Highlights • TNF (despite its name) failed clinical trials as an anti-cancer agent. • TNF is a critical component of cell death and inflammation. • Therapeutic blockade of TNF by mAbs and TNFR-fusion ...proteins ameliorates inflammatory diseases. • Anti-TNF biologics are currently being investigated in neuropathology. • New anti-TNF therapeutics are required to simultaneously permit TNF's role in normal biology and/or selectively block individual TNFR pathways.
The formal recognition and genetic understanding of the autoinflammatory diseases has defined mechanisms of self-directed inflammation that are independent of adaptive immunity.
Diverse physiological and pathological conditions that impact on protein folding of the endoplasmic reticulum (ER) cause ER stress. The unfolded protein response (UPR) and the ER-associated ...degradation (ERAD) pathway are activated to cope with ER stress. In rheumatoid arthritis (RA), inflammation and ER stress work in parallel by driving inflammatory cells to release cytokines that induce chronic ER stress pathways. This chronic ER stress may contribute to the pathogenesis of RA through synoviocyte proliferation and proinflammatory cytokine production. Therefore, ER stress pathways and their constituent elements are attractive targets for RA drug development. In this review, we integrate current knowledge of the contribution of ER stress to the overall pathogenesis of RA, and suggest some therapeutic implications of these discoveries.
ER stress and the subsequent UPR play complex, but complementary, roles in the pathogenesis of RA.
Inflammatory cytokines, autoantibodies, hypoxia, and low glucose levels, which are among the essential pathological hallmarks of RA, may act in concert as ER stressors in the synovium.
Both conventional and unconventional UPR signaling pathways are involved in proinflammatory cytokine production and the development of the apoptosis-resistant phenotype of synovial cells in RA.
GRP78/BiP plays a Janus-like role in the inflammatory milieu and pathogenesis of RA, and both its administration and inhibition have potential therapeutic benefits in the management of patients with RA.
Targeting the IRE1 branch of the UPR as well as synoviolin, an ER-resident E3 ubiquitin ligase, may prevent some of the pathological features of RA and has significant therapeutic potential in RA.
The spectrum of systemic autoinflammatory disorders broadens continually. In part, this is due to the more widespread application of massive parallel sequencing, helping with novel gene discovery in ...this and other areas of rare diseases. Some of the conditions that have been described fit neatly into a conventional idea of autoinflammation. Others, such as interferon-mediated autoinflammatory diseases, are broadening the concept which we consider to be autoinflammatory disorders. There is also a widening of the clinical phenotypes associated with certain genetic mutations, as genetic testing is used more regularly and increasing numbers of patients are screened. It is also increasingly evident that both autoinflammatory and autoimmune problems are frequently seen as complications of primary immunodeficiency disorders. The aim of this review is to provide an update on some recently discovered conditions and to discuss how these disorders help to define the concept of autoinflammation. The review will also cover recent discoveries in the biology of innate-immune-mediated inflammation and describe how this has provided the biological rationale for using anti-interleukin-1 therapies in the treatment of many such conditions. Finally, we discuss the importance of recognising somatic mutations as causes of autoinflammatory clinical phenotypes and provide practical advice on how this could be tackled in everyday clinical practice.
The master pro-inflammatory cytokine, tumour necrosis factor (TNF), has been shown to modulate multiple signalling pathways, with wide-ranging downstream effects. TNF plays a vital role in the ...typical immune response through the regulation of a number of pathways encompassing an immediate inflammatory reaction with significant innate immune involvement as well as cellular activation with subsequent proliferation and programmed cell death or necrosis. As might be expected with such a broad spectrum of cellular effects and complex signalling pathways, TNF has also been implicated in a number of disease states, such as rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease. Since the time of its discovery over 40 years ago, TNF ligand and its receptors, TNF receptor (TNFR) 1 and 2, have been categorised into two complementary superfamilies, namely TNF (TNFSF) and TNFR (TNFRSF), and 19 ligands and 29 receptors have been identified to date. There have been significant advances in our understanding of TNF signalling pathways in the last decade, and this short review aims to elucidate some of the most recent advances involving TNF signalling in health and disease.
Autoinflammation as a distinct disease category was first reported in 1999 as a group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation, known as ...periodic fever syndromes. Since this original description, the focus has shifted considerably to the inclusion of complex multifactorial conditions with an autoinflammatory basis. Furthermore, the boundaries of what are considered to be autoinflammatory disorders are constantly evolving and currently encompass elements of immunodeficiency and autoimmunity. Notable developments in the intervening 20 years include substantial progress in understanding how the different inflammasomes are activated, how infection is sensed by the innate immune system and how intracellular signalling systems are consequently activated and integrated with many different cellular functions in the autoinflammatory process. With these developments, the field of autoinflammation is moving from a gene-centric view of innate immune-mediated disease towards a systems-based concept, which describes how various convergent pathways, including pyrin and the actin cytoskeleton, protein misfolding and cellular stress, NF-κB dysregulation and interferon activation, contribute to the autoinflammatory process. The development and adoption of a systems-based concept of systemic autoinflammatory diseases is anticipated to have implications for the development of treatments that target specific components of the innate immune system.
The list of genes associated with systemic inflammatory diseases has been steadily growing because of the explosion of new genomic technologies. Significant advances in the past year have deepened ...our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: haploinsufficiency of A20, otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis.
The scope of autoinflammation has been broadened to include defects in deubiquitination and cellular redox homeostasis. At the clinical level, we discuss the biological rationale for treatment with cytokine inhibitors and colchicine in respective conditions and the use of interleukin-1 antagonism for diagnostic and therapeutic purposes in the management of undifferentiated autoinflammatory disorders.
Gene discoveries coupled with studies of molecular function provide knowledge into the biology of inflammatory responses and form the basis for genomically informed therapies. Diseases of dysregulated ubiquitination constitute a novel category of human inflammatory disorders.
The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are ...characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.
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