HLA-DR characterization of a Chippewa Indian subpopulation with high prevalence of rheumatoid arthritis

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176

Sdnuclear RNP were quantitated by enzyme-linked immunosorbent assay in 106 white patients with systemic lupus erythematosus. Two Ro autoantibody subgroups were identified that differed quantitatively, genetically, and clinically. The subgroup having anti-Ro only demonstrated significantly lower mean anti-Ro levels than did the subgroup with concomitant anti-La and showed a strong association with the linked HLA alleles DR2 and DQwl. The anti-Ro with anti-La sub- group was associated with the linked HLA alleles B8, DR3, DRw52, and DQw2 (DR3 was primary), and this subgroup consisted of patients with older ages at disease onset, sicca complex, and less renal involvement. Overall, the relative risk (RR) for having anti-Ro was highest in HLA-DR21DR3 heterozygotes compared with non-DR2/DR3 heterozygotes (RR 15) and all other DR combinations (RR 7), suggesting a compound effect of 2 immune responses. Heterozygotes for HLA-DQwl/ DQw2 demonstrated significantly higher mean levels of anti-Ro, which may be indicative of trans gene interaction at HLA-DQ. These data suggest the hypothesis that HLA genes exert their major effects on Ro/La autoantibody subsets of systemic lupus erythematosus.Genetic predisposition to systemic lupus erythematosus (SLE) has been associated with several alleles of the major histocompatibility complex (MHC). Those most consistently reported include HLA-B8, DR2, DR3, and DQwl, as well as null alleles of the HLA-linked second and fourth components of complement (1-8). When autoantibody subsets of SLE are considered, certain HLA antigen correlations become stronger. Most notably, in patients with SLE and in patients with other autoimmune diseases expressing anti-Ro and anti-La, HLA-DR3 andlor DR2 are found in the majority (4,5,9-13). Thus, MHC control of these immune responses, either qualitatively or quantitatively, has been suggested. Recently, enzyme-linked immunosorbent assays (ELISA) have been developed to measure anti-Ro, anti-La, and the anti-Sdnuclear RNP (anti-SmhRNP) complex (14)(15)(16)(17)(18)(19)(20). By virtue of being more sensitive and quantitative, these assays may provide greater insight into the role

Section: Methodsmentioning

confidence: 99%

Two ro (ss‐a) autoantibody responses in systemic lupus erythematosus

Hamilton

Harley

Bias

et al. 1988

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176

“…Sequence homologies among DR3, DR5, and DRw6, as well as the DRw52 subtypes (Dw24-Dw26), suggest that DRwSZbearing haplotypes constitute a "gene family" that is evolutionarily distinct from other haplotypes (42,44,45) (Figure 3). The HLA-DRw8 haplotype appears to have evolved from the DRw52 family, but because of a large deletion encompassing the 3' untranslated portion of DRPl through the coding sequences of (46). and therefore, should have only DRPI, and no DRP3, coding sequences.…”

Section: Discussionmentioning

confidence: 99%

HLA‐D Region genes associated with autoantibody responses to histidyl‐transfer RNA synthetase (Jo‐1) and other translation‐related factors in myositis

Goldstein

Duvic

Targoff

et al. 1990

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Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class I1 specificities by Southern blotting with HLA-DRP, DQP, and D Q a probes. The association of HLA-DR3 (DRwl7) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLADRw8, an HLA-DRw52 haplotype on which the DRp3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DRS, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DRPl first hypervariable region at amino acid positions 9-13. Thus, this DRPl region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.Inflammatory myositis, particularly polymyositis in adults and dermatomyositis in children, has been associated with HLA-B8 and DR3 in white individuals (1,2). In an earlier study using serologic HLA typing (3), the specific subset of myositis patients with serum anti-histidyl-transfer RNA (tRNA) synthetase (antiJo-1) autoantibodies (4) had an even higher frequency of HLA-DR3 than myositis patients overall; all 11 patients with serum anti-Jo-1 antibodies had either HLA-DR3 and/or HLA-DRw6. It was hypothesized that this autoimmune response in myositis may be

“…HLA typing for A, B, C, DR, and DQ antigens was performed as previously described (10). The families studied in Houston had all been HLA typed by the Immunogenetics Laboratory at The Johns Hopkins University School of Medicine; those studied in Oklahoma City had been HLA typed by the laboratory of the Division of Rheumatology, Immunology, and Allergy of the Oklahoma Medical Research Foundation.…”

Section: Methodsmentioning

confidence: 99%

Genetic studies of Ro (SS‐A) and La (SS‐B) autoantibodies in families with systemic lupus erythematosus and primary sjögren's syndrome

Arnett

Hamilton

Reveille

et al. 1989

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Using enzyme-linked immunosorbent assays, autoantibodies to Ro (SS-A) were detected in the sera of 21 % of the first-degree relatives and 1 I % of the seconddegree relatives of anti-R-positive probands with systemic lupus erythematosus (SLE) or primary Sjogren's syndrome, as compared with 3% of normal control subjects (P = 0.003 and P = 0.09, respectively). In a parallel study, anti-Ro occurred in 28% of the firstdegree relatives of unselected members of families of SLE patients, regardless of the proband's serologic status, compared with 6% of the relatives from normal healthy families. Antibodies to La and to Sdnuclear RNP were infrequent. Anti-Ro occurred in 41% of the relatives considered to have a dominant, non-HLAlinked "autoimmune trait" by virtue of having any Submitted for publication September 22, 1988; accepted in revised form December 13, 1988. autoimmune disorder andlor serologic abnormality (antinuclear antibodies, anti-single-stranded DNA, or biologic false-positive VDRL test result), as compared with only 2% of the healthy, seronegative relatives without the trait (P = 0.009). Moreover, HLA-DR2 and/or DR3 occurred in 90% of anti-Rwpositive subjects, regardless of their clinical status. These results demonstrate that the Ro autoantibody response occurs frequently in relatives of patients with SLE and is genetically mediated by both major histocompatibility complex and non-major histocompatibility complex effects.