Modulation of toll-like receptor function has therapeutic potential in autoimmune disease

Clanchy, Felix I. L.; Sacre, Sandra

doi:10.1517/14712598.2010.534080

Cited by 23 publications

(20 citation statements)

References 158 publications

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“…Activation of TLRs has been linked to the pathogenesis of various autoimmune inflammatory diseases including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease (Clanchy and Sacre, 2010). Among the TLR family members, TLR4 has been recognized as being important for islet cell inflammation and eventually β cell loss in the course of T1D development.…”

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

Wang

Cao

Wang

et al. 2015

Toxicology and Applied Pharmacology

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Section: Introductionmentioning

confidence: 99%

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

Wang

Cao

Wang

et al. 2015

Toxicology and Applied Pharmacology

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“…This indicates that the upstream mechanisms that generate inflammation are still functional and most likely unaffected by these treatments. Many studies from both murine and human models have suggested a role for a family of innate immune receptors, the Toll-like receptors (TLRs) in RA pathogenesis [5]. …”

Section: Introductionmentioning

confidence: 99%

Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance

et al. 2012

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IntroductionEndosomal toll-like receptors (TLRs) have recently emerged as potential contributors to the inflammation observed in human and rodent models of rheumatoid arthritis (RA). This study aims to evaluate the role of endosomal TLRs and in particular TLR7 in the murine collagen induced arthritis (CIA) model.MethodsCIA was induced by injection of collagen in complete Freund's adjuvant. To investigate the effect of endosomal TLRs in the CIA model, mianserin was administered daily from the day of disease onset. The specific role of TLR7 was examined by inducing CIA in TLR7-deficient mice. Disease progression was assessed by measuring clinical score, paw swelling, serum anti-collagen antibodies histological parameters, cytokine production and the percentage of T regulatory (Treg) cells.ResultsTherapeutic administration of mianserin to arthritic animals demonstrated a highly protective effect on paw swelling and joint destruction. TLR7-/- mice developed a mild arthritis, where the clinical score and paw swelling were significantly compromised in comparison to the control group. The amelioration of arthritis by mianserin and TLR7 deficiency both corresponded with a reduction in IL-17 responses, histological and clinical scores, and paw swelling.ConclusionsThese data highlight the potential role for endosomal TLRs in the maintenance of inflammation in RA and support the concept of a role for TLR7 in experimental arthritis models. This study also illustrates the potential benefit that may be afforded by therapeutically inhibiting the endosomal TLRs in RA.

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“…The increasing recognition that viruses, and in particular EBV, can be etiological factors driving the development of MS or other autoimmune diseases in genetically susceptible individuals further strengthens the potential of administering anti-viral therapies to people affected by these disorders [12]. In line with this view, the increased TLR7 gene expression observed upon IFN-β might be part of a specific antiviral program induced by this cytokine that could counteract dysregulated responses to viral infection in MS patients.Targeting TLRs and modulating their functions are increasingly recognized as potential therapeutics for different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and MS [15,53]. Indeed, a common trait of most autoimmune disorders is a chronic inflammation occurring at specific sites within the body or as a systemic complication suggested to be sustained also by TLR activation.…”

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confidence: 99%

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

et al. 2013

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The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN-β, a first-line therapy for relapsing-remitting MS patients, upon stimulation with TLR. IFN-β restored the frequency of TLR7-induced IgM and IgG-secreting cells in MS patients to the levels found in healthy donors, showing a specific deficiency in the TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS-derived PBMCs, TLR7-mediated production of IL-6 and the ex vivo expression of B-cell-activating factor of the TNF family, two crucial cytokines for B-cell differentiation and survival, were induced by IFN-β. Depletion of monocytes, which are key producers of both IL-6 and B-cellactivating factor of the TNF family, showed that TLR7-mediated B-cell differentiation into Ig-secreting cells is strongly dependent on the cross-talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS-affected individuals as compared with those from healthy donors, which was rescued by IFN-β therapy. Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN-β-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS.Keywords: B cell r IFN-β r Monocyte r Multiple sclerosis r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionGrowing evidence is accumulating on the central role that B lymphocytes play in the immunopathology of multiple sclerosis (MS) [1,2]. For example, oligoclonal IgG bands, found in the cerebrospinal fluid of more than 90% of patients with MS, indicate an intrathecal Ab production [3]. The presence of clonally Correspondence: Dr. Eliana Marina Coccia e-mail: eliana.coccia@iss.it expanded B cells, plasma cells, complement and myelin-specific Abs in chronic MS lesions also suggested an intrathecal, Agdriven humoral immune response in the central nervous system of MS sufferers [4][5][6]. In addition, B-cell follicle-like structures are detectable in the meninges of MS patients [7,8]. More recently, B-cell depleting therapies, such as Rituximab (that targets the B lymphocyte surface antigen CD20 [9][10][11]), together with * These authors contributed equally to this work. Eur. J. Immunol. 2013Immunol. . 43: 1963Immunol. -1972 Ocrelizumab and Ofatumumab (two other humanized anti-CD20 monoclonal Abs), are proving their efficacy at various stages of clinical development [12]. All together these findings contribute to the compelling evidence that B cells and the humoral immune response are implicated in the pathogenesis of MS and suggest the therapeutic implications that all this may have for the treatment of this disease. B lymphocytes play an essential role in bridging innate and adaptive immunity. To differentiate into specialized cells capable of communicating with helper T cells and undergo Ab divers...

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Modulation of toll-like receptor function has therapeutic potential in autoimmune disease

Cited by 23 publications

References 158 publications

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

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