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

Abstract

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.

RESULTS:

Immunization of C57BL/6-derived mice transgenic for human HLA-DR4 with 70K and either CFA or U1 RNA led to anti-70K antibodies in 62% of mice (21 of 34), and diversified anti-RNP immune responses. MCTD-like lung disease also developed in 50% of immunized mice (17 of 34), and anti-70K antibodies were strongly correlated with lung disease. CFA and U1 RNA were comparably able to induce this syndrome. Mice deficient in Toll-like receptor 3 (TLR-3) also developed this same syndrome when immunized with 70K and CFA. However, TLR-3(-/-) mice failed to develop MCTD-like lung disease when treated with 70K and U1 RNA. Rather, TLR-3(-/-) mice immunized with 70K and U1 RNA developed an autoimmune syndrome characterized by glomerulonephritis typical of SLE.

CONCLUSION:

Exposure to 70K in an appropriate context is sufficient to induce autoimmunity and target organ injury consistent with MCTD. This system represents a new model of autoimmune interstitial lung disease, and establishes a closer link between anti-70K immunity and MCTD-like lung disease. Of note, changes in innate immune signaling can cause the same trigger to lead to the development of SLE-like nephritis rather than MCTD-like lung disease.

• Authors: Eric L Greidinger, YunJuan Zang, Kimberly Jaimes, Scott Hogenmiller, Mehdi Nassiri, Pablo Bejarano, Glen N Barber, Robert W Hoffman
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 54 Issue 2 Pg. 661-9 (Feb 2006) ISSN: 0004-3591 [Print] United States
• PMID: 16453294 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Autoantibodies
• Autoantigens
• Ribonucleoprotein, U1 Small Nuclear
• Snrnp70 protein, mouse
• Freund's Adjuvant

Topics

• Animals
• Autoantibodies (immunology)
• Autoantigens (immunology)
• Autoimmunity (immunology)
• Disease Models, Animal
• Female
• Freund's Adjuvant (administration & dosage, immunology)
• Lung Diseases, Interstitial (immunology, pathology)
• Lupus Nephritis (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mixed Connective Tissue Disease (complications, immunology, pathology)
• Ribonucleoprotein, U1 Small Nuclear (administration & dosage, immunology)