. Am J Hum Genet 1987; 39: 584-602. 3. Gregersen PK, Silver J, Winchester RJ: The shared eprtope hypotheses. Arthrrbs Rheum 1987; 30: 1205-1213. 4. Todd JA, Acha-Orbea H, Bell JI, et a/: A molecular basrs for MHC class II-associated autormmunrty. Scrence 1988; 240: 1003-1009. 5. Hamilton RG, Harley JB, Bias W, et a/; Two Ro (%-A) autoantIbody responses in systemic lupus erythematosus. Correlabon of HLA-DRIDQ specrfrcibes with quantrtatrve expression of Ro (SS-A) autoantrbody. Arthrtbs Rheum 1988; 31: 496-505. 6. Alexander EL, Arnett FC, Provost TT, Stevens MB: Stogren’s syndrome. assocratron of anbRo (SS-A) antibodies wrth vasculrtrs, hematologlc abnormalrtres, and serologrc hyperreacbvlty. Ann Intern Med 1983; 98: 155-159. 7. Watson RM, Lane AT, Barnet NK, et a/: Neonatal lupus erythematosus. a clrnrcal, sero logical and immunogenetrc study wrth revrew of the literature. Medicine (Baltrmore) 1984, 63: 362-378. 8. Gammon WR, Heise ER, Burke WA, et al Increased frequency of HLADRZ rn patients with autoanbbodres to eprdermolysis bullosa acqutsrta anbgen: evidence that the expression of autoimmunity to type VII collagen IS HLA class II assocrated. J Invest Dermatol 1988; 91: 228-232. 9. Yoshida S, Akizuki M, Mimori T, et al: The preciprtatlng anbbody to an acrdic nuclear protein antigen, the Jo-l, in connective trssue drseases: a marker for a subset of polymyosttrs with rnterstitral pulmonary hbrosrs. Arthnbs Rheum 1983; 26: 604-611. 10. Wilson RW, Provost TT, Bras WB, et al: Sjogren’s syndrome. influence of multrple HLA-D regron alloanbgens on clrnlcal and serologic expression. Arthritrs Rhuem 1984: 27: 1245-1253. 11. Harley JB, Rerchlin M, Arnett FC, et al: Gene interactton at HLA-DQ enhances autoantibody productron rn primary Sjogren’s syndrome. Scrence 1986; 232: 1145-1147. 12. Goldstern R. DUVICM, Targoff IN, et al: Serologrc and restncbon enzyme studies of HLA-D region genes in myositrs (abstr). Arthritis Rheum 1988; 31: S33. 13. Goldstern R, Olsen ML, Arnett FC, et al Deletion of C4A genes rn black Amerrcans with systemic lupus erythematosus (abstr). Arthritis Rheum 1988; 31: S22. 14. Kemp ME, Atkrnson JP, Skanes VM, et at Deletion of C4A genes rn patrents with systemrc lupus erythematosus. Arthritis Rheum 1987; 30: 1015-1022. 15. Goldstein R, Arnett FC, McLean RH. Bias WB, DUVICM: Molecular heterogeneity of complement component C4 null and 21.hydroxylase genes in systemrc lupus erythema. tosus. Arthntrs Rheum 1988 31: 736-744.
December 23, 1988
The American Journal of Medicine
Volume 85 (suppl 6A)
41
Current concepts about the roles of human leukocyte antigen (HLA) and complement genes in predisposing to connective tissue diseases are reviewed. Precise localization of disease conferring alleles and epitopes is confounded by two major phenomena: (1) clinical and serologic heterogeneity of the diseases and associations of several different HLA alleles with different and often overlapping autoantibody responses; and (2) linkage disequilibrium of many potentially relevant gene loci located on the disease-associated HLA haplotypes. Using molecular genetic tools in serologitally homogeneous patient populations, and across racial lines, the Ro (S&A) and La (SS-B) autoantibody responses in systemic lupus erythematosus and Sjiigren’s syndrome appear to associate most strongly with HLA-DQ alleles, whereas the anti-Jo-l autoantibody in myositis correlates best with HLA-DRw52. A gene deletion of C4A within HLA predisposes to systemic lupus erythematosus in both white and black patients.
From the Divrsion of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, and Department of Dermatology, The University of Texas Medical School at Houston, Houston, Texas. This study was supported by grants from the Arthritis Foundation, Texas Gulf Coast Chapter, and an Arthritis Foundation Clinical Research Center Grant. Requests for reprints should be addressed to Dr. Frank C. Arnett, University of Texas Medical School, P.O. Box 20708, Houston, Texas 77225.
