Toll-uslični receptori u patogenezi sistemskog eritemskog lupusa [Toll-like receptors in pathogenesis of systemic lupus erythematosus]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperreactive B cells that produce autoantibodies against nucleic acids and related structures. In lupus-prone mice, Toll-like receptor 9 (TLR9) stimulation with DNA-containing immune complexes leads to autoreactive B cell survival and differentiation which could be abolished by chloroquine, a TLR9 signaling inhibitor otherwise used in SLE treatment. Also, patients are at increased risk of an infection. Activation of innate immunity via TLR4 is necessary for the resistance to Gram- bacteria, one of the leading causes of mortality in SLE. Here we investigated if chloroquine and low-dose corticosteroid treatment modulate the expression of TLR9 in B cells, TLR4 on monocytes, levels of circulating DNA and B-cell stimulatory cytokines in peripheral blood of SLE patients and controls. In vitro, we interrogated if chloroquine or steroids modulate B cell activation by synthetic TLR9 ligand CpGor monocyte activation by TLR4 ligand LPS. Results suggest that chloroquine inhibits TLR9-induced B cell activation in vitro and contributes to a decrease in serum DNA level ex vivo, without affecting the pro-inflammatory cytokine production vital for the adequate response to bacterial infection. Thus, investigation of activation and signalization mechanisms of the innate immune system receptors in patients contributes to understanding of SLE pathogenesis

RNA recognition by human TLR8 can lead to autoimmune inflammation.

Studies on the role of the RNA receptor TLR8 in inflammation have been limited by its different function in human versus rodents. We have generated multiple lines of transgenic mice expressing different levels of human TLR8. The high copy number chimeras were unable to pass germline; developed severe inflammation targeting the pancreas, salivary glands, and joints; and the severity of the specific phenotypes closely correlated with the huTLR8 expression levels. Mice with relatively low expression levels survived and bred successfully but had increased susceptibility to collagen-induced arthritis, and the levels of huTLR8 correlated with proinflammatory cytokines in the joints of the animals. At the cellular level, huTLR8 signaling exerted a DC-intrinsic effect leading to up-regulation of co-stimulatory molecules and subsequent T cell activation. A pathogenic role for TLR8 in human diseases was suggested by its increased expression in patients with systemic arthritis and the correlation of TLR8 expression with the elevation of IL-1β levels and disease status. We found that the consequence of self-recognition via TLR8 results in a constellation of diseases, strikingly distinct from those related to TLR7 signaling, and points to specific inflammatory diseases that may benefit from inhibition of TLR8 in humans

Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types

Toll-like receptors in pathogenesis of systemic lupus erythematosus

Sistemski eritemski lupus (SLE) je autoimunosna bolest karakterizirana hiperreaktivnim B-limfocitima od kojih neki stvaraju auto-antitijela na nukleinske kiseline i srodne antigene, te povećanim rizikom za infekcije. Animalni modeli SLE-a pokazali su da aktivacija Toll-u sličnog receptora 9 (TLR9) DNA-imunokompleksima stimulira i diferencira autoreaktivne B-limfocite. To se dokida blokadom TLR9 signalnog puta klorokinom, koji se uspješno koristi u liječenju SLE-a. Aktivacija urođene imunosti nakon prepoznavanja bakterijskih komponenata putem TLR4 pak je ključna za adekvatnu obranu od Gram- bakterija, važnog uzroka smrtnosti u SLE-u. Ovdje je istraženo da li liječenje klorokinom i niskim dozama kortikosteroida modulira izražaj TLR9 i TLR4 u B-limfocitima odnosno monocitima SLEbolesnika, te cirkulirajuću DNA i citokine koji aktiviraju B-limfocite (IL-10 i BAFF) ex vivo. In vitro je ispitan utjecaj lijekova na aktivaciju B-limfocita sintetskom DNA i produkciju IL-10 i BAFF-a, te na aktivaciju monocita i sekreciju TNF-α i IL-6 stimulacijom TLR4 signalnog puta lipopolisaharidom. Rezultati su pokazali da klorokin inhibira aktivaciju TLR9 u B-limfocitima in vitro, te pridonosi sniženju razine cirkulirajuće DNA, potencijalnog TLR9 liganda, ex vivo. Klorokin ujedno ne ometa prepoznavanje komponenata Gram- bakterija i sekreciju proupalnih citokina važnih za obranu od infekcije. Razumijevanje aktivacije i signalizacije receptora urođene imunosti važno je za razumijevanje patogeneze SLE-a i razvoj ciljanih terapija.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperreactive B cells that produce autoantibodies against nucleic acids and related structures. In lupus-prone mice, Toll-like receptor 9 (TLR9) stimulation with DNA-containing immune complexes leads to autoreactive B cell survival and differentiation which could be abolished by chloroquine, a TLR9 signaling inhibitor otherwise used in SLE treatment. Also, patients are at increased risk of an infection. Activation of innate immunity via TLR4 is necessary for the resistance to Gram- bacteria, one of the leading causes of mortality in SLE. Here we investigated if chloroquine and low-dose corticosteroid treatment modulate the expression of TLR9 in B cells, TLR4 on monocytes, levels of circulating DNA and B-cell stimulatory cytokines in peripheral blood of SLE patients and controls. In vitro, we interrogated if chloroquine or steroids modulate B cell activation by synthetic TLR9 ligand CpGor monocyte activation by TLR4 ligand LPS. Results suggest that chloroquine inhibits TLR9-induced B cell activation in vitro and contributes to a decrease in serum DNA level ex vivo, without affecting the pro-inflammatory cytokine production vital for the adequate response to bacterial infection. Thus, investigation of activation and signalization mechanisms of the innate immune system receptors in patients contributes to understanding of SLE pathogenesis

