Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients

Kaneoka, Hidetoshi; Hsu, Kou-Ching; Takeda, Yoshihiko; Sharp, Gordon C.; Hoffman, Robert W.

doi:10.1002/art.1780350113

Cited by 80 publications

(42 citation statements)

References 53 publications

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“…In contrast, evidence of a primary association with the HLA-DR locus is provided by our study and that by Kaneoka et a1 (40). Among our patients, all but 1 of those whose disease remained undifferentiated had either HLA-DR2 or DR4.…”

Section: Discussioncontrasting

confidence: 48%

“…The association with more than one HLA allele may be explained by the shared epitope hypothesis as in RA (33). In the molecular genetic analysis study by Kaneoka et al, an association was found between the presence of autoantibodies to the 70-kd polypeptide and a shared epitope that was present exclusively on most HLA-DR2 and DR4 subtypes (excluding DRB1*1601 and *1602 subtypes of DR2 and *0402 subtype of DR4) (40). The epitope consists of 7 amino acids at the HLA-DRB 1 region.…”

Section: Discussionmentioning

confidence: 99%

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Hla type as a predictor of mixed connective tissue disease differentiation ten‐year clinical and immunogenetic followup of 46 patients

Gendi

Welsh

Venrooij

et al. 1995

Arthritis & Rheumatism

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Objective. To determine any clinical or genetic markers of differentiation and outcome in a previously described cohort of 46 patients with mixed connective tissue disease (MCTD).Methods. Patients were clinically evaluated, chart notes reviewed, and HLA subtyping and immunology profiles performed where possible. Eleven had died and 7 were lost to followup.Results. MCTD had differentiated into systemic lupus erythematosus in 12 patients and into systemic sclerosis in 13. The latter was associated with HLA-DR5 (P = 0.038), and nondifferentiation was associated with HLA-DR2 or DR4 (P = 0.007). Three HLA-DR4 positive patients had MCTD that evolved into rheumatoid arthritis. Erosive and/or deforming arthritis was associated with HLA-DR1 or DR4 (P = 0.015). HLA-DR3 was associated with interstitial lung fibrosis (P = 0.044) and keratoconjunctivitis sicca (0.001 < P < 0.01). Severe Raynaud's phenomenon predicted higher mortality (0.01 < P < 0.05). Conclusion.We suggest that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease. Those whose disease remains undifferentiated might be considered a distinct subset.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Hla type as a predictor of mixed connective tissue disease differentiation ten‐year clinical and immunogenetic followup of 46 patients

Gendi

Welsh

Venrooij

et al. 1995

Arthritis & Rheumatism

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“…Subfamilyspecific PCR was performed as described above and the products were subjected to gel isolation and direct DNA sequencing as described previously [14,22]. In brief, the amplified DNA was isolated from a 5% polyacrylamide gel using ammonium acetate and EDTA.…”

Section: Methodsmentioning

confidence: 99%

Structural Analysis of TCRα and β Chains from Human T‐Cell Clones Specific for Small Nuclear Ribonucleoprotein Polypeptides Sm‐D, Sm‐B and U1–70 kDa: TCR Complementarity Determining Region 3 Usage Appears Highly Conserved

et al. 2001

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Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are systemic autoimmune diseases that are characterized by the presence of autoantibodies reactive with U small nuclear RNP (snRNP) autoantigens. Both B and T cells are important in the pathogenesis of the disease, and T-and B-cell immunity against snRNP polypeptides have been shown to be linked in vivo. Currently, several alternative hypotheses for the pathogenesis of these diseases have been proposed. These include loss of tolerance, modified self-antigens, molecular mimicry and nondirected immune activation. To help distinguish between the various models of disease pathogenesis, we have characterized the T-cell receptor (TCR) CDR3 from a large panel of well-characterized human T-cell clones and lines specific for individual snRNP polypeptides. The results presented here reveal highly restricted TCR usage across patients by the snRNP-reactive T cells based on the deduced amino acid sequence of the CDR3 loop. These data support the hypothesis that T-cell responses against self antigens in SLE and MCTD are antigen driven and that there are a limited number of T-cell epitopes present on the snRNP autoantigens.

