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Novel Autoantigens Associated with Lupus Nephritis.

Onishi S, Adnan E, Ishizaki J, Miyazaki T, Tanaka Y, Matsumoto T, Suemori K, Shudou M, Okura T, Takeda H, Sawasaki T, Yasukawa M, Hasegawa H - PLoS ONE (2015)

Bottom Line: To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system.Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA.These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

No MeSH data available.


Related in: MedlinePlus

Changes in antibody levels and clinical findings in patients with lupus nephritis.▲ LN1, ♦ LN2, ● LN3, ◊ LN4, ○ LN5, □ LN6, ■ LN7. (A) Anti-RRP8 antibody, (B) anti-TNP1 antibody, (C) SLEDAI, (D) anti-dsDNA antibody, (E) C3, and (F) C4. The active and inactive phases of LN were defined as 4≤ and 0 of the renal SLEDAI score, respectively.
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pone.0126564.g005: Changes in antibody levels and clinical findings in patients with lupus nephritis.▲ LN1, ♦ LN2, ● LN3, ◊ LN4, ○ LN5, □ LN6, ■ LN7. (A) Anti-RRP8 antibody, (B) anti-TNP1 antibody, (C) SLEDAI, (D) anti-dsDNA antibody, (E) C3, and (F) C4. The active and inactive phases of LN were defined as 4≤ and 0 of the renal SLEDAI score, respectively.

Mentions: Among 11 patients with active LN, 7 were compared for their levels of anti-RRP8 and anti-TNP1 antibodies between the active (at onset) and inactive (after remission) phases. In the other 4 patients, the sera after remission had not been stocked. Both the anti-RRP8 and anti-TNP1 antibodies were significantly decreased in the inactive phase (Fig 5). The SLEDAI scores and the levels of anti-dsDNA antibodies were also decreased, and the levels of C3 and C4 were increased significantly, although some patients still retained high titers of anti-dsDNA antibodies or hypocomplementemia even after improvement of nephritis. In LN1, the level of anti-RRP8 antibody decreased from 11.7 units to 1.2 units after remission, whereas that of anti-dsDNA antibodies increased from 65.7 IU/ml to 77.8 IU/ml. In LN2, the level of anti-TNP1 antibody decreased from 11.9 units to 3.7 units after remission, whereas the level of anti-dsDNA antibodies increased from 24.9 IU/ml to 49.1 IU/ml. These findings suggest that the levels of anti-RRP8 and anti-TNP1 antibodies do not correlate with those of anti-dsDNA antibodies in some LN patients.


Novel Autoantigens Associated with Lupus Nephritis.

Onishi S, Adnan E, Ishizaki J, Miyazaki T, Tanaka Y, Matsumoto T, Suemori K, Shudou M, Okura T, Takeda H, Sawasaki T, Yasukawa M, Hasegawa H - PLoS ONE (2015)

Changes in antibody levels and clinical findings in patients with lupus nephritis.▲ LN1, ♦ LN2, ● LN3, ◊ LN4, ○ LN5, □ LN6, ■ LN7. (A) Anti-RRP8 antibody, (B) anti-TNP1 antibody, (C) SLEDAI, (D) anti-dsDNA antibody, (E) C3, and (F) C4. The active and inactive phases of LN were defined as 4≤ and 0 of the renal SLEDAI score, respectively.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476694&req=5

pone.0126564.g005: Changes in antibody levels and clinical findings in patients with lupus nephritis.▲ LN1, ♦ LN2, ● LN3, ◊ LN4, ○ LN5, □ LN6, ■ LN7. (A) Anti-RRP8 antibody, (B) anti-TNP1 antibody, (C) SLEDAI, (D) anti-dsDNA antibody, (E) C3, and (F) C4. The active and inactive phases of LN were defined as 4≤ and 0 of the renal SLEDAI score, respectively.
Mentions: Among 11 patients with active LN, 7 were compared for their levels of anti-RRP8 and anti-TNP1 antibodies between the active (at onset) and inactive (after remission) phases. In the other 4 patients, the sera after remission had not been stocked. Both the anti-RRP8 and anti-TNP1 antibodies were significantly decreased in the inactive phase (Fig 5). The SLEDAI scores and the levels of anti-dsDNA antibodies were also decreased, and the levels of C3 and C4 were increased significantly, although some patients still retained high titers of anti-dsDNA antibodies or hypocomplementemia even after improvement of nephritis. In LN1, the level of anti-RRP8 antibody decreased from 11.7 units to 1.2 units after remission, whereas that of anti-dsDNA antibodies increased from 65.7 IU/ml to 77.8 IU/ml. In LN2, the level of anti-TNP1 antibody decreased from 11.9 units to 3.7 units after remission, whereas the level of anti-dsDNA antibodies increased from 24.9 IU/ml to 49.1 IU/ml. These findings suggest that the levels of anti-RRP8 and anti-TNP1 antibodies do not correlate with those of anti-dsDNA antibodies in some LN patients.

Bottom Line: To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system.Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA.These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

No MeSH data available.


Related in: MedlinePlus