Comparison of CpG s-ODNs, chromatin immune complexes, and dsDNA fragment immune complexes in the TLR9-dependent activation of rheumatoid factor B cells

Marshak‐Rothstein, Ann; Busconi, Liliana; Lau, Christina M.; Tabor, Abigail S.; Leadbetter, Elizabeth A.; Akira, Shizuo; Krieg, Arthur Μ.; Lipford, Grayson B.; Viglianti, Gregory A.; Rifkin, Ian R.

doi:10.1177/09680519040100040801

Cited by 34 publications

(14 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent investigations provide evidence that TLR functions are not strictly limited to the recognition of exogenous, microbial antigens. TLRs were found to interact also with endogenous (host-derived) ligands [3] such as mammalian stress proteins [4], [5], degradation products of hyaluronic acid [6], beta defensin [7] and DNA fragments including (hypomethylated) CpG motifs [8]. The capacity to regulate innate and adaptive immune reactivity combined with the ability to recognize exogenous as well as autologous antigen ligands qualify TLRs for central roles not only in host resistance against microbial pathogens but also in the control of immunological tolerance and in the development of autoimmune disorders [9].…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice

et al. 2013

View full text Add to dashboard Cite

Background/ObjectiveToll-like receptors (TLR) mediate the recognition of microbial constituents and stress-induced endogenous ligands by the immune system. They may also be involved in the maintenance or break down of tolerance against autologous antigens. The aim of our investigation was to study the consequence of TLR4 deficiency on the development of insulin-deficient diabetes in the NOD mouse.MethodsThe TLR4 defect of the C57BL/10ScN mouse was backcrossed onto the NOD background and the effect of TLR4 deficiency on diabetes development was analysed by in vivo and in vitro studies.ResultsCompared to animals with wildtype TLR4 expression (TLR4+/+), female NOD mice carrying a homozygous TLR4 defect (TLR4−/−), showed significant acceleration of diabetes development, with a younger age at diabetes onset (TLR4+/+ 177±22 d, TLR−/−: 118±21 d; p<0.01). Pancreata of 120 d old TLR4−/− NOD mice revealed increased proportions of islets with advanced stages of immune cell infiltration compared to TLR4+/+ mice (p<0.05). TLR4 deficiency did not affect the susceptibility of islet cells to the beta cell damaging mediators nitric oxide or the inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interferon gamma. The lack of TLR4 further had no effect on the frequency of regulatory T-cells but reduced their capacity to inhibit T-cell proliferation.ConclusionsOur findings demonstrate that TLR4 deficiency results in an acceleration of diabetes development and immune cell infiltration of islets in NOD mice. We conclude that TLR4 is involved in the progression of the insulitis process thereby controlling the development of insulin-deficient diabetes in NOD mice.

show abstract

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice

et al. 2013

View full text Add to dashboard Cite

show abstract

“…We were subsequently able to confirm a role for TLR9 when the AM14 receptor was bred onto a TLR9-deficient background. However, although the response of TLR9-deficient AM14 cells was markedly reduced relative to wild-type B cells, it was consistently higher than the response of AM14 MyD88-deficient cells [12]. Importantly, the residual activity of the AM14 TLR9-deficient cells could be further reduced by chloroquine and s-ODN 2088 (Fig.…”

Section: The Role Of Tlr9 In the Activation Of Am14 B Cellsmentioning

confidence: 94%

The role of toll-like receptors in systemic autoimmune disease

Marshak‐Rothstein

Busconi

Lau

et al. 2005

International Congress Series

View full text Add to dashboard Cite

“…Notably, the TLR9 -/-AM14 response to anti-hapten/ 382 Busconi, Lau, Tabor et al haptenated DNA fragments was much more dramatically reduced. 12 We reasoned that the residual activity of TLR9 -/-AM14 B cells reflected either an IL-1/IL-18 dependent response to large chromatin-containing immune complexes, or the contribution of a TLR other than TLR9. To distinguish between these possibilities, the AM14 H and L chain were bred on to mice expressing the 3d mutation.…”

Section: Anti-nucleosome Mab Activation Of Am14 B Cells Is Partially mentioning

confidence: 99%

“…AM14 TLR9-deficient mice, described previously, 11,12 were bred and maintained in micro-isolator cages at the BUSM laboratory animal science center. The AM14 heavy and light chain transgenes have now also been crossed into mice that express the 3d mutation that disrupts signaling through TLR3, TLR7 and TLR9.…”

Section: Micementioning

confidence: 99%

DNA and RNA autoantigens as autoadjuvants

Busconi¹,

Lau²,

Tabor³

et al. 2006

J. Endotoxin Res.

Self Cite

View full text Add to dashboard Cite

AM14 B cells are a prototype for those low affinity autoreactive B cells that routinely mature as naïve cells in peripheral lymphoid tissues. These cells express a transgene-encoded receptor specific for IgG2a and can be effectively activated by immune complexes that incorporate either mammalian DNA or mammalian RNA that has been released from dead or dying cells. Activation depends on the ability of the B-cell receptor to deliver antigen to an internal vesicular compartment containing either Toll-like receptor-9 (TLR9) or TLR7. Since TLR9 and TLR7 are thought to recognize microbial DNA and RNA preferentially, it is important to determine under what conditions mammalian DNA and RNA become effective TLR ligands, and whether the determining factor is delivery or structure. This issue has been addressed by using IgG2a mAbs to deliver immune complexes preloaded with defined fragments of DNA or RNA, or by using modified ODNs/ORNs. The data demonstrate that only certain nucleic acid sequences or structures can induce autoreactive B-cell proliferation, even when delivery to the appropriate TLR compartment is facilitated by uptake through the B-cell receptor (BCR).

show abstract

Comparison of CpG s-ODNs, chromatin immune complexes, and dsDNA fragment immune complexes in the TLR9-dependent activation of rheumatoid factor B cells

Cited by 34 publications

References 27 publications

Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice

Toll-Like Receptor 4 Deficiency Accelerates the Development of Insulin-Deficient Diabetes in Non-Obese Diabetic Mice

The role of toll-like receptors in systemic autoimmune disease

DNA and RNA autoantigens as autoadjuvants

Contact Info

Product

Resources

About