38
December
23, 1988
The American Journal of Medicine
enes encoding effector molecules of the immune G system are being increasingly implicated in the development of such autoimmune disorders as systemic lupus erythematosus (SLE), Sjogren’s syndrome, and polymyositis. The strongest disease associations described thus far have been with class II alleles of the major histocompatibility complex (MHC), and with genetic deficiencies of complement components, especially C2 and C4, whose genes also map within the human leukocytic antigen (HLA) region [Il. Family studies suggest, however, that MHC and complement genes alone cannot fully explain multiple cases of the same or, as is more often the case, different autoimmune diseases in the same kindred [2]. HLA haplotypes are not shared among affected relatives, including sibs, any more often than expected by normal Mendelian segregation. Also, healthy relatives who have serum autoantibodies and/or abnormalities of lymphocyte function do not necessarily share HLA haplotypes or alleles with their affected family members 111.Formal genetic analyses of such families suggest the presence of a dominant, non-HLA linked, “autoimmune trait.” MHC alleles appear to act epistatically with this as yet undefined genetic factor and promote expression of the autoimmune disease “phenotype” 121. Thus, different HLA antigens show associations with different diseases in families and in unrelated groups of patients. Given the caveat that the MHC is probably not the only genetic system involved, the elucidation of the precise MHC alleles and their roles in the expression of SLE, Sjdgren’s syndrome, and polymyositis is nevertheless an important task. “Epitopes” on certain HLA molecules have been identified that appear to confer susceptibility to several other autoimmune diseases, such as rheumatoid arthritis, pemphigus vulgar-is, and type I diabetes mellitus [3,4]. Identification of similar nucleotide or peptide sequences relevant to SLE, Sjogren’s syndrome, and polymyositis is confounded by two major problems. DISEASE HETEROGENEITY Clinical and serologic heterogeneity characterize each of these diseases, and there is considerable overlap among them (Figure 1). Multiple autoantibodies to DNA and RNA complexes are the rule, with some antibody systems being disease-specific (anti-dsDNA and anti-Sm in SLE.; antiJo- and other translationrelated specificities m polymyositis) and others crossing nosologic lines (anti-R0 and anti-La in both SLE and Sjbgren’s syndrome and rarely polymyositis) [l]. Several of these autoantibodies correlate strongly with certain disease features, suggesting that they
Volume 85 (suppl 6A)
SYMPOSIUM
ON IMMUNOGENETICS
OF THE RHEUMATIC
SLE
PRIMARY SS
High
Figure 1. Schematic representation of the clinical, serologic, and immunogenetic overlap of SLE and primary Sjdgren’s syndrome (SS). Ro = antibodies to Ro (.%-A); La = antibodies to La @S-B); Sm/RNP = antibodies to Sm (Smith) and/or nuclear ribonucleoprotein; EBA = antibodies to epidermolysis bullosa acquisita antigen; SCLE = subacute cutaneous lupus crythematosus.
DISEASES / ARNETT ET AL
-
levels Anti-R0
DQwllEQG2
of -
Vasculitis SCLE Neonatal
may play pathogenetic roles. For example, anti-R0 @S-A) usually accompanied by anti-La @S-B) occurs in patients with older onset SLE who usually develop sicca symptoms (secondary Sjogrens’ syndrome) and/ or characteristic photosensitive lesions, have a low incidence of lupus nephritis, and demonstrate hyperglobulinemia and serum rheumatoid factor activity [5]. Patients with primary Sjogren’s syndrome who have this same autoantibody profile often show these same features and are at risk for vasculitis and hematologic cytopenias [6]. Women who possess anti-R0 regardless of disease subset, may bear infants with congenital heart block or lupus dermatitis, probably by virtue of transplacental passage of antibodies 171. Lupus patients with antibodies to type 7 procollagen (epidermolysis bullosa acquisita) develop bullous skin lesions consequent to antibody attack on the basement membrane [3]. Polymyositis patients with autoantibodies to Jo-l (histidyl tRNA synthetase) almost invariably have inflammatory interstitial lung disease 191.Thus, these clinical disease entities appear to represent composites of multiple overlapping immune responses. Importantly! certain autoantibodies show stronger associations with HLA specificities than do their parent diseases (Table I). Lupus patients with antiepidermolysis bullosa acquisita are almost all HLADRt-positive [8]. Anti-Ro- and anti-La-positive patients, regardless of disease! are largely DR3- or DR2 [5,10,11]-positive, and the highest autoantibody levels are found in DQwllDQw2 heterozygotes. If anti-Ro-
lesions Lupus
