Human autoantibodies against the 70‐kd polypeptide of u1 small nuclear rnp are associated with hla‐dr4 among connective tissue disease patients

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Objective. To test whether immunizing mice with autoantigens closely linked to mixed connective tissue disease (MCTD) could induce an MCTD-like clinical syndrome distinguishable from systemic lupus erythematosus (SLE).Methods. Transgenic and knockout C57BL/6-derived mice were immunized subcutaneously at age 8-12 weeks with U1-70-kd small nuclear RNP (70K) fusion protein along with either Freund's complete adjuvant (CFA) or U1 RNA. After 2 months, mice were killed and analyzed histologically and serologically. Mixed connective tissue disease (MCTD) is a systemic autoimmune syndrome characterized by antibodies to components of the U1 small nuclear RNP (U1 snRNP), whose clinical manifestations partly overlap those seen in systemic lupus erythematosus (SLE) (1). In contrast to lupus, though, major end organ manifestations, including glomerulonephritis (GN), are not typical features of MCTD. Rather, lung disease, an uncommon manifestation of SLE, is the leading cause of death in MCTD (2). While animal models involving anti-RNP autoantibodies have been previously described (3-7), these models have either demonstrated no clinical disease or manifested double-stranded DNA (dsDNA) antibodies and GN, and thus have not been models of the distinctive features of MCTD.Recent evidence has suggested that components of the U1 snRNP complex may participate directly in provoking the anti-RNP responses seen in MCTD. Autoantibodies in MCTD recognize intact and apoptotically modified forms of individual U1 snRNP proteins (8,9), and frequently also recognize structures composed of multiple subunits of the U1 snRNP macromolecule (10). Moreover, anti-RNP antibodies have been found to interact with lung tissue in ways that could mediate MCTD lung pathology (11). In a small series of mice, we have previously found that direct immunization of a Dr.

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen

Greidinger¹,

Zang²,

Jaimes³

et al. 2006

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“…In Japanese patients, MCTD was found to be associated with HLA-DRB 1 *0401 (corresponding to the T cell-defined Dw4 subtype) (37). An association of HLA-DR4 and DRw53 with antibodies to the 70-kd polypeptide of U1 RNP in patients with MCTD and SLE has been reported (38). Anti-RNP antibodies in Caucasian patients with SLE were found by Olsen et a1 to be associated with the HLA-DQw5-associated DQA1*0101 and DQB1*0501, the HLA-DQwtLassociated DQB 1 *0302, and HLA-DR4 (39).…”

Section: Discussionmentioning

confidence: 96%

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

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.

“…Despite efforts to explain this clinical heterogeneity in patients with anti-U1 RNP antibody based on immunoreactivities against individual U1 RNP constituent proteins (70K, A, B/B', and C ) or immunoglobulin allotypes, no strong and reproducible clinical associations with these markers have been reported except in the case of anti-70K reactivity, which is associated with Raynaud's phenomenon, sclerodactyly, hand swelling, telangiectasias, and abnormal esophageal motility (2).…”

mentioning

confidence: 99%

Clinical correlations with HLA type in Japanese patients with connective tissue disease and anti–U1 small nuclear RNP antibodies

Kuwana

Okano

Kaburaki

et al. 1996

Objective. To elucidate the roles of HLA genes in the clinical presentation of patients with connective tissue disease and serum anti-U1 small nuclear RNP antibody.Methods. HLA class I antigens and HLA class I1 alleles were determined in 43 Japanese patients with anti-U1 RNP antibody alone, by microcytotoxicity testing and DNA typing, respectively. Prospectively recorded clinical and laboratory features were analyzed in relation to HLA class I and class I1 types.Results. DQB1*0303 was associated with lupusrelated symptoms including fever, malar rash, oral ulcers, hypocomplementemia, and high-titer antidouble-stranded DNA antibody. Other HLA-clinical associations included DR2 with pleuritis, DR4 with hand swelling, and DRB1*0405 with arthritis.Conclusion. These HLA-clinical associations explain, in part, the heterogeneous clinical presentation in patients with anti-U1 RNP antibody.Autoantibody to U1 small nuclear RNP is a dominant feature of the autoimmune response that occurs in patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) (1). However, the clinical presentation of patients with anti-U1 RNP antibody is variable; for example, some patients have SLE alone, but others have overlapping symptoms of systemic sclerosis (SSc) and myositis (1).Supported by the Scleroderma Grant for Intractable Disease from the Japanese Ministry of Health and Welfare, and grants-in-aid from the Ministry of Education, Science, and Culture, Japan.Masataka Kuwana, MD, Junichi Kaburaki, MD: Keio University School of Medicine, Tokyo, Japan; Yutaka Okano, MD: Nippon Kokan Hospital, Kawasaki, Japan; Hidetoshi Inoko, PhD: Tokai University School of Medicine, Isehara, Japan.Address reprint requests to Masataka Kuwana, MD, Division of Rheumatology, Department of Medicine, Keio University School of Medicine, 35 Shinano-machi; Shinjuku-ku, Tokyo 160, Japan.Submitted for publication November 20, 1995; accepted in revised form January 30, 1996. Despite efforts to explain this clinical heterogeneity in patients with anti-U1 RNP antibody based on immunoreactivities against individual U1 RNP constituent proteins (70K, A, B/B', and C ) or immunoglobulin allotypes, no strong and reproducible clinical associations with these markers have been reported except in the case of anti-70K reactivity, which is associated with Raynaud's phenomenon, sclerodactyly, hand swelling, telangiectasias, and abnormal esophageal motility (2).Recent molecular analyses of HLA class I1 genes have revealed associations between various antinuclear antibodies and polymorphisms of HLA (3). We have reported that immunoreactivities against individual U1 RNP constituent proteins as well as antibody titer were associated with several shared epitopes located on HLA-DR and D Q genes (4). In the present study, we sought HLA-clinical associations in Japanese patients with connective tissue disease and anti-U1 RNP antibody, to better define the role of HLA genes in the clinical presentation. PATIENTS AND METHODSPatients. Forty-three unrelated Ja...