Toll-like receptors in pathogenesis of systemic lupus erythematosus

Sistemski eritemski lupus (SLE) je autoimunosna bolest karakterizirana hiperreaktivnim B-limfocitima od kojih neki stvaraju auto-antitijela na nukleinske kiseline i srodne antigene, te povećanim rizikom za infekcije. Animalni modeli SLE-a pokazali su da aktivacija Toll-u sličnog receptora 9 (TLR9) DNA-imunokompleksima stimulira i diferencira autoreaktivne B-limfocite. To se dokida blokadom TLR9 signalnog puta klorokinom, koji se uspješno koristi u liječenju SLE-a. Aktivacija urođene imunosti nakon prepoznavanja bakterijskih komponenata putem TLR4 pak je ključna za adekvatnu obranu od Gram- bakterija, važnog uzroka smrtnosti u SLE-u. Ovdje je istraženo da li liječenje klorokinom i niskim dozama kortikosteroida modulira izražaj TLR9 i TLR4 u B-limfocitima odnosno monocitima SLEbolesnika, te cirkulirajuću DNA i citokine koji aktiviraju B-limfocite (IL-10 i BAFF) ex vivo. In vitro je ispitan utjecaj lijekova na aktivaciju B-limfocita sintetskom DNA i produkciju IL-10 i BAFF-a, te na aktivaciju monocita i sekreciju TNF-α i IL-6 stimulacijom TLR4 signalnog puta lipopolisaharidom. Rezultati su pokazali da klorokin inhibira aktivaciju TLR9 u B-limfocitima in vitro, te pridonosi sniženju razine cirkulirajuće DNA, potencijalnog TLR9 liganda, ex vivo. Klorokin ujedno ne ometa prepoznavanje komponenata Gram- bakterija i sekreciju proupalnih citokina važnih za obranu od infekcije. Razumijevanje aktivacije i signalizacije receptora urođene imunosti važno je za razumijevanje patogeneze SLE-a i razvoj ciljanih terapija.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperreactive B cells that produce autoantibodies against nucleic acids and related structures. In lupus-prone mice, Toll-like receptor 9 (TLR9) stimulation with DNA-containing immune complexes leads to autoreactive B cell survival and differentiation which could be abolished by chloroquine, a TLR9 signaling inhibitor otherwise used in SLE treatment. Also, patients are at increased risk of an infection. Activation of innate immunity via TLR4 is necessary for the resistance to Gram- bacteria, one of the leading causes of mortality in SLE. Here we investigated if chloroquine and low-dose corticosteroid treatment modulate the expression of TLR9 in B cells, TLR4 on monocytes, levels of circulating DNA and B-cell stimulatory cytokines in peripheral blood of SLE patients and controls. In vitro, we interrogated if chloroquine or steroids modulate B cell activation by synthetic TLR9 ligand CpGor monocyte activation by TLR4 ligand LPS. Results suggest that chloroquine inhibits TLR9-induced B cell activation in vitro and contributes to a decrease in serum DNA level ex vivo, without affecting the pro-inflammatory cytokine production vital for the adequate response to bacterial infection. Thus, investigation of activation and signalization mechanisms of the innate immune system receptors in patients contributes to understanding of SLE pathogenesis