positive lupus patients are removed from consideration, the HLA-DR3 and a large proportion of the HLA-DR2 associations with SLE itself are lost [51. Similarly, the anti-Ro/anti-La responses in primary Sjogren’s syndrome [lo] and the antiJo- response in polymyositis [12] account largely for the HLA-DR3 associations with these diseases. The HLA specificity that is maintained in antibody-negative patients with Sjogren’s syndrome or polymyositis is HLA-DRw52 [10,121. LINKAGE DISEQUILIBRIUM OF MHC GENES The second level of complexity falls within the MHC itself where primary disease and autoantibody associations are confounded by linkage disequilibrium. Two major extended HLA haplotypes bearing multiple gene loci account for most correlations with these diseases in white patients (Figure 2). The HLA-B8, DR3 haplotype carries DR-beta-I-encoding DR3, DR-betaIII-encoding DRw52a, the DQ-alpha and beta-alleles for DQw2, and a C4A gene deletion in the class III region resulting in the C4A null phenotype (C4AQO). The HLA-B’7, DR2 haplotypes carries DR-beta-1 encoding DR2, as well as DQ-alpha and -beta alleles encoding DQwl . Important questions arise from knowledge of the MHC infrastructure. First, which disease-associated alleles actually carry the disease conferring “epitopes” and which are only “piggybacked” because of linkage disequilibrium? Second, is it possible that there are several cis- and trans-associated effects, as suggested
December 23, 1988
The American Journal of Medicine
Volume 85 (suppl 6A)
39
SYhlF’OSIUMON IMMUNOGEN~CS OF THE RHEUMATICDISEASESI ARNEll ET AL TABLE I HlA Associations with Diseases and Autoantibodies Disease and Autoantibodies
RelativeRisks
HLA Associations
Systemic lupus erythematosus
DR3 DRZ, DQwl C4AQO
233 3
Anti-R0without anti-la Anti.Rowith an&La Highest anti-R0 levels
DR2, DQwl DR3 DQwlIDQwP
-
Anti-EEA
DR2, DQwl
13
AntiSm/nRNP
Negative association with DR3 and OQwllDQw2
Primary Sjogren’ssyndrome
0.18
DR3 DRw52 DRw52 DR3 DR2 OR2 and/or DR3 DR3 DQwllDQwP
Secondary Sjogren’ssyndrome Anti-R0 positives
Anti-Lapositives Highest anti-R0 and La levels Poiymyositis
Anti-Jo-l
ii
ii
4-10 ; i: -
DR3 DRw52
i
DRw52a
18
IA = epidermolysis bullosa acquisita
HLA-DQ
HLA-DR
CLASS
III
C4A.C4B I /
DQw2
DR3
DRw52a
C4AQO
--HLA-B
HLA-C
D
m I
1
ee
cw7
figure Other
Haplotypes
by the earlier studies [5,10,111, or are the relevant epitopes represented on multiple alleles and a dosage effect results? For example, the DR-beta-III allele DRw52 carried on DR3,5,w6 and w8 haplotypes correlates most strongly with the disease Sjogren’s syndrome, the DR-beta-1 alleles DR3 and DR2 are more strongly associated with the presence of Ro antibodies, and DQwl/DQw2 heterozygosity correlates with high autoantibody levels [16,111. Such questions can now be better addressed using newer molecular genetic techniques; however, the use of homogeneous patient populations, especially with respect to specific autoantibody responses, and across ethnic lines are most likely to be fruitful. Three examples in which we have recently used these approaches follow:
40
December
23,
1988
2. Schematic representation of gene loci within the MHC on three haplotypes associated with susceptibility to SLE.
C4AQO
The American Journal of Medicine
1. Studies of HLA class I and II antigens by serologic typing have shown no consistent associations with SLE in black subjects. Reveille et al (manuscript in preparation) recently examined class II alleles in black patients with lupus using restriction fragment length polymorphisms and found no disturbances in frequencies of DR or DQ alleles or their subtypes. With a C4 probe and the restriction enzymes Hind III and Taq I, however, a deletion of the C4A gene was found in 24 percent of 80 black patients with SLE and in only ‘7percent of ‘72 normal black subjects (relative risk, 4.2) 1133. Unlike white patients with SLE and a C4A deletion [14,15], only a fraction of black patients had the B8, DR3 phenotype. Nonetheless, all of the C4A-deleted black patients and control subjects had
Volume 85 (suppl 64
SYMF’OSIUM ON IMMUNOGENETICS
HLA-DR2 or DR3. Thus, this class III association provides the strongest genetic risk factor yet identified for SLE in black patients; however, possible confounding effects from linked DR2 and DR3 haplotypes remain. 2. Recent restriction fragment length polymorphism analyses of DR and DQ alleles in SLE and Sjogren’s syndrome patients having anti-R0 and antiLa antibodies have confirmed the previous associations in white subjects and shown a weaker correlation with DR3 in black subjects. DQwl. UDQw2.1 heterozygosity emerges as the strongest risk factor in both races (manuscript in preparation). 3. In similar studies of myositis, HLA-DR3 strongly correlates with disease in white patients but is not increased in black patients [12]. Instead, DRw52 is significantly increased in both races (relative risk, 4.7). Among antiJo- positive subjects, the DRw52a subtype is almost universally found and confers a relative risk of 18. Thus, disease and this abnormal immune response appear to localize to the DRbeta-III gene. Although such studies are likely to more precisely define the MHC contributions to these diseases, complete understanding must await more fundamental knowledge of other genes predisposing to autoimmunity per se, as well as non-germline events (environmental triggers and/or somatic mutations) suggested by lack of complete autoimmune disease concordance in monozygotic twins.
