Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identificantion of circulating DNA and renal localization of DNA-anti-DNA complexes.

Izui, Shozo; Lambert, Paul Henri; Fournié, Gilbert J.; Türler, Hans; Miescher, P. A.

doi:10.1084/jem.145.5.1115

Cited by 178 publications

(64 citation statements)

References 36 publications

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“…Indeed, LPS, a major TLR4 ligand, accelerates the disease when administered into BW mice and induces anti-ssDNA and anti-dsDNA Abs and IgG glomerular deposits in normal mice (34). In addition, transgenic mice that constitutively expressed the chaperone molecule gp96 and consequently overexpressed TLR4 on the cell surface developed a lupus-like disease probably due to an enforced TLR4 response to LPS since overexpression of the Tlr4 gene alone was sufficient to induce the disease (26).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram+ and Gram− bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.

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Section: Discussionmentioning

confidence: 99%

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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“…Kiyotaki et al (9) demonstrated that peripheral blood lymphocytes from active and inactive SLE patients produced anti-DNA antibodies when stimulated with DNA and T-subsets insensitive to antilymphocyte antibody. Polyclonal stimulator, e.g., bacterial lypopolysaccharide, caused the transformation of normal murine B-cells into anti-DNA antibody forming cells in vitro and in vivo (4,6,7,18). These lines of evidence have shown that B-cells are ready to convert to autoantibody producing cells when some information comes in.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Anti‐DNA Antibody Formation

Nakamura¹,

Akahoshi

Kashiwazaki

1986

Microbiology and Immunology

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The mechanism(s) of anti-DNA antibody formation was comparatively investigated using in vitro human and murine B-cell culture systems. T-cell homogenate (TH) from SLE patients converted normal human B-cells to anti-DNA specific antibody-forming plasma cells (anti-DNA-SPC) when cultured with calf thymic native DNA as antigen. TH of normal human donors suppressed the formation of anti-DNA-SPC from normal human B-cell cultures even when SLE TH and DNA were added to the cultures. B-cells derived from SLE patients were insensitive to normal human TH, and resulted in the formation of many anti-DNA-SPC. TH of young and old NZB mice stimulated the formation of anti-DNA-SPC from not only NZB but also C57BL/6 murine bone marrow cultures in the presence of DNA antigen. Human and murine TH, and both B-cell cultures were reciprocally combined to test whether xenogeneic TH stimulated B-cell cultures from different species. Xenogeneic TH was effective in triggering differentiation of xenogeneic B-cells with respect to anti-DNA-SPC. The elimination of helper T-subsets (Th) resulted in the generation of fewer anti-DNA-SPC, whereas the elimination of suppressor T-subsets (Ts) caused the formation of many anti-DNA-SPC. Among organ homogenates, e.g., liver, kidney and, brain, and T-cells from old NZB mice, TH was most effective in the stimulation of anti-DNA-SPC. The effective substance was sensitive to RNase-A, but resistant to pronase and DNase-I. Phenol extracted T-cell RNA retained its activity. We concluded that the functional modulation of helper T-cells, which reflects RNA molecules, could be the main etiology of autoantibody formation against DNA by both human and murine B-cells.Anti-DNA antibodies frequently observed in patients with autoimmune diseases, particularly in systemic lupus erythematosus (SLE), and sometimes in Sjogren's syndrome and rheumatoid arthritis, have been used to evaluate therapeutic effects and clinical features of patients. The mechanisms involved in anti-DNA antibodyformation have not yet been elucidated, and many of the basic immunological problems to be clarified are included in the topic of autoantibody-formation, e.g., the disruption of self tolerance, and the maintenance of immunological tolerance against 703

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“…Indeed, anti-DNA antibodies were eluted from kidneys of mice injected with LPS. However, the anti-DNA antibodies represented only a fraction of the immunoglobulins deposited in the kidneys, suggesting that other IC were also involved (10).…”

Section: Idiotypic Analysis Of the Immunoglobulins Eluted From Kidneymentioning

confidence: 99%

“…The estimated amount of anti-T15 idiotype antibodies was similar. Discussion A single injection of bacterial LPS in mice has been previously shown (10) to induce glomerular lesions associated with other features of systemic lupus erythematosus, such as the production of anti-DNA antibodies and circulating IC. The glomeruli showed only minimum histologic alterations, but electron microscopy demonstrated electron-dense deposits within the glomerular basement membrane, and immunofluorescence studies showed glomerular deposits of immunoglobulins and complement, suggesting the presence of IC.…”

Section: Idiotypic Analysis Of the Immunoglobulins Eluted From Kidneymentioning

confidence: 99%

“…It has been observed that polyclonal B cell activation, experimentally induced by B cell mitogens or naturally occurring in the course of some autoimmune or infectious diseases, is often associated with the production of circulating IC (3,5,10,11). This led to suggesting that a wide expression of the B cell repertoire, including rheumatoid factor-like antibodies and anti-idiotype autoantibodies, might generate IC formed by immunoglobulin interactions.…”

Section: Idiotypic Analysis Of the Immunoglobulins Eluted From Kidneymentioning

confidence: 99%

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Deposition of idiotype-anti-idiotype immune complexes in renal glomeruli after polyclonal B cell activation.

Goldman¹,

Rose²,

Hochmann³

et al. 1982

The Journal of Experimental Medicine

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We investigated the possible role of idiotypic interactions in the pathogenesis of the glomerular lesions observed in mice undergoing polyclonal B cell activation. BALB/c mice were studied for the presence of renal deposits of T15 idiotype-anti-T15 idiotype-immune complexes (IC) after injection of bacterial lipopolysaccharides (LPS). The T15 idiotype is the major idiotype of BALB/c mice anti-phosphorylcholine (PC) antibodies, which are cross-reactive with the idiotype of the TEPC-15 myeloma protein. This model was used because T15 idiotype-anti-T15 idiotype IC have been detected in the circulation of BALB/c mice after polyclonal B cell activation. First, an idiotype-specific immunofluorescence technique allowed us to detect T15 idiotype-bearing immunoglobulins in glomeruli from day 6 to day 28 after LPS injection. Second, fluorescein isothiocyanate-conjugated TEPC-15 myeloma protein was found to localize in the glomeruli after in vivo injection 18 d after LPS administration. This renal localization was shown to be idiotype-specific and could be quantified in a trace-labeling experiment. Third, kidney-deposited immunoglobulins of mice injected with LPS were eluted, radiolabeled, and analyzed by radioimmunoassay. Both T15 idiotype-bearing immunoglobulins and anti-T15 idiotype antibodies were detected in the eluates, providing further evidence for a renal deposition of T15 idiotype-anti-T15 idiotype IC. Polyclonal B cell activation is likely to result in a simultaneous triggering of many idiotypic clones and of corresponding anti-idiotypic clones represented in the B cell repertoire. This could lead to the formation of a variety of idiotype-anti-idiotype IC that could participate in the development of glomerular lesions.

show abstract

Features of systemic lupus erythematosus in mice injected with bacterial lipopolysaccharides: identificantion of circulating DNA and renal localization of DNA-anti-DNA complexes.

Cited by 178 publications

References 36 publications

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Mechanism of Anti‐DNA Antibody Formation

Deposition of idiotype-anti-idiotype immune complexes in renal glomeruli after polyclonal B cell activation.

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