Moving towards a systems-based classification of innate immune-mediated diseases

Savic, Sinisa; Caseley, Emily A.; McDermott, Michael F.

doi:10.1038/s41584-020-0377-5

Cited by 65 publications

(97 citation statements)

References 141 publications

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“…Monocytes from patients with CF showed increased production of IL-1β and IL-18, which was associated with higher activity of caspase-1 and raised extracellular ASCs [28]; interestingly, inhibition of ENaC decreased the exacerbated secretion IL-1β and IL-18 only in monocytes with CF mutations, while this inhibitory effect was not seen in monocytes from patients with other inflammatory conditions [28]. Furthermore, the increased levels of IL-1β and IL-18 were also detected in the sera of patients with CF [28], indicating an essential role of these two cytokines in the pathogenesis of this disease, further supporting the autoinflammatory phenotype seen in patients with CF [31,175,176]. Moreover, the CFTR modulators Ivacaftor/Lumacaftor and Ivacaftor/Tezacaftor showed a powerful anti-inflammatory effect in patients with CF, reducing the levels of IL-18, and both IL-1β and IL-18, correspondingly, in monocytes and serum of patients with CF [177].…”

Section: Monocytesmentioning

confidence: 61%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

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Section: Monocytesmentioning

confidence: 61%

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

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“…Skewing towards myeloid cell production is also observed in chronic inflammation and autoimmune diseases. 48 Also, studies in murine autoimmune arthritis and systemic lupus erythematosus (SLE) models showed deregulation of haematopoiesis with skewing towards the myeloid lineage at the expense of lymphopoiesis. 49,50 Regarding signalling pathways, recently, Zhang et al showed that during LPS challenge, the TLR4-TRIF pathway impairs HSC function, whereas the TLR4-MyD88 pathway mainly affects myeloid lineage-committed cells.…”

Section: Alters Hsc Function and May Increase Genetic Alterationsmentioning

confidence: 99%

Microbial sensing by haematopoietic stem and progenitor cells: Vigilance against infections and immune education of myeloid cells

Sioud

2020

Scand J Immunol

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Bone marrow haematopoietic stem and progenitor cells (HSPCs) express pattern recognition receptors such as Toll-like receptors (TLRs) to sense microbial products and activation of these innate immune receptors induces cytokine expression and redirects bone marrow haematopoiesis towards the increased production of myeloid cells. Secreted cytokines by HSPCs in response to TLR ligands can act in an autocrine or paracrine manner to regulate haematopoiesis. Moreover, tonic activation of HSPCs by microbiota-derived compounds might educate HSPCs to produce superior myeloid cells equipped with innate memory responses to combat pathogens. While haematopoietic stem cell activation through TLRs meets the increased demand for blood leucocytes to protect the host against infection, persistent exposure to inflammatory cytokines or microbial products might impair their function and even induce malignant transformation. This review highlights the potential outcomes of HSPCs in response to TLR ligands. How to cite this article: Sioud M. Microbial sensing by haematopoietic stem and progenitor cells: Vigilance against infections and immune education of myeloid cells.

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“…Several monogenic autoinflammatory syndromes have been characterized that lead to erroneous assembly of the inflammasome, causing dramatic IL‐1β‐driven inflammatory responses. These disorders can be collectively referred to as inflammasomopathies and arise from defects in the NLRP and pyrin sensors ( NLRP1, NLRP3, NLRP12, NLRC4, MEFV ), pyrin metabolism ( MVK ) and pyrin‐actin cytoskeleton organization ( PSTPIP1, WDR1, ARPC1B ) required for inflammasome assembly 116,163 . The NLR family of pattern‐recognition receptors are a group of proteins that are highly conserved across species 14,164 .…”

Section: Primary Immunodeficiencies Caused By Immunological Gain‐of‐fmentioning

confidence: 99%

“…Here, we will discuss the most well‐described monogenic inflammasomopathies of the NLRP and pyrin sensors. Reviews of the other pyrin inflammasome‐mediated autoinflammatory disorders can be found elsewhere 163,172 …”

Section: Primary Immunodeficiencies Caused By Immunological Gain‐of‐fmentioning

confidence: 99%

“…The process of ubiquitination crucially orchestrates NF‐κB signaling 216 . Further complicating the picture, patients with deficiencies in genes encoding components of the linear ubiquitin chain assembly complex (LUBAC) such as HOIL‐1 and HOIP actually present with recurrent bacterial infections 163 . This can be explained because these mutations specifically lead to absent NF‐κB activity in fibroblasts and B‐cells, whereas NF‐κB activity is increased in monocytes 224 .…”

Section: Primary Immunodeficiencies Caused By Immunological Gain‐of‐fmentioning

confidence: 99%

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Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

Made

Hoischen

Netea

et al. 2020

Immunological Reviews

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In the last decade, the paradigm of primary immunodeficiencies (PIDs) as rare recessive familial diseases that lead to broad, severe, and early‐onset immunological defects has shifted toward collectively more common, but sporadic autosomal dominantly inherited isolated defects in the immune response. Patients with PIDs constitute a formidable area of research to study the genetics and the molecular mechanisms of complex immunological pathways. A significant subset of PIDs affect the innate immune response, which is a crucial initial host defense mechanism equipped with pattern‐recognition receptors. These receptors recognize pathogen‐ and damage‐associated molecular patterns in both the extracellular and intracellular space. In this review, we will focus on primary immunodeficiencies caused by genetic defects in cytosolic pattern‐recognition receptor pathways. We discuss these PIDs organized according to their mutational mechanisms and consequences for the innate host response. The advanced understanding of these pathways obtained by the study of PIDs creates the opportunity for the development of new host‐directed treatment strategies.

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Moving towards a systems-based classification of innate immune-mediated diseases

Abstract: This is a repository copy of Moving towards a systems-based classification of innate immune-mediated diseases.

Cited by 65 publications

References 141 publications

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Microbial sensing by haematopoietic stem and progenitor cells: Vigilance against infections and immune education of myeloid cells

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

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