Toll-like receptors in systemic autoimmune disease

Marshak‐Rothstein, Ann

doi:10.1038/nri1957

Cited by 983 publications

(891 citation statements)

References 127 publications

Supporting

Mentioning

866

Contrasting

Unclassified

Order By: Relevance

“…20 What could be the cause of the type I IFN signature in SSc patients? Infectious agents are suspected to be associated with the development and progression of SSc (reviewed in Hamamdzic et al 21 ), and therefore this may serve as a potential mechanism for the induction of type I IFN in this disease.…”

Section: Discussionmentioning

confidence: 99%

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

et al. 2009

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

et al. 2009

View full text Add to dashboard Cite

“…3c). The presence of an elevated steady-state number of apoptotic cells in these mutant mice is likely to contribute to the development of autoimmune disease 45 , as unremoved apoptoticcell debris presents danger signals and autoantigens 46,47 , and elevated numbers of apoptotic cells are often seen in the germinal centres of lymph nodes and other lymphoid organs in human autoimmune syndromes 48,49 . At the same time, apoptotic cells are known to have multiple immunomodulatory -but generally immunosuppressive -effects on APCs [50][51][52] .…”

Section: Tam Regulation Of Phagocytosismentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

show abstract

“…Since synergistic BCR and nucleic-acid sensing TLR signalling have been shown to activate autoreactive B cells and promote their expansion and differentiation to antibody-forming cells, TLR signalling in B6.NZBc13 B cells was investigated [6][7][8]. Poly(I:C), a dsRNA analogue, was found to enhance the proliferation and survival of congenic B cells in a cell-intrinsic manner.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, increased proportions of peripheral B cells expressing edited and endogenous heavy chains were observed in these anergized congenic mice, suggesting that the intrinsic B-cell defect in B6.NZBc13 mice alters peripheral B-cell selection and/ or survival. Furthermore, high titres of anti-chromatin and-Sm/ ribonucleoprotein (RNP) were observed.Since synergistic BCR and nucleic-acid sensing TLR signalling have been shown to activate autoreactive B cells and promote their expansion and differentiation to antibody-forming cells, TLR signalling in B6.NZBc13 B cells was investigated [6][7][8]. Poly(I:C), a dsRNA analogue, was found to enhance the proliferation and survival of congenic B cells in a cell-intrinsic manner.…”

mentioning

confidence: 99%

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

View full text Add to dashboard Cite

Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including hightitre anti-chromatin antibody production, abnormal B-and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. Keywords: Autoimmunity . B cells . TLRs Supporting Information available online IntroductionSystemic lupus erythematosus is a chronic autoimmune disorder characterized by the production of antibodies directed against nuclear antigens (ANAs). Similar to human lupus, the New Zealand Black (NZB) mouse produces antibodies directed against nuclear antigens, develops Coomb's positive hemolytic anaemia, and exhibits a number of phenotypic and functional B-cell abnormalities (reviewed in [1]). Although glomerulonephritis is mild in these mice, severe nephritis develops when the NZB background is crossed onto a permissive MHC haplotype (H-2 bm12 ), indicating that this mouse possesses a full complement of non-MHC lupus susceptibility genes [2].Generation of congenic mice, by introgression of homozygous chromosomal intervals from the NZB mouse strain onto a normal mouse C57BL/6 (B6) background, has been a particularly useful technique for characterizing susceptibility loci and their role in disease genesis [3]. In our mapping study of (B6 Â NZB) F 2 mice, we identified a locus on NZB chromosome (c) 13 that was linked to increased B-cell activation and abnormal IgM production [4]. To further characterize this locus, we generated congenic mice with an NZB c13 interval (denoted B6.NZBc13). B6.NZBc13 mice spontaneously developed autoimmunity characterized by hightitre IgM and IgG anti-chromatin antibody production, increased 527T-cell activation, expansion of DCs, and the development of mild glomerulonephritis [5]. Moreover, as predicted from our mapping study, B6.NZBc13 mice closely recapitulated the abnormal polyclonal B-cell activation and B-cell subset distribution...

show abstract

Toll-like receptors in systemic autoimmune disease

Cited by 983 publications

References 127 publications

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

Immunobiology of the TAM receptors

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

Contact Info

Product

Resources

About