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“…Prior studies assessing potential HLA phenotypic associations with the anti-Sm and anti-RNP responses have been few in number, of limited sample size, and often did not distinguish between patients with anti-Sm and/or anti-RNP (6,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Moreover, the serologic HLA typing employed in these studies is unable to detect the more extensive polymorphisms of HLA class I1 alleles, which is now possible with molecular methods.…”

mentioning

confidence: 99%

Contrasting molecular patterns of mhc class ii alleles associated with the anti‐sm and anti‐rnp precipitin autoantibodies in systemic lupus erythematosus

Olsen¹,

Arnett²,

Reveille³

1993

Arthritis & Rheumatism

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Objective. To find evidence of a potential genetic predisposition to the anti-Sm or anti-RNP precipitin autoantibody responses.Methods. HLA-DR and DQ alleles determined by restriction fragment length polymorphism andor oligotyping in 49 subjects with either anti-Sm alone or anti-RNP alone were compared with those in 139 racematched normal control subjects and 59 race-matched lupus patients without anti-Sm and anti-RNP autoantibodies.Results. Black patients with anti-Sm precipitin had increased frequencies of HLA-DR2 and the DQw6-associated DQAl*0102 (P = 0.007, odds ratio [OR] = 6.7) and DQB1*0602 (P = 0.001, OR = 9.1) chain alleles compared with normal black control subjects. Black patients with anti-RNP precipitin showed significant increases in the DQwS-associated DQA1*0101 (P = 0.03, OR = 5.5) and DQB1*0501 (P = 0.002, OR = 23.3) chain alleles compared with lupus patients without anti8m or RNP. White patients with anti-RNP precipitin showed an increased frequency of the DQw8-associated allele DQB1*0302 (P = 0.02, OR = 3.7) compared with normal controls, as well as an increased frequency of the DQwS-associated alleles DQA1*0101 and DQB1*0501 (P = 0.05, OR = 4.2) compared with lupus patients without anti-Sm or RNP. There were no specific HLA-DR2 or DR4 subtype associations found with either anti-Sm or RNP precipitin autoantibodies.Conclusion. There are distinct patterns of major histocompatibility complex class I1 allele associations with the anti-Sm versus the anti-RNP precipitin autoantibody responses, and HLA-DQ associations may be more primary than HLA-DR associations.Autoantibodies to the uridine-rich small nuclear ribonucleoproteins (U snRNP), transcriptional enzymes for splicing messenger RNA, arise spontaneously in patients with the autoimmune disease systemic lupus erythematosus (SLE). In fact, anti-Sm (Smith) autoantibodies, the autoepitopes of which reside on U l , U2, U4, U5, and U6 snRNP, are highly specific for SLE. Anti-RNP, which recognizes different antigens on U1 RNP, is often co-expressed with anti-Sm in lupus patients or may occur alone in SLE or in other systemic diseases, including mixed connective tissue disease, scleroderma, and polymyositis (1). Both anti-Sm and anti-RNP appear to occur more commonly in blacks than whites with SLE (2).SLE is a clinically and serologically heterogeneous disease in which genetic factors appear to play an important role. Earlier studies have demonstrated weak associations with the HLA-DR2 and DR3 alleles in Caucasians (3,4). Stronger HLA class I1 correlations have been found for certain SLE autoantibody subsets than for the disease itself (5-7). Such findings suggest that the immune responses to these autoanti-

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Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients

Cited by 80 publications

References 53 publications

Hla type as a predictor of mixed connective tissue disease differentiation ten‐year clinical and immunogenetic followup of 46 patients

Hla type as a predictor of mixed connective tissue disease differentiation ten‐year clinical and immunogenetic followup of 46 patients

Structural Analysis of TCRα and β Chains from Human T‐Cell Clones Specific for Small Nuclear Ribonucleoprotein Polypeptides Sm‐D, Sm‐B and U1–70 kDa: TCR Complementarity Determining Region 3 Usage Appears Highly Conserved

Contrasting molecular patterns of mhc class ii alleles associated with the anti‐sm and anti‐rnp precipitin autoantibodies in systemic lupus erythematosus

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