Toll-like receptors in pathogenesis of systemic lupus erythematosus

Sistemski eritemski lupus (SLE) je autoimunosna bolest karakterizirana hiperreaktivnim B-limfocitima od kojih neki stvaraju auto-antitijela na nukleinske kiseline i srodne antigene, te povećanim rizikom za infekcije. Animalni modeli SLE-a pokazali su da aktivacija Toll-u sličnog receptora 9 (TLR9) DNA-imunokompleksima stimulira i diferencira autoreaktivne B-limfocite. To se dokida blokadom TLR9 signalnog puta klorokinom, koji se uspješno koristi u liječenju SLE-a. Aktivacija urođene imunosti nakon prepoznavanja bakterijskih komponenata putem TLR4 pak je ključna za adekvatnu obranu od Gram- bakterija, važnog uzroka smrtnosti u SLE-u. Ovdje je istraženo da li liječenje klorokinom i niskim dozama kortikosteroida modulira izražaj TLR9 i TLR4 u B-limfocitima odnosno monocitima SLEbolesnika, te cirkulirajuću DNA i citokine koji aktiviraju B-limfocite (IL-10 i BAFF) ex vivo. In vitro je ispitan utjecaj lijekova na aktivaciju B-limfocita sintetskom DNA i produkciju IL-10 i BAFF-a, te na aktivaciju monocita i sekreciju TNF-α i IL-6 stimulacijom TLR4 signalnog puta lipopolisaharidom. Rezultati su pokazali da klorokin inhibira aktivaciju TLR9 u B-limfocitima in vitro, te pridonosi sniženju razine cirkulirajuće DNA, potencijalnog TLR9 liganda, ex vivo. Klorokin ujedno ne ometa prepoznavanje komponenata Gram- bakterija i sekreciju proupalnih citokina važnih za obranu od infekcije. Razumijevanje aktivacije i signalizacije receptora urođene imunosti važno je za razumijevanje patogeneze SLE-a i razvoj ciljanih terapija.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperreactive B cells that produce autoantibodies against nucleic acids and related structures. In lupus-prone mice, Toll-like receptor 9 (TLR9) stimulation with DNA-containing immune complexes leads to autoreactive B cell survival and differentiation which could be abolished by chloroquine, a TLR9 signaling inhibitor otherwise used in SLE treatment. Also, patients are at increased risk of an infection. Activation of innate immunity via TLR4 is necessary for the resistance to Gram- bacteria, one of the leading causes of mortality in SLE. Here we investigated if chloroquine and low-dose corticosteroid treatment modulate the expression of TLR9 in B cells, TLR4 on monocytes, levels of circulating DNA and B-cell stimulatory cytokines in peripheral blood of SLE patients and controls. In vitro, we interrogated if chloroquine or steroids modulate B cell activation by synthetic TLR9 ligand CpGor monocyte activation by TLR4 ligand LPS. Results suggest that chloroquine inhibits TLR9-induced B cell activation in vitro and contributes to a decrease in serum DNA level ex vivo, without affecting the pro-inflammatory cytokine production vital for the adequate response to bacterial infection. Thus, investigation of activation and signalization mechanisms of the innate immune system receptors in patients contributes to understanding of SLE pathogenesis

Understanding Human Autoimmunity and Autoinflammation Through Transcriptomics.

Transcriptomics, the high-throughput characterization of RNAs, has been instrumental in defining pathogenic signatures in human autoimmunity and autoinflammation. It enabled the identification of new therapeutic targets in IFN-, IL-1- and IL-17-mediated diseases. Applied to immunomonitoring, transcriptomics is starting to unravel diagnostic and prognostic signatures that stratify patients, track molecular changes associated with disease activity, define personalized treatment strategies, and generally inform clinical practice. Herein, we review the use of transcriptomics to define mechanistic, diagnostic, and predictive signatures in human autoimmunity and autoinflammation. We discuss some of the analytical approaches applied to extract biological knowledge from high-dimensional data sets. Finally, we touch upon emerging applications of transcriptomics to study eQTLs, B and T cell repertoire diversity, and isoform usage. Annu Rev Immunol 2017; 35:33