Antibodies from systemic lupus erythematosus (SLE) sera define differential release of autoantigens from cell lines undergoing apoptosis

Huggins, Mary L.; Todd, Ian; Cavers, M; Pavuluri, Sivapriya; Tighe, Patrick J.; Powell, R J

doi:10.1046/j.1365-2249.1999.01063.x

Cited by 29 publications

(14 citation statements)

References 24 publications

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“…26 However, H1 was only detected in cell lysates of Jurkat cells, but not in U937. Other studies showed that Jurkat cells and human activated lymphocytes accumulate nucleosomes in the cytoplasm during apoptosis.…”

Section: Discussionmentioning

confidence: 94%

Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Gabler

Blank

Hieronymus

et al. 2004

Annals of the Rheumatic Diseases

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Objective: To evaluate the presence of histones and nucleosomes in cell lysates of freshly isolated peripheral blood mononuclear cells (PBMC), fully activated lymphoblasts, or lymphoblasts after induction of apoptosis. Methods: Each histone class (H1, H2A, H2B, H3, and H4) was detected by western blot analysis with specific antibodies. Annexin V/propidium iodide (PI) staining was performed for each treatment to distinguish viable, early, and late apoptotic, and necrotic cells. DNA degradation was evaluated by PI staining in a hypotonic buffer. Results: All five histones were detected in cell lysates of activated lymphoblasts in higher concentrations than in lysates of PBMC. An additional significant increase of H2A, H2B, H3, H4, and complete nucleosomes in cell lysates of lymphoblasts was found during interleukin (IL)2 deprivation for 8 or 24 hours. The content of these histones or nucleosomes in cell lysates decreased after delayed IL2 readdition. H1 content in cell lysates was not affected by IL2 deprivation or addition. Quantities of H2A, H2B, H3, and H4 in cell lysates correlated significantly with signs of early apoptosis. UV-B light exposure or etoposide treatment of lymphoblasts resulted in a distinct increase for each histone class in cell lysates compared with standard curves. No bands for post-translationally modified histones were detected in cell lysates in contrast with signals in nuclear preparations. Conclusion: Extranuclear accumulation of histones and nucleosomes is an early event of apoptosis in human lymphoblasts. Dysregulation of early apoptosis might support the induction of autoimmunity against nuclear components.

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Section: Discussionmentioning

confidence: 94%

Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Gabler

Blank

Hieronymus

et al. 2004

Annals of the Rheumatic Diseases

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“…It will be important to characterize specific antigen targets being recognized by the autoantibodies to find clues to the mechanism of lost tolerance. Based on many studies linking apoptosis to autoimmune responses (Casciola-Rosen et al, 1994;Huggins et al, 1999;van Nieuwenhuijze et al, 2003;Hall et al, 2004), we have hypothesized that silica-associated autoimmunity may be triggered through apoptotic events that expose new or modified epitopes that become antigenic (Brown et al, 2004b;Pfau et al, 2004). It is possible that there is a similar mechanism with asbestos since it has also been reported to cause apoptosis by defined pathways (Hamilton et al, 1996;Shukla et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Asbestos-Induced Autoimmunity in C57Bl/6 Mice

Pfau

Sentissi

et al. 2008

Journal of Immunotoxicology

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Environmental impacts on autoimmunity have significant public health implications. Epidemiological studies have shown associations between exposure to airborne silicates, such as crystalline silica or asbestos, and autoimmunity, but the etiology remains unclear. The purpose of this study was to test the hypothesis that asbestos could lead to a specific pattern of autoantibodies and pathology indicative of systemic autoimmune disease (SAID). Female C57Bl/6 mice were instilled intratracheally with 2 doses × 60 µg/mouse of amphibole asbestos (tremolite), wollastonite (a nonfibrogenic control fiber), or saline alone. Serum samples were collected and urine was checked for protein bi-weekly for 7 months. By 26 weeks, the asbestos-instilled animals had a significantly higher frequency of positive anti-nuclear antibody (ANA) tests compared to wollastonite and saline groups. The majority of positive ANAs showed homogeneous or combined homogeneous/speckled patterns, and tested positive for antibodies to dsDNA and SSA/Ro 52. Serum isotyping showed no significant changes in IgM, IgA, or IgG subclasses. However, there was an overall decrease in the mean IgG serum concentration in asbestos-instilled mice. IgG immune complex deposition was demonstrated in the kidneys of asbestos-instilled mice, with evidence of glomerular and tubule abnormalities suggestive of glomerulonephritis. Flow cytometry demonstrated moderate changes in the percentages of CD25 + Tsuppressor cells and B1a B-cells in the superficial cervical lymph nodes of the asbestos-instilled mice. These data demonstrate that asbestos leads to immunologic changes consistent with the development of autoimmunity. This study provides a non-autoimmune prone murine model for use in future elucidation of mechanisms involved in asbestos-induced autoimmune disease.

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“…In animal models of autoimmune disease, such as experimental allergic encephalomyelitis and collagen-induced arthritis, tolerance is broken by activating T cells present in the repertoire by immunization with appropriate Ags under inflammatory conditions (37)(38)(39)(40)(41). In the case of human autoimmune diseases, many factors have been proposed to mediate the breakage of T cell tolerance including cross-reactive microbial proteins or superantigens, environmental irritants, nonspecific tissue injury with exposure of normally cryptic Ags, and modification of protein Ags, which renders them immunogenic (3,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Several proteins associated with autoimmune disorders are, for example, cleaved during apoptosis (17, 19 -20, 23).…”

Section: Discussionmentioning

confidence: 99%

Distinct Autoreactive T Cell Responses to Native and Fragmented DNA Topoisomerase I: Influence of APC Type and IL-2

Oriss

Wright

2001

The Journal of Immunology

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Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which T cell responses to various autoantigens, including DNA topoisomerase I (Topo I), have been implicated. We investigated whether dendritic cells, generally considered to be the most potent APCs for the initiation of immune responses, would present either of two forms of Topo I to T cells more efficiently than PBMC APCs. Using cells from healthy controls and SSc patients, several important observations were made. First, neither APC type was able to initiate T cell proliferative responses to full-length native Topo I unless exogenous IL-2 was added. This is in contrast to vigorous T cell proliferation in response to Topo I polypeptide fragments presented by either APC type. Second, T cell responses to the full-length form of Topo I presented by dendritic cells were considerably lower than responses to Ag presented by PBMC APCs. Finally, no secondary T cell responses were observed unless the same Ag/APC combination as that used in the primary stimulation was maintained. These data indicate that different peptides are generated based upon the form of the Topo I and the APC that processes it. Taken together, these results suggest that a very specific combination of antigenic form and APC may be involved in breaking tolerance to Topo I in the early stages of development of SSc.

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Antibodies from systemic lupus erythematosus (SLE) sera define differential release of autoantigens from cell lines undergoing apoptosis

Cited by 29 publications

References 24 publications

Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Extranuclear detection of histones and nucleosomes in activated human lymphoblasts as an early event in apoptosis

Asbestos-Induced Autoimmunity in C57Bl/6 Mice

Distinct Autoreactive T Cell Responses to Native and Fragmented DNA Topoisomerase I: Influence of APC Type and IL-2

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