OF THE RHEUMATIC
DISEASES / ARNEll
ET AL
REFERENCES 1. Goldstern R, Arnett FC: The genetrcs of rheumatrc diseases in man Rheum Dis Clin N Am 1987; 13: 487-510. 2. Bias WB, Reveille JD, Beaty TH, Arnett FC: Evrdence that autormmunrty rn man IS a Mendelian dominant ban. Am J Hum Genet 1987; 39: 584-602. 3. Gregersen PK, Silver J, Winchester RJ: The shared eprtope hypotheses. Arthrrbs Rheum 1987; 30: 1205-1213. 4. Todd JA, Acha-Orbea H, Bell JI, et a/: A molecular basrs for MHC class II-associated autormmunrty. Scrence 1988; 240: 1003-1009. 5. Hamilton RG, Harley JB, Bias W, et a/; Two Ro (%-A) autoantIbody responses in systemic lupus erythematosus. Correlabon of HLA-DRIDQ specrfrcibes with quantrtatrve expression of Ro (SS-A) autoantrbody. Arthrtbs Rheum 1988; 31: 496-505. 6. Alexander EL, Arnett FC, Provost TT, Stevens MB: Stogren’s syndrome. assocratron of anbRo (SS-A) antibodies wrth vasculrtrs, hematologlc abnormalrtres, and serologrc hyperreacbvlty. Ann Intern Med 1983; 98: 155-159. 7. Watson RM, Lane AT, Barnet NK, et a/: Neonatal lupus erythematosus. a clrnrcal, sero logical and immunogenetrc study wrth revrew of the literature. Medicine (Baltrmore) 1984, 63: 362-378. 8. Gammon WR, Heise ER, Burke WA, et al Increased frequency of HLADRZ rn patients with autoanbbodres to eprdermolysis bullosa acqutsrta anbgen: evidence that the expression of autoimmunity to type VII collagen IS HLA class II assocrated. J Invest Dermatol 1988; 91: 228-232. 9. Yoshida S, Akizuki M, Mimori T, et al: The preciprtatlng anbbody to an acrdic nuclear protein antigen, the Jo-l, in connective trssue drseases: a marker for a subset of polymyosttrs with rnterstitral pulmonary hbrosrs. Arthnbs Rheum 1983; 26: 604-611. 10. Wilson RW, Provost TT, Bras WB, et al: Sjogren’s syndrome. influence of multrple HLA-D regron alloanbgens on clrnlcal and serologic expression. Arthritrs Rhuem 1984: 27: 1245-1253. 11. Harley JB, Rerchlin M, Arnett FC, et al: Gene interactton at HLA-DQ enhances autoantibody productron rn primary Sjogren’s syndrome. Scrence 1986; 232: 1145-1147. 12. Goldstern R. DUVICM, Targoff IN, et al: Serologrc and restncbon enzyme studies of HLA-D region genes in myositrs (abstr). Arthritis Rheum 1988; 31: S33. 13. Goldstern R, Olsen ML, Arnett FC, et al Deletion of C4A genes rn black Amerrcans with systemic lupus erythematosus (abstr). Arthritis Rheum 1988; 31: S22. 14. Kemp ME, Atkrnson JP, Skanes VM, et at Deletion of C4A genes rn patrents with systemrc lupus erythematosus. Arthritis Rheum 1987; 30: 1015-1022. 15. Goldstein R, Arnett FC, McLean RH. Bias WB, DUVICM: Molecular heterogeneity of complement component C4 null and 21.hydroxylase genes in systemrc lupus erythema. tosus. Arthntrs Rheum 1988 31: 736-744.
December 23, 1988
The American Journal of Medicine
Volume 85 (suppl 6A)
41