Role of toll-like receptors in systemic sclerosis

2013 ◽  
Vol 15 ◽  
Author(s):  
Marzena Ciechomska ◽  
Rachel Cant ◽  
James Finnigan ◽  
Jacob M. van Laar ◽  
Steven O'Reilly
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Current Knowledge ◽  
Cell Damage ◽  
Gene Signature ◽  
Signalling Pathways ◽  
Toll Like Receptors ◽  
Systemic Autoimmune Diseases ◽  
Intracellular Signalling Pathways

Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target.

Role of Positron Emission Tomography for Central Nervous System Involvement in Systemic Autoimmune Diseases: Status and Perspectives

2018 ◽  
Vol 25 (26) ◽  
pp. 3096-3104 ◽  
Author(s):  
Daniele Mauro ◽  
Gaetano Barbagallo ◽  
Salvatore D`Angelo ◽  
Pasqualina Sannino ◽  
Saverio Naty ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Central Nervous System ◽  
Nervous System ◽  
Autoimmune Diseases ◽  
Pet Imaging ◽  
Emission Tomography ◽  
Cns Involvement ◽  
Systemic Autoimmune Diseases ◽  
Positron Emission

In the last years, an increasing interest in molecular imaging has been raised by the extending potential of positron emission tomography [PET]. The role of PET imaging, originally confined to the oncology setting, is continuously extending thanks to the development of novel radiopharmaceutical and to the implementation of hybrid imaging techniques, where PET scans are combined with computed tomography [CT] or magnetic resonance imaging[MRI] in order to improve spatial resolution. Early preclinical studies suggested that 18F–FDG PET can detect neuroinflammation; new developing radiopharmaceuticals targeting more specifically inflammation-related molecules are moving in this direction. Neurological involvement is a distinct feature of various systemic autoimmune diseases, i.e. Systemic Lupus Erythematosus [SLE] or Behcet’s disease [BD]. Although MRI is largely considered the gold-standard imaging technique for the detection of Central Nervous System [CNS] involvement in these disorders. Several patients complain of neuropsychiatric symptoms [headache, epilepsy, anxiety or depression] in the absence of any significant MRI finding; in such patients the diagnosis relies mainly on clinical examination and often the role of the disease process versus iatrogenic or reactive forms is doubtful. The aim of this review is to explore the state-of-the-art for the role of PET imaging in CNS involvement in systemic rheumatic diseases. In addition, we explore the potential role of emerging radiopharmaceutical and their possible application in aiding the diagnosis of CNS involvement in systemic autoimmune diseases.

scholarly journals The Neuroinflammatory Role of Pericytes in Epilepsy

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 759
Author(s):  
Gaku Yamanaka ◽  
Fuyuko Takata ◽  
Yasufumi Kataoka ◽  
Kanako Kanou ◽  
Shinichiro Morichi ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Current Knowledge ◽  
Morphological Changes ◽  
Cell Damage ◽  
Neurovascular Unit ◽  
Experimental Studies ◽  
Intractable Epilepsy ◽  
In Vivo Studies

Pericytes are a component of the blood–brain barrier (BBB) neurovascular unit, in which they play a crucial role in BBB integrity and are also implicated in neuroinflammation. The association between pericytes, BBB dysfunction, and the pathophysiology of epilepsy has been investigated, and links between epilepsy and pericytes have been identified. Here, we review current knowledge about the role of pericytes in epilepsy. Clinical evidence has shown an accumulation of pericytes with altered morphology in the cerebral vascular territories of patients with intractable epilepsy. In vitro, proinflammatory cytokines, including IL-1β, TNFα, and IL-6, cause morphological changes in human-derived pericytes, where IL-6 leads to cell damage. Experimental studies using epileptic animal models have shown that cerebrovascular pericytes undergo redistribution and remodeling, potentially contributing to BBB permeability. These series of pericyte-related modifications are promoted by proinflammatory cytokines, of which the most pronounced alterations are caused by IL-1β, a cytokine involved in the pathogenesis of epilepsy. Furthermore, the pericyte-glial scarring process in leaky capillaries was detected in the hippocampus during seizure progression. In addition, pericytes respond more sensitively to proinflammatory cytokines than microglia and can also activate microglia. Thus, pericytes may function as sensors of the inflammatory response. Finally, both in vitro and in vivo studies have highlighted the potential of pericytes as a therapeutic target for seizure disorders.

scholarly journals Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Gianchecchi ◽  
Domenico V. Delfino ◽  
Alessandra Fierabracci
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

scholarly journals Atypical Chemokine Receptors in Cardiovascular Disease

2019 ◽  
Vol 119 (04) ◽  
pp. 534-541 ◽  
Author(s):  
Selin Gencer ◽  
Emiel van der Vorst ◽  
Maria Aslani ◽  
Christian Weber ◽  
Yvonne Döring ◽  
...  
Keyword(s):  
G Protein ◽  
Chemokine Receptors ◽  
Cellular Response ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Signalling Pathways ◽  
Atherosclerosis Development ◽  
G Protein Coupled ◽  
Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

scholarly journals Beverages in Rheumatoid Arthritis: What to Prefer or to Avoid

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3155 ◽  
Author(s):  
Mrinalini Dey ◽  
Maurizio Cutolo ◽  
Elena Nikiphorou
Keyword(s):  
Rheumatoid Arthritis ◽  
Patient Management ◽  
Current Knowledge ◽  
Signalling Pathways ◽  
Main Body ◽  
Future Studies ◽  
Downstream Effects ◽  
Controversial Topic ◽  
Diet And Lifestyle

Background: The role of nutrition in the pathogenesis of rheumatic diseases, including rheumatoid arthritis (RA), has gained increasing attention in recent years. A growing number of studies have focussed on the diverse nutritional contents of beverages, and their possible role in the development and progression of RA. Main body: We aimed to summarise the current knowledge on the role of a range of beverages in the context of RA. Beverages have a key role within the mosaic of autoimmunity in RA and potential to alter the microbiome, leading to downstream effects on inflammatory pathways. The molecular contents of beverages, including coffee, tea, and wine, have similarly been found to interfere with immune signalling pathways, some beneficial for disease progression and others less so. Finally, we consider beverages in the context of wider dietary patterns, and how this growing body of evidence may be harnessed by the multidisciplinary team in patient management. Conclusions: While there is increasing work focussing on the role of beverages in RA, integration of discussions around diet and lifestyle in our management of patients remains sparse. Nutrition in RA remains a controversial topic, but future studies, especially on the role of beverages, are likely to shed further light on this in coming years.

scholarly journals The Many Faces of Interleukin-6: The Role of IL-6 in Inflammation, Vasculopathy, and Fibrosis in Systemic Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Theresa C. Barnes ◽  
Marina E. Anderson ◽  
Robert J. Moots
Keyword(s):  
Systemic Sclerosis ◽  
Endothelial Cell ◽  
Interleukin 6 ◽  
Signalling Pathways ◽  
Endothelial Cell Dysfunction ◽  
Potential Therapeutic Target ◽  
Cell Dysfunction ◽  
Significant Interest ◽  
The Many

Interleukin-6 is currently attracting significant interest as a potential therapeutic target in systemic sclerosis (SSc). In this paper, the biology of interleukin-6 is reviewed, and the evidence for interleukin-6 dysregulation in SSc is explored. The role of inteleukin-6 classical and trans signalling pathways in SSc relevant phenomena such as chronic inflammation, autoimmunity, endothelial cell dysfunction, and fibrogenesis is discussed. The existing evidence that interventions designed to block interleukin-6 signalling are of therapeutic relevance in SSc is evaluated.

scholarly journals Chemokines: understanding their role in T-lymphocyte biology

1998 ◽  
Vol 333 (3) ◽  
pp. 457-470 ◽  
Author(s):  
Stephen G. WARD ◽  
John WESTWICK
Keyword(s):  
T Lymphocytes ◽  
Chemokine Receptors ◽  
Protein Tyrosine Kinase ◽  
Cell Function ◽  
Signalling Pathways ◽  
Cc Chemokine ◽  
Intracellular Signalling Pathways ◽  
And Function ◽  
Hiv 1

The chemokines are a complex superfamily of small, secreted proteins that were initially characterized through their chemotactic effects on a variety of leucocytes. The superfamily is divided into families based on structural and genetic considerations and have been termed the CXC, CC, C and CX3C families. Chemokines from these families have a key role in the recruitment and function of T lymphocytes. Moreover, T lymphocytes have also been identified as a source of a number of chemokines. T lymphocytes also express most of the known CXC and CC chemokine receptors to an extent that depends on their state of activation/differentiation and/or the activating stimuli. The expression of two chemokine receptors, namely CXCR4 and CCR5, together with the regulated production of their respective ligands, appears to be extremely important in determining sensitivity of T cells to HIV-1 infection. The intracellular events which mediate the effects of chemokines, particularly those elicited by the CC chemokine RANTES, include activation of both G-protein- and protein tyrosine kinase-coupled signalling pathways. The present review describes our current understanding of the structure and expression of chemokines and their receptors, the effects of chemokines on T-cell function(s), the intracellular signalling pathways activated by chemokines and the role of certain chemokines and chemokine receptors in determining sensitivity to HIV-1 infection.

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