A novel DNA/histone H4 peptide complex detects autoantibodies in systemic lupus erythematosus sera

Panza, Filomena; Alcaro, Maria C.; Petrelli, Fiorella; Angelotti, Francesca; Pratesi, Federico; Rovero, Paolo; Migliorini, Paola

doi:10.1186/s13075-016-1117-8

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…25 Moreover, peptides derived from histone H4 have been shown to be peptide autoepitopes that are recognized by T cells in both human and murine lupus, 26 and autoantibodies against the DNA/histone H4 peptide complex could be detected in the sera of 56% of a cohort of patients with SLE. 27 However, histone H4 is encoded by multiple genes and the functional differences of HIST1H4K with other histone H4 coding genes are not yet known. Thus, the pathogenetic role of increased expression of HIST1H4K in patients with SLE requires further study.…”

Section: Discussionmentioning

confidence: 99%

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus

Hc²,

et al. 2018

Lupus

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Objective To investigate whether the aberrant expression of non-coding RNAs (ncRNAs) in T cells from patients with systemic lupus erythematosus (SLE) could contribute to the pathogenesis of lupus. Methods Expression profiles of RNA transcripts in T cells from three patients with SLE and three controls were analyzed by microarray analysis. Potentially aberrant-expressed ncRNAs were validated using T cell samples from 23 patients with SLE and 17 controls. Transfection studies and microarray analyses were conducted to search for any gene expression that is regulated by specific ncRNAs. Results Initial analysis revealed differential expression of 18 ncRNAs in SLE T cells. After validation, decreased expression of H/ACA box small nucleolar RNA 12 (SNORA12) was confirmed in SLE T cells (0.69-fold, P = 0.007) compared with normal T cells, and its expression level was inversely associated with higher SLE disease activity scores. Jurkat cells transfected with a plasmid encoding SNORA12 showed increased expression of two genes and decreased expression of 15 genes in Jurkat cells. These changes of gene expression were significantly associated with the SLE pathway in the Kyoto Encyclopedia of Genes and Genomes map using microarray analysis. Overexpression of SNORA12 altered the expression of CD69, decreased the expression of histone cluster 1 H4 family member k (HIST1H4K), inhibited the secretion of interferon gamma and the expression of HIST1H4K was increased in SLE T cells. Conclusion Among the ncRNAs, we found that the expression level of SNORA12, which belongs to the family of small nucleolar RNAs, was lower in SLE T cells and affected T cell function. This novel finding suggests that aberrant-expressed snoRNAs lead to dysfunction of T cells and may be involved in the immunopathogenesis of SLE.

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Section: Discussionmentioning

confidence: 99%

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus

Hc²,

et al. 2018

Lupus

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“…However, the materials used in assays limit their utilization, and researchers have been working on developing new suitable assays with high sensitivity and specificity. Panza et al explored a novel assay that uses complexed histone peptides (PK201/CAT plasmid) with a fragment from Crithidia luciliae, which has more simple procedures (61). We utilized trypoanosoma equiperdum (TE) that containing uniformed dsDNA but no histone in the cell nucleus or kinetonucleus, which is much easier for purification with a simpler structure (62).…”

Section: The Detection Of Anti-dsdna Antibodiesmentioning

confidence: 99%

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

2019

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Systemic lupus erythematosus (SLE) is characterized by high-titer serological autoantibodies, including antibodies that bind to double-stranded DNA (dsDNA). The origin, specificity, and pathogenicity of anti-dsDNA antibodies have been studied from a wider perspective. These autoantibodies have been suggested to contribute to multiple end-organ injuries, especially to lupus nephritis, in patients with SLE. Moreover, serum levels of anti-DNA antibodies fluctuate with disease activity in patients with SLE. By directly binding to self-antigens or indirectly forming immune complexes, anti-dsDNA antibodies can accumulate in the glomerular and tubular basement membrane. These autoantibodies can also trigger the complement cascade, penetrate into living cells, modulate gene expression, and even induce profibrotic phenotypes of renal cells. In addition, the expression of suppressor of cytokine signaling 1 is reduced by anti-DNA antibodies simultaneously with upregulation of profibrotic genes. Anti-dsDNA antibodies may even participate in the pathogenesis of SLE by catalyzing hydrolysis of certain DNA molecules or peptides in cells. Recently, anti-dsDNA antibodies have been explored in greater depth as a therapeutic target in the management of SLE. A substantial amount of data indicates that blockade of pathogenic anti-dsDNA antibodies can prevent or even reverse organ damage in murine models of SLE. This review focuses on the recent research advances regarding the origin, specificity, classification, and pathogenicity of anti-dsDNA antibodies and highlights the emerging therapies associated with them.

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“…When modified histones are exposed to the immune system in the extracellular space, they are recognized as foreign and dangerous by receptors of the innate immune system, such as TLRs. Therefore, the H4/PK assay is usually a reliable and simple test that is valuable for the differential diagnosis and evaluation of symptomatic activity in SLE patients (26).…”

Section: Discussionmentioning

confidence: 99%

Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects

Arneth

2019

Front. Immunol.

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Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs. The pathogenesis of SLE remains unclear, with numerous studies pointing to a combination of genetic and environmental factors. A critical stage in SLE development is cell necrosis, in which undegraded chromatin and nucleoproteins are released into the blood, resulting in circulating cell-free DNA and serum nucleoproteins that trigger anti-dsDNA autoantibody production. This systematic literature review aimed to examine whether SLE stems from a DNA degradation and elimination defect. Materials and Methods: An advanced literature search was conducted in PubMed using the following keywords: [(“SLE” OR “Systemic Lupus Erythematosus” OR “Lupus”)] AND [(“DNA” OR “DNA Degradation”)] AND [(“Defect Elimination”)]. More articles were obtained from the references of the identified articles and basic Google searches. Twenty-five peer-reviewed articles published within the past 10 years (2007–2018) were included for review. Results: The findings of each study are summarized in Tables 1 , 2 . Discussion and Conclusion: The etiopathogenesis of SLE remains controversial, which limits therapeutic inventions for this disease. However, SLE is a DNA degradation and elimination disorder caused by uncleared histones and nuclear material that leak into the extracellular space and form cell-free DNA, triggering an immune response that destroys tissues and organs. Under normal conditions, apoptosis allows DNA and other nuclear material to be efficiently cleared through degradation and additional complex mechanisms such that this material does not trigger the immune system to produce nuclear autoantibodies.

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A novel DNA/histone H4 peptide complex detects autoantibodies in systemic lupus erythematosus sera

Cited by 4 publications

References 34 publications

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus

Decreased T cell expression of H/ACA box small nucleolar RNA 12 promotes lupus pathogenesis in patients with systemic lupus erythematosus

Anti-double Stranded DNA Antibodies: Origin, Pathogenicity, and Targeted Therapies

